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Sample records for aldh gene variants

  1. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors

    DEFF Research Database (Denmark)

    Husemoen, Lise Lotte Nystrup; Fenger, Mogens; Friedrich, Nele;

    2008-01-01

    BACKGROUND: Genetic variation in ethanol metabolism may have an influence on both alcohol drinking habits and the susceptibility to health effects of alcohol drinking. Such influences are likely to bias exposure-disease associations in epidemiologic studies of health effects of alcohol drinking. In...... a Caucasian population, we examined the association of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genetic variants with alcohol drinking habits, biomarkers of alcohol exposure, and risk factors for cardiovascular disease. METHODS: The study population consisted of 1,216 Danish men...... and women aged 15-77 years participating in a health examination in 1998. The health examination included a self-administered questionnaire (alcohol drinking habits), a physical examination (blood pressure), and various blood tests [alanine aminotransferase (ALAT), erythrocyte mean corpuscular volume...

  2. Refined Geographic Distribution of the Oriental ALDH2*504Lys (nee 487Lys) Variant

    Science.gov (United States)

    Li, Hui; Borinskaya, Svetlana; Yoshimura, Kimio; Kal’ina, Nina; Marusin, Andrey; Stepanov, Vadim A.; Qin, Zhendong; Khaliq, Shagufta; Lee, Mi-Young; Yang, Yajun; Mohyuddin, Aisha; Gurwitz, David; Mehdi, Syed Qasim; Rogaev, Evgeny; Jin, Li; Yankovsky, Nikolay K.; Kidd, Judith R.; Kidd, Kenneth K.

    2010-01-01

    Summary Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures. PMID:19456322

  3. Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31

    DEFF Research Database (Denmark)

    Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Helgadottir, Hafdis T;

    2014-01-01

    Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using...

  4. Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping.

    Science.gov (United States)

    Vasiliou, V; Bairoch, A; Tipton, K F; Nebert, D W

    1999-08-01

    As currently being performed with an increasing number of superfamilies, a standardized gene nomenclature system is proposed here, based on divergent evolution, using multiple alignment analysis of all 86 eukaryotic aldehyde dehydrogenase (ALDH) amino-acid sequences known at this time. The ALDHs represent a superfamily of NAD(P)(+)-dependent enzymes having similar primary structures that oxidize a wide spectrum of endogenous and exogenous aliphatic and aromatic aldehydes. To date, a total of 54 animal, 15 plant, 14 yeast, and three fungal ALDH genes or cDNAs have been sequenced. These ALDHs can be divided into a total of 18 families (comprising 37 subfamilies), and all nonhuman ALDH genes are named here after the established human ALDH genes, when possible. An ALDH protein from one gene family is defined as having approximately or = 60% amino-acid identity and are expected to be located at the same subchromosomal site. For naming each gene, it is proposed that the root symbol 'ALDH' denoting 'aldehyde dehydrogenase' be followed by an Arabic number representing the family and, when needed, a letter designating the subfamily and an Arabic number denoting the individual gene within the subfamily; all letters are capitalized in all mammals except mouse and fruit fly, e.g. 'human ALDH3A1 (mouse, Drosophila Aldh3a1).' It is suggested that the Human Gene Nomenclature Guidelines (http://++www.gene.ucl.ac.uk/nomenclature/guidelines.h tml) be used for all species other than mouse and Drosophila. Following these guidelines, the gene is italicized, whereas the corresponding cDNA, mRNA, protein or enzyme activity is written with upper-case letters and without italics, e.g. 'human, mouse or Drosophila ALDH3A1 cDNA, mRNA, or activity'. If an orthologous gene between species cannot be identified with certainty, sequential naming of these genes will be carried out in chronological order as they are reported to us. In addition, 20 human ALDH variant alleles that have been reported

  5. Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis

    OpenAIRE

    Macgregor, Stuart; Lind, Penelope A; Bucholz, Kathleen K.; Hansell, Narelle K.; Madden, Pamela A. F.; Richter, Melinda M; Montgomery, Grant W.; Martin, Nicholas G.; Heath, Andrew C.; John B Whitfield

    2008-01-01

    Alcohol dependence (AD) is a complex disorder with environmental and genetic origins. The role of two genetic variants in ALDH2 and ADH1B in AD risk has been extensively investigated. This study tested for associations between nine polymorphisms in ALDH2 and 41 in the seven ADH genes, and alcohol-related flushing, alcohol use and dependence symptom scores in 4597 Australian twins. The vast majority (4296) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for AD. Th...

  6. Allelic variants of ADH, ALDH and the five factor model of personality in alcohol dependence syndrome

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    S K Salujha

    2014-01-01

    Full Text Available Background: The etiology of alcohol dependence is a complex interplay of biopsychosocial factors. The genes for alcohol-metabolizing enzymes: Alcohol dehydrogenase (ADH2 and ADH3 and aldehyde dehydrogenase (ALDH2 exhibit functional polymorphisms. Vulnerability of alcohol dependence may also be in part due to heritable personality traits. Aim: To determine whether any association exists between polymorphisms of ADH2, ADH3 and ALDH2 and alcohol dependence syndrome in a group of Asian Indians. In addition, the personality of these patients was assessed to identify traits predisposing to alcoholism. Materials and Methods: In this study, 100 consecutive males with alcohol dependence syndrome attending the psychiatric outpatient department of a tertiary care service hospital and an equal number of matched healthy controls were included with their consent. Blood samples of all the study cases and controls were collected and genotyped for the ADH2, ADH3 and ALDH2 loci. Personality was evaluated using the neuroticism, extraversion, openness (NEO personality inventory and sensation seeking scale. Results: Allele frequencies of ADH2FNx012 (0.50, ADH3FNx011 (0.67 and ALSH2FNx012 (0.09 were significantly low in the alcohol dependent subjects. Personality traits of NEO personality inventory and sensation seeking were significantly higher when compared to controls. Conclusions: The functional polymorphisms of genes coding for alcohol metabolizing enzymes and personality traits of NEO and sensation seeking may affect the propensity to develop dependence.

  7. Human Aldehyde Dehydrogenase Genes: Alternatively-Spliced Transcriptional Variants and Their Suggested Nomenclature

    Science.gov (United States)

    Black, William J.; Stagos, Dimitrios; Marchitti, Satori A.; Nebert, Daniel W.; Tipton, Keith F.; Bairoch, Amos; Vasiliou, Vasilis

    2011-01-01

    OBJECTIVE The human aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 genes encoding enzymes critical for NAD(P)+-dependent oxidation of endogenous and exogenous aldehydes, including drugs and environmental toxicants. Mutations in ALDH genes are the molecular basis of several disease states (e.g. Sjögren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia) and may contribute to the etiology of complex diseases such as cancer and Alzheimer’s disease. The aim of this nomenclature update was to identify splice transcriptional variants principally for the human ALDH genes. METHODS Data-mining methods were used to retrieve all human ALDH sequences. Alternatively-spliced transcriptional variants were determined based upon: a) criteria for sequence integrity and genomic alignment; b) evidence of multiple independent cDNA sequences corresponding to a variant sequence; and c) if available, empirical evidence of variants from the literature. RESULTS AND CONCLUSION Alternatively-spliced transcriptional variants and their encoded proteins exist for most of the human ALDH genes; however, their function and significance remain to be established. When compared with the human genome, rat and mouse include an additional gene, Aldh1a7, in the ALDH1A subfamily. In order to avoid confusion when identifying splice variants in various genomes, nomenclature guidelines for the naming of such alternative transcriptional variants and proteins are recommended herein. In addition, a web database (www.aldh.org) has been developed to provide up-to-date information and nomenclature guidelines for the ALDH superfamily. PMID:19823103

  8. Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations

    OpenAIRE

    Peng Giia-Sheun; Yin Shih-Jiun

    2009-01-01

    Abstract Alcoholism is a complex behavioural disorder. Molecular genetics studies have identified numerous candidate genes associated with alcoholism. It is crucial to verify the disease susceptibility genes by correlating the pinpointed allelic variations to the causal phenotypes. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for ethanol metabolism in humans. Both ADH and ALDH exhibit functional polymorphisms among racial populations; the...

  9. Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations

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    Peng Giia-Sheun

    2009-01-01

    Full Text Available Abstract Alcoholism is a complex behavioural disorder. Molecular genetics studies have identified numerous candidate genes associated with alcoholism. It is crucial to verify the disease susceptibility genes by correlating the pinpointed allelic variations to the causal phenotypes. Alcohol dehydrogenase (ADH and aldehyde dehydrogenase (ALDH are the principal enzymes responsible for ethanol metabolism in humans. Both ADH and ALDH exhibit functional polymorphisms among racial populations; these polymorphisms have been shown to be the important genetic determinants in ethanol metabolism and alcoholism. Here, we briefly review recent advances in genomic studies of human ADH/ALDH families and alcoholism, with an emphasis on the pharmacogenetic consequences of venous blood acetaldehyde in the different ALDH2 genotypes following the intake of various doses of ethanol. This paper illustrates a paradigmatic example of phenotypic verifications in a protective disease gene for substance abuse.

  10. Association of ADHIB and ALDH2 gene polymorphisms with alcohol dependence: A pilot study from India

    OpenAIRE

    Vaswani Meera; Prasad Pushplata; Kapur Suman

    2009-01-01

    Abstract Functional polymorphism in the genes encoding alcohol dehydrogenase (ADH) 1B and aldehyde dehydrogenase (ALDH) 2 are considered most important among several genetic determinants of alcohol dependence, a complex disorder. There is no report on the widely studied Arg47His and Glu487Lys polymorphisms from Indian alcoholdependent populations. In this paper, we report, for the first time, allelic and genotypic frequencies of Arg47His and Glu487Lys single nucleotide polymorphisms (SNPs) in...

  11. Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis.

    Science.gov (United States)

    González-Fernández, Rebeca; Hernández, Jairo; Martín-Vasallo, Pablo; Puopolo, Maria; Palumbo, Angela; Ávila, Julio

    2016-05-01

    Oxidative stress (OS) plays an important role in all physiological processes. The effect of OS on cellular processes is modulated by the ability of the cell to express genes implicated in the reversal of lipid, protein, and DNA injury. Aldehyde dehydrogenase 3, member A2 (ALDH3A2) is a ubiquitous enzyme involved in lipid detoxification. The objective of this study was to investigate the expression ofALDH3A2in human granulosa-lutein (GL) cells of women undergoing in vitro fertilization (IVF) and its relationship with age, infertility diagnosis, and IVF outcome variables. Relative expression levels ofALDH3A2were determined by quantitative reverse transcription-polymerase chain reaction. To investigate the effect of age onALDH3A2expression, 72 women between 18 and 44 years of age with no ovarian factor (NOF) were analyzed. To evaluate the effect of infertility diagnosis onALDH3A2expression, the following groups were analyzed: 22 oocyte donors (ODs), 24 women >40 years old (yo) with tubal or male factor and no ovarian pathology, 18 poor responders (PRs), 19 cases with endometriosis (EM), and 18 patients with polycystic ovarian syndrome (PCOS). In NOF,ALDH3A2expression correlated positively with age and with the doses of follicle-stimulating hormone and luteinizing hormone administered and negatively with the number of total and mature oocytes. When different groups were analyzed,ALDH3A2expression levels were higher in patients >40 yo and in PR compared to OD. On the contrary, EM and PCOS levels were lower than expected for age. These data suggest that GL cellALDH3A2expression levels correlate with age, cause of infertility, and ovarian response to stimulation. PMID:26449735

  12. Interaction of DRD2TaqI, COMT, and ALDH2 genes associated with bipolar II disorder comorbid with anxiety disorders in Han Chinese in Taiwan.

    Science.gov (United States)

    Hu, Ming-Chuan; Lee, Sheng-Yu; Wang, Tzu-Yun; Chang, Yun-Hsuan; Chen, Shiou-Lan; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Chen-Lin; Lee, I Hui; Chen, Po See; Yang, Yen Kuang; Lu, Ru-Band

    2015-06-01

    It is hypothesized that dopaminergic genes-dopamine type-2 receptor (DRD2), aldehyde dehydrogenase 2 (ALDH2), and catechol-O-methyltransferase (COMT)-are associated with bipolar disorder (BP) and anxiety disorder (AD). Bipolar II (BP-II) is reported to be highly comorbid with AD. We examined whether interactions among these three genes are susceptibility factors in BP-II with AD (BP-II(+AD)) and without AD (BP-II(-AD)). In this study, we hypothesize that the interaction of the dopaminergic genes between BP-II(+AD) and BP-II(-AD) is significant different. We recruited 1260 participants: 495 with BP-II(-AD), 170 with BP-II(+AD), and 595 healthy controls without BP-II or AD. Genotyping was done using polymerase chain reactions plus restriction fragment length polymorphism analysis. Genotypic frequencies of the DRD2TaqIA, COMT, and ALDH2 polymorphisms between the two BP-II groups were nonsignificant. In logistic regression, the ALDH2 and DRD2TaqIA genes showed a main effect that was protective against BP-II(-AD) (odds ratio [OR] = 0.497, p = 0.010, and OR = 0.415, p = 0.017, respectively). The interaction of DRD2TaqIA A1/A1 and ALDH2*1/*1 had a significant risk effect on the BP-II(-AD) group (OR = 7.177, p II(-AD) (OR = 0.205, p = 0.047). All of the significant results described above are found only in BP-II(-AD). This study supports the hypothesis the interaction of the dopaminergic genes between BP-II(+AD) and BP-II(-AD) is significant different,, and provides additional evidence that the DRD2TaqIA A1/A1, ALDH2*1/*1 and COMT genes interact in BP-II(-AD) but not in BP-II(+AD). PMID:25430946

  13. Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders.

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    Moreno-Ramos, Oscar A; Olivares, Ana María; Haider, Neena B; de Autismo, Liga Colombiana; Lattig, María Claudia

    2015-01-01

    Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding. PMID:26352270

  14. The Genetics of Alcohol Metabolism: Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants

    OpenAIRE

    Edenberg, Howard J

    2007-01-01

    The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date pri...

  15. Expression, crystallization and preliminary X-ray crystallographic analysis of aldehyde dehydrogenase (ALDH) from Bacillus cereus

    International Nuclear Information System (INIS)

    Aldehyde dehydrogenase (ALDH) catalyses the oxidation of aldehydes using NAD(P)+ as a cofactor. The aldh gene from B. cereus was cloned; the protein was expressed, purified and crystallized, and a preliminary X-ray crystallography analysis was performed. Aldehyde dehydrogenase (ALDH) catalyses the oxidation of aldehydes using NAD(P)+ as a cofactor. Most aldehydes are toxic at low levels. ALDHs are used to regulate metabolic intermediate aldehydes. The aldh gene from Bacillus cereus was cloned and the ALDH protein was expressed, purified and crystallized. A crystal of the ALDH protein diffracted to 2.6 Å resolution and belonged to the monoclinic space group P21, with unit-cell parameters a = 83.5, b = 93.3, c = 145.5 Å, β = 98.05°. Four protomers were present in the asymmetric unit, with a corresponding VM of 2.55 Å3 Da−1 and a solvent content of 51.8%

  16. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt;

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant....

  17. Caracterización de polimorfismos de los genes ADH2, ADH3, ALDH2 y CYP2E1 y su relación con el alcoholismo en una población colombiana

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    Claudia Méndez

    2015-12-01

    Full Text Available Objective:Identify and characterize polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 in a Colombian population residing in the city of Bogotá and determine its possible relationship to the alcoholism.Methods:ADH2, ADH3, ALDH2, and CYP2E1 genotypes a population of 148 individuals with non-problematic alcohol and 65 individuals with alcoholism were determined with TaqMan probes and PCR-RFLP. DNA was obtained from peripheral blood white cells.Results:Significant difference was found in family history of alcoholism and use of other psychoactive substances to compare alcoholics with controls. When allelic frequencies for each category (gender were considered, frequency of A2 allele carriers in ADH2 was found higher in male patients than controls. In women, the relative frequency for c1 allele in CYP2E1 was lower in controls than alcoholics. The ALDH2 locus is monomorphic. No significant differences in allele distributions of the loci examined to compare two populations were observed, however when stratifying the same trend was found that these differences tended to be significant.Conclusions:This study allows us to conclude the positive association between family history of alcoholism and alcoholism suggesting that there is a favourable hereditary predisposition. Since substance dependence requires interaction of multiple genes, the combination of genotypes ADH2 * 2, CYP2E1 * 1 combined with genotype homozygous ALDH2 * 1 found in this study could be leading to the population to a potential risk to alcoholism. 

  18. The roles of aldehyde dehydrogenases (ALDHs in the PDH bypass of Arabidopsis

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    Lin Ming

    2009-03-01

    Full Text Available Abstract Background Eukaryotic aldehyde dehydrogenases (ALDHs, EC 1.2.1, which oxidize aldehydes into carboxylic acids, have been classified into more than 20 families. In mammals, Family 2 ALDHs detoxify acetaldehyde. It has been hypothesized that plant Family 2 ALDHs oxidize acetaldehyde generated via ethanolic fermentation, producing acetate for acetyl-CoA biosynthesis via acetyl-CoA synthetase (ACS, similar to the yeast pathway termed the "pyruvate dehydrogenase (PDH bypass". Evidence for this pathway in plants has been obtained from pollen. Results To test for the presence of the PDH bypass in the sporophytic tissue of plants, Arabidopsis plants homozygous for mutant alleles of all three Family 2 ALDH genes were fed with 14C-ethanol along with wild type controls. Comparisons of the incorporation rates of 14C-ethanol into fatty acids in mutants and wild type controls provided direct evidence for the presence of the PDH bypass in sporophytic tissue. Among the three Family 2 ALDHs, one of the two mitochondrial ALDHs (ALDH2B4 appears to be the primary contributor to this pathway. Surprisingly, single, double and triple ALDH mutants of Arabidopsis did not exhibit detectable phenotypes, even though a Family 2 ALDH gene is required for normal anther development in maize. Conclusion The PDH bypass is active in sporophytic tissue of plants. Blocking this pathway via triple ALDH mutants does not uncover obvious visible phenotypes.

  19. Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

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    Bryony A. Thompson

    2015-03-01

    Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

  20. Common Gene Variants Account for Most Genetic Risk for Autism

    Science.gov (United States)

    ... Releases News Release Sunday, July 20, 2014 Common gene variants account for most genetic risk for autism ... genetic risk for autism comes from versions of genes that are common in the population rather than ...

  1. Retinal Targets ALDH Positive Cancer Stem Cell and Alters the Phenotype of Highly Metastatic Osteosarcoma Cells

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    Xiaodong Mu

    2015-01-01

    Full Text Available Aldehyde dehydrogenase (ALDH is a cancer stem cell marker. Retinoic acid has antitumor properties, including the induction of apoptosis and inhibition of proliferation. Retinal, the precursor of retinoic acid, can be oxidized to retinoic acid by dehydrogenases, including ALDH. We hypothesized that retinal could potentially be transformed to retinoic acid with higher efficiency by cancer stem cells, due to the higher ALDH activity. We previously observed that ALDH activity is greater in highly metastatic K7M2 osteosarcoma (OS cells than in nonmetastatic K12 OS cells. We also demonstrated that ALDH activity correlates with clinical metastases in bone sarcoma patients, suggesting that ALDH may be a therapeutic target specific to cells with high metastatic potential. Our current results demonstrated that retinal preferentially affected the phenotypes of ALDH-high K7M2 cells in contrast to ALDH-low K12 cells, which could be mediated by the more efficient transformation of retinal to retinoic acid by ALDH in K7M2 cells. Retinal treatment of highly metastatic K7M2 cells decreased their proliferation, invasion capacity, and resistance to oxidative stress. Retinal altered the expression of metastasis-related genes. These observations indicate that retinal may be used to specifically target metastatic cancer stem cells in OS.

  2. Myostatin: genetic variants, therapy and gene doping

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    André Katayama Yamada

    2012-09-01

    Full Text Available Since its discovery, myostatin (MSTN has been at the forefront of muscle therapy research because intrinsic mutations or inhibition of this protein, by either pharmacological or genetic means, result in muscle hypertrophy and hyperplasia. In addition to muscle growth, MSTN inhibition potentially disturbs connective tissue, leads to strength modulation, facilitates myoblast transplantation, promotes tissue regeneration, induces adipose tissue thermogenesis and increases muscle oxidative phenotype. It is also known that current advances in gene therapy have an impact on sports because of the illicit use of such methods. However, the adverse effects of these methods, their impact on athletic performance in humans and the means of detecting gene doping are as yet unknown. The aim of the present review is to discuss biosynthesis, genetic variants, pharmacological/genetic manipulation, doping and athletic performance in relation to the MSTN pathway. As will be concluded from the manuscript, MSTN emerges as a promising molecule for combating muscle wasting diseases and for triggering wide-ranging discussion in view of its possible use in gene doping.Desde sua descoberta, a miostatina (MSTN entrou na linha de frente em pesquisas relacionadas às terapias musculares porque mutações intrínsecas ou inibição desta proteína tanto por abordagens farmacológicas como genéticas resultam em hipertrofia muscular e hiperplasia. Além do aumento da massa muscular, a inibição de MSTN potencialmente prejudica o tecido conectivo, modula a força muscular, facilita o transplante de mioblastos, promove regeneração tecidual, induz termogênese no tecido adiposo e aumenta a oxidação na musculatura esquelética. É também sabido que os atuais avanços em terapia gênica têm uma relação com o esporte devido ao uso ilícito de tal método. Os efeitos adversos de tal abordagem, seus efeitos no desempenho de atletas e métodos para detectar doping genético s

  3. Effects of ALDH2*2 on Alcohol Problem Trajectories of Asian American College Students

    OpenAIRE

    Luczak, Susan E.; Yarnell, Lisa M.; Prescott, Carol A.; Myers, Mark G.; Liang, Tiebing; Wall, Tamara L.

    2014-01-01

    The variant aldehyde dehydrogenase allele, ALDH2*2, consistently has been associated with protection against alcohol dependence, but the mechanism underlying this process is not known. This study examined growth trajectories of alcohol consumption (frequency, average quantity, binge drinking, maximum drinks) and problems over the college years and then tested whether the ALDH2 genotype mediated or moderated the relationship between alcohol consumption and problems. Asian American college stud...

  4. Arrhythmogenic KCNE gene variants: current knowledge and future challenges

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    Shawn M Crump

    2014-01-01

    Full Text Available There are twenty-five known inherited cardiac arrhythmia susceptibility genes, all of which encode either ion channel pore-forming subunits or proteins that regulate aspects of ion channel biology such as function, trafficking and localization. The human KCNE gene family comprises five potassium channel regulatory subunits, sequence variants in each of which are associated with cardiac arrhythmias. KCNE gene products exhibit promiscuous partnering and in some cases ubiquitous expression, hampering efforts to unequivocally correlate each gene to specific native potassium currents. Likewise, deducing the molecular etiology of cardiac arrhythmias in individuals harboring rare KCNE gene variants, or more common KCNE polymorphisms, can be challenging. In this review we provide an update on putative arrhythmia-causing KCNE gene variants, and discuss current thinking and future challenges in the study of molecular mechanisms of KCNE-associated cardiac rhythm disturbances.

  5. Cellobiohydrolase I gene and improved variants

    Science.gov (United States)

    Adney, William S.; Decker, Stephen R.; Mc Carter, Suzanne; Baker, John O.; Nieves, Raphael; Himmel, Michael E.; Vinzant, Todd B.

    2008-05-20

    The disclosure provides a method for preparing an active exoglucanase in a heterologous host of eukaryotic origin. The method includes mutagenesis to reduce glycosylation of the exoglucanase when expressed in a heterologous host. It is further disclosed a method to produce variant cellobiohydrolase that is stable at high temperature through mutagenesis.

  6. Aldehyde Dehydrogenase-2 (ALDH2) Ameliorates Chronic Alcohol Ingestion-Induced Myocardial Insulin Resistance and Endoplasmic Reticulum Stress

    OpenAIRE

    Li, Shi-Yan; Gilbert, Sara A. B.; Li, Qun; Ren, Jun

    2009-01-01

    Chronic alcohol intake leads to insulin resistance and alcoholic cardiomyopathy, which appears to be a result of the complex interaction between genes and environment. This study was designed to examine the impact of aldehyde dehydrogenase-2 (ALDH2) transgenic overexpression on alcohol-induced insulin resistance and myocardial injury. ALDH2 transgenic mice were produced using chicken β-actin promoter. Wild-type FVB and ALDH2 mice were fed a 4% alcohol or control diet for 12 wks. Cell shorteni...

  7. The Clinical Significance of Unknown Sequence Variants in BRCA Genes

    International Nuclear Information System (INIS)

    Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance

  8. The Clinical Significance of Unknown Sequence Variants in BRCA Genes

    Energy Technology Data Exchange (ETDEWEB)

    Calò, Valentina; Bruno, Loredana; Paglia, Laura La; Perez, Marco; Margarese, Naomi [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy); Gaudio, Francesca Di [Department of Medical Biotechnologies and Legal Medicine, University of Palermo, Palermo (Italy); Russo, Antonio, E-mail: lab-oncobiologia@usa.net [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy)

    2010-09-10

    Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance.

  9. Variant in oxytocin receptor gene is associated with amygdala volume

    OpenAIRE

    Furman, Daniella J; Chen, Michael C.; Gotlib, Ian H.

    2011-01-01

    The oxytocin system plays a significant role in modulating stress responses in animals and humans; perturbations in this system may contribute to the pathogenesis of psychiatric disorder. Attempts to identify clinically relevant genetic variants in the oxytocin system have yielded associations between polymorphisms of the oxytocin receptor (OXTR) gene and both autism and major depression. To date, however, little is known about how such variants affect brain structures implicated in these dis...

  10. Correlations Between Polymorphisms of Extracellular Superoxide Dismutase, Aldehyde Dehydrogenase-2 Genes, as Well as Drinking Behavior and Pancreatic Cancer

    Institute of Scientific and Technical Information of China (English)

    Chao-xian Zhang; Yong-mei Qin; Li-ke Guo

    2014-01-01

    Objective To investigate the correlation between drinking behavior combined with polymorphisms of extracellular superoxide dismutase (EC-SOD) and aldehyde dehydrogenase-2 (ALDH2) genes and pancreatic cancer. Methods The genetic polymorphisms of EC-SOD and ALDH2 were analyzed by polymerase chain reaction restriction fragment length polymorphism in the peripheral blood leukocytes obtained from 680 pancreatic cancer cases and 680 non-cancer controls. Subsequently the frequency of genotype was compared between the pancreatic cancer patients and the healthy controls.The relationship of drinking with pancreatic cancer was analyzed. Results The frequencies of EC-SOD (C/G) and ALDH2 variant genotypes were 37.35% and 68.82%respectively in the pancreatic cancer cases, and were significantly higher than those in the healthy controls (21.03% and 44.56%, all P Conclusion EC-SOD (C/G), ALDH2 variant genotypes and drinking might be the risk factors of pancreatic cancer.

  11. Gene variant linked to lung cancer risk

    Science.gov (United States)

    A variation of the gene NFKB1, called rs4648127, is associated with an estimated 44 percent reduction in lung cancer risk. When this information, derived from samples obtained as part of a large NCI-sponsored prevention clinical trial, was compared with d

  12. Pathological assessment of mismatch repair gene variants in Lynch syndrome

    DEFF Research Database (Denmark)

    Rasmussen, Lene Juel; Heinen, Christopher D; Royer-Pokora, Brigitte; Drost, Mark; Tavtigian, Sean; Hofstra, Robert M W; de Wind, Niels

    2012-01-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose...... attention to common misconceptions about functional assays and endorse development of an integrated approach comprising validated assays for diagnosis of VUS in patients suspected of LS....

  13. Incomplete penetrance of biallelic ALDH1A3 mutations.

    Science.gov (United States)

    Plaisancié, Julie; Brémond-Gignac, Dominique; Demeer, Bénédicte; Gaston, Véronique; Verloes, Alain; Fares-Taie, Lucas; Gerber, Sylvie; Rozet, Jean-Michel; Calvas, Patrick; Chassaing, Nicolas

    2016-04-01

    The formation of a properly shaped eye is a complex developmental event that requires the coordination of many induction processes and differentiation pathways. Microphthalmia and anophthalmia (MA) represent the most severe defects that can affect the ocular globe during embryonic development. When genetic, these ocular disorders exhibit large genetic heterogeneity and extreme variable expressivity. Around 20 monogenic diseases are known to be associated with MA as main phenotype and the penetrance of mutations is usually full in the patients. Some of these genes encode proteins involved in the vitamin A pathway, tightly regulated during eye development. One of those retinoic acid synthesis genes is ALDH1A3 and biallelic mutations in that gene have been recently found to lead to MA phenotype in patients. Interestingly, we report here the lack of ocular defect in a girl carrying the same homozygous mutation in the ALDH1A3 gene than the affected members of her family. Thus, this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families. Furthermore, these data contribute to the more general understanding that we have for the complex genetic inheritance of these MA phenotypes. PMID:26873617

  14. CEACAM6 gene variants in inflammatory bowel disease.

    Directory of Open Access Journals (Sweden)

    Jürgen Glas

    Full Text Available BACKGROUND: The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6 acts as a receptor for adherent-invasive E. coli (AIEC and its ileal expression is increased in patients with Crohn's disease (CD. Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD. METHODOLOGY: In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC, and 1,350 healthy, unrelated controls was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839. In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. CONCLUSIONS: This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

  15. Functional characterization of BRCA1 gene variants by mini-gene splicing assay

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Dandanell, Mette; Jønson, Lars;

    2014-01-01

    are pathogenic or benign. Here we validate a mini-gene splicing assay by comparing the results of 24 variants with previously published data from RT-PCR analysis on RNA from blood samples/lymphoblastoid cell lines. The analysis showed an overall concordance of 100%. In addition, we investigated 13...... BRCA1 variants of unknown clinical significance or putative variants affecting splicing by in silico analysis and mini-gene splicing assay. Both the in silico analysis and mini-gene splicing assay classified six BRCA1 variants as pathogenic (c.80+1G>A, c.132C>T (p.=), c.213-1G>A, c.670+1delG, c.4185+1G......Mutational screening of the breast cancer susceptibility gene BRCA1 leads to the identification of numerous pathogenic variants such as frameshift and nonsense variants, as well as large genomic rearrangements. The screening moreover identifies a large number of variants, for example, missense...

  16. Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in androgen responsive human prostate cancer cell LNCaP.

    Science.gov (United States)

    Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen-responsive gene in prostate cancer epithelial cells (LNCaP). In the present study we attempted to identify if any of the three ALDH1A/RA synt...

  17. Gene duplication and hypermutation of the pathogen Resistance gene SNC1 in the Arabidopsis bal variant.

    Science.gov (United States)

    Yi, Hankuil; Richards, Eric J

    2009-12-01

    The bal defect in the Arabidopsis thaliana Columbia strain was spontaneously generated in an inbred ddm1 (decrease in DNA methylation 1) mutant background in which various genetic and epigenetic alterations accumulate. The bal variant displays short stature and curled leaves due to the constitutive activation of defense signaling. These bal phenotypes are metastable and phenotypic suppression is evident in more than one-third of ethyl methanesulfonate (EMS)-treated bal M(1) plants. The semidominant bal allele maps to the RPP5 (recognition of Peronospora parasitica 5) locus, which includes a cluster of disease Resistance (R) genes, many of which show an increase in steady-state expression levels in the bal variant. Here, we report that activation of RPP5 locus R genes and dwarfing in the bal variant are caused by a 55-kb duplication within the RPP5 locus. Although many RPP5 locus R genes are duplicated in the bal variant, the duplication of SNC1 alone is necessary and sufficient for the phenotypic changes in the bal variant. Missense mutations in the SNC1 gene were identified in all three phenotypically suppressed EMS-treated bal lines investigated, indicating that the high-frequency phenotypic instability induced by EMS treatment is caused by a genetic mechanism. We propose that the high degree of variation in SNC1-related sequences among Arabidopsis natural accessions follows the two-step mechanism observed in the bal variant: gene duplication followed by hypermutation. PMID:19797048

  18. Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine.

    Science.gov (United States)

    Bean, Lora J H; Hegde, Madhuri R

    2016-06-01

    Revolutionary changes in sequencing technology and the desire to develop therapeutics for rare diseases have led to the generation of an enormous amount of genomic data in the last 5 years. Large-scale sequencing done in both research and diagnostic laboratories has linked many new genes to rare diseases, but has also generated a number of variants that we cannot interpret today. It is clear that we remain a long way from a complete understanding of the genomic variation in the human genome and its association with human health and disease. Recent studies identified susceptibility markers to infectious diseases and also the contribution of rare variants to complex diseases in different populations. The sequencing revolution has also led to the creation of a large number of databases that act as "keepers" of data, and in many cases give an interpretation of the effect of the variant. This interpretation is based on reports in the literature, prediction models, and in some cases is accompanied by functional evidence. As we move toward the practice of genomic medicine, and consider its place in "personalized medicine," it is time to ask ourselves how we can aggregate this wealth of data into a single database for multiple users with different goals. PMID:26931283

  19. Melanocortin-1 receptor gene variants in four Chinese ethnic populations

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    There is strong relationship between melanocortin-1 receptor (MC1R) gene variants and human hair color and skin type.Based on a sequencing study of MC1R gene in 50 individuals from the Uygur,Tibetan,Wa and Dai ethnic populations,we discuss the occurrence of 7 mc1r variants consisting of 5 nonsynonymous sites (Val60Leu,Arg67Gln,Val92Met,Arg163Gln and Ala299Val) and 2 synonymous sites (C414T and A942G),among which C414T and Ala299Val were reported for the first time.Confirmation and analysis were also made of 122 individuals at three common point mutations (Val92Met,Arg163Gln,A942G) using PCR-SSCP.The frequency of Arg163Gln variant varies in the four ethnic populations,with percentage of 40%,85.0%,66.2% and 72.7%,respectively,while those of Val92Met and A942G are roughly similar in these four populations.The different environments,migration and admixture of various ethnic groups in China might have impact on the observed frequency of Arg163Gln.

  20. Protein expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 in young patients with oral squamous cell carcinoma.

    Science.gov (United States)

    Kaminagakura, E; Caris, A; Coutinho-Camillo, C; Soares, F A; Takahama-Júnior, A; Kowalski, L P

    2016-06-01

    The purpose of this study was to evaluate the expression of the enzymes involved in the biotransformation of tobacco and alcohol. A study group of 41 young patients (≤40 years old) with oral squamous cell carcinoma (OSCC) was compared to 59 control subjects (≥50 years old) with tumours of similar clinical stages and topographies. The immunohistochemical expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 was evaluated using the tissue microarray technique. There was a predominance of males, smokers, and alcohol drinkers in both groups. Most tumours were located in the tongue (43.9% vs. 50.8%), were well-differentiated (63.4% vs. 56.6%), and were in clinical stages III or IV (80.5% vs. 78.0%). No difference was observed in the expression of CYP1A1, ALDH1A1, or ALDH2 between the two groups. CYP1A1 and ALDH2 protein expression had no influence on the prognosis. The immunoexpression of CYP1B1 was significantly higher in the control group than in the young group (Pexpression improved relapse-free survival in young patients. These results suggest a lower risk of recurrence with increased metabolism of carcinogens by CYP1B1. Further studies involving other genes and proteins are necessary to complement the results of this research. PMID:26944893

  1. Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice.

    OpenAIRE

    Selden, R F; Wagner, T E; Blethen, S; Yun, J S; Rowe, M E; Goodman, H M

    1988-01-01

    The nucleotide sequence of the human growth hormone variant gene, one of the five members of the growth hormone gene family, predicts that it encodes a growth hormone-like protein. As a first step in determining whether this gene is functional in humans, we have expressed a mouse metallothionein I/human growth hormone variant fusion gene in mouse L cells and in transgenic mice. The growth hormone variant protein expressed in transiently transfected L cells is distinct from growth hormone itse...

  2. A GABBR2 gene variant modifies pathophysiology in Huntington's disease.

    Science.gov (United States)

    Philpott, April L; Fitzgerald, Paul B; Bailey, Neil W; Churchyard, Andrew; Georgiou-Karistianis, Nellie; Cummins, Tarrant D R

    2016-05-01

    Striatal degeneration in Huntington's disease (HD) causes changes in cortico-subcortical pathways. Transcranial magnetic stimulation (TMS) is a valuable tool for assessing pathophysiology within these pathways, yet has had limited application in HD. As cortico-subcortical pathways are largely mediated by GABA and dopamine receptor genes, understanding how these genes modulate neurophysiology in HD may provide new insights into how underlying pathology maps onto clinical phenotype. Twenty-nine participants with HD underwent motor cortex stimulation, while corticospinal excitability, cortical inhibition and intracortical facilitation were indexed via peripheral electromyography. Single-nucleotide polymorphism mapping was performed across six genes that are known to modulate cortico-subcortical pathways (GABRA2, GABBR1, GABBR2, DRD1, DRD2, DRD4). Genetic associations with six TMS measures and age at onset were investigated. Our hierarchical multiple regression analysis, controlling for CAG and age, revealed that a GABBR2 variant, predicted to be disease-causative, was significantly associated with corticospinal excitability at corrected levels. A subsequent uncorrected exploratory analysis revealed associations between GABBR2, GABRA2 and DRD2 variants with TMS measures of corticospinal excitability and cortical inhibition in HD, as well as with age at onset. Our findings support the notion that uncovering genetic associations with pathophysiological measures and age at onset is an important way forward in terms of generating meaningful biomarkers with diagnostic and prognostic sensitivity, and identifying novel human-validated targets for future clinical trials. PMID:27033668

  3. Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics

    Science.gov (United States)

    Hu, Yi-Juan; Berndt, Sonja I.; Gustafsson, Stefan; Ganna, Andrea; Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Leach, Irene Mateo; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M.; van Meurs, Joyce B.J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M.; Kiemeney, Lambertus A.; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F.; Martin, Nicholas G.; Metspalu, Andres; Morris, Andrew D.; Nieminen, Markku S.; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Ouwehand, Willem H.; Palmer, Lyle J.; Penninx, Brenda; Power, Chris; Province, Michael A.; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M.; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J.; Snieder, Harold; Sørensen, Thorkild I.A.; Spector, Timothy D.; Stefansson, Kari; Tönjes, Anke; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; van der Harst, Pim; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Wichmann, H.-Erich; Wilson, James F.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunian, Talin; Heid, Iris M.; Hunter, David; Kaplan, Robert C.; Karpe, Fredrik; Moffatt, Miriam; Mohlke, Karen L.; O’Connell, Jeffrey R.; Pawitan, Yudi; Schadt, Eric E.; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P.; Thorsteinsdottir, Unnur; van Duijn, Cornelia M.; Visscher, Peter M.; Di Blasio, Anna Maria; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Morris, Andrew P.; Meyre, David; Scherag, André; McCarthy, Mark I.; Speliotes, Elizabeth K.; North, Kari E.; Loos, Ruth J.F.; Ingelsson, Erik; Hirschhorn, Joel; North, Kari E.; Ingelsson, Erik; Lin, Dan-Yu

    2013-01-01

    Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying “causal” rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available. PMID:23891470

  4. Interleukin-4 receptor alpha gene variants and allergic disease

    Directory of Open Access Journals (Sweden)

    Hall Ian P

    2000-06-01

    Full Text Available Abstract The interleukin-4 (IL-4 signalling cascade has been identified as a pathway potentially important in the development of asthma. Genetic variants within this signalling pathway might contribute to the risk of developing asthma in a given individual. A number of polymorphisms have been described within the IL-4 receptor α (IL-4Rα gene. In addition polymorphism occurs in the promoter for the IL-4 gene itself. This commentary accompanies a paper by C Ober et al describing the contribution of IL-4Rα polymorphism to susceptibility to asthma and atopy in the Hutterite population and other outbred populations collected during the collaborative studies on the genetics of asthma (CSGA programme.

  5. ALDH1A2 (RALDH2 genetic variation in human congenital heart disease

    Directory of Open Access Journals (Sweden)

    Mesquita Sonia MF

    2009-11-01

    ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.

  6. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

    DEFF Research Database (Denmark)

    Mills, Philippa B; Footitt, Emma J; Mills, Kevin A;

    2010-01-01

    Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-alpha-aminoadipic semialdehyde/L-Delta1-piperideine 6-carboxylate. However, whilst...... normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on...

  7. Low expression of aldehyde deyhdrogenase 1A1 (ALDH1A1) is a prognostic marker for poor survival in pancreatic cancer

    International Nuclear Information System (INIS)

    Aldehyde deyhdrogenase 1 (ALDH1) has been characterised as a cancer stem cell marker in different types of tumours. Additionally, it plays a pivotal role in gene regulation and endows tumour cells with augmented chemoresistance. Recently, ALDH1A1 has been described as a prognostic marker in a pancreatic cancer tissue microarray. The aim of this study was to reevaluate the expression of ALDH1A1 as a prognostic marker on whole-mount tissue sections. Real-time-quantitative-PCR (qRT-PCR) and Western blotting were used to evaluate the expression profile of ALDH1A1 in seven pancreatic cancer cell lines and one non-malignant pancreatic cell line. Immunostaining against ALDH1A1 and Ki-67 was performed on paraffin-embedded samples from 97 patients with pancreatic cancer. The immunohistochemical results were correlated to histopathological and clinical data. qRT-PCR and Western blotting revealed a different expression pattern of ALDH1A1 in different malignant and non-malignant pancreatic cell lines. Immunohistochemical analysis demonstrated that ALDH1A1 was confined to the cellular cytoplasm and occurred in 72 cases (74%), whereas it was negative in 25 cases (26%). High expression of ALDH1A1 was significantly correlated to an increased proliferation rate (Spearman correlation, p = 0.01). Univariate and multivariate analyses showed that decreased expression of ALDH1A1 is an independent adverse prognostic factor for overall survival. Immunonhistochemical analysis on whole-mount tissue slides revealed that ALDH1A1 is more abundantly expressed in pancreatic cancer than initially reported by a tissue microarray analysis. Moreover, high expression of ALDH1A1 correlated significantly with the proliferation of tumour cells. Intriguingly, this study is the first which identifies low expression of ALDH1A1 as an independent adverse prognostic marker for overall survival in pancreatic cancer

  8. The human gene damage index as a gene-level approach to prioritizing exome variants

    Science.gov (United States)

    Itan, Yuval; Shang, Lei; Boisson, Bertrand; Patin, Etienne; Bolze, Alexandre; Moncada-Vélez, Marcela; Scott, Eric; Ciancanelli, Michael J.; Lafaille, Fabien G.; Markle, Janet G.; Martinez-Barricarte, Ruben; de Jong, Sarah Jill; Kong, Xiao-Fei; Nitschke, Patrick; Belkadi, Aziz; Bustamante, Jacinta; Puel, Anne; Boisson-Dupuis, Stéphanie; Stenson, Peter D.; Gleeson, Joseph G.; Cooper, David N.; Quintana-Murci, Lluis; Claverie, Jean-Michel; Zhang, Shen-Ying; Abel, Laurent; Casanova, Jean-Laurent

    2015-01-01

    The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI. PMID:26483451

  9. High-performance web services for querying gene and variant annotation

    OpenAIRE

    Xin, Jiwen; Mark, Adam; Afrasiabi, Cyrus; Tsueng, Ginger; Juchler, Moritz; Gopal, Nikhil; Stupp, Gregory S.; Putman, Timothy E.; Ainscough, Benjamin J.; Griffith, Obi L.; Torkamani, Ali; Whetzel, Patricia L.; Mungall, Christopher J.; Mooney, Sean D; Su, Andrew I

    2016-01-01

    Efficient tools for data management and integration are essential for many aspects of high-throughput biology. In particular, annotations of genes and human genetic variants are commonly used but highly fragmented across many resources. Here, we describe MyGene.info and MyVariant.info, high-performance web services for querying gene and variant annotation information. These web services are currently accessed more than three million times permonth. They also demonstrate a generalizable cloud-...

  10. Variants in the vitamin D receptor gene and asthma

    Directory of Open Access Journals (Sweden)

    Wjst Matthias

    2005-01-01

    Full Text Available Abstract Background Early lifetime exposure to dietary or supplementary vitamin D has been predicted to be a risk factor for later allergy. Twin studies suggest that response to vitamin D exposure might be influenced by genetic factors. As these effects are primarily mediated through the vitamin D receptor (VDR, single base variants in this gene may be risk factors for asthma or allergy. Results 951 individuals from 224 pedigrees with at least 2 asthmatic children were analyzed for 13 SNPs in the VDR. There was no preferential transmission to children with asthma. In their unaffected sibs, however, one allele in the 5' region was 0.5-fold undertransmitted (p = 0.049, while two other alleles in the 3' terminal region were 2-fold over-transmitted (p = 0.013 and 0.018. An association was also seen with bronchial hyperreactivity against methacholine and with specific immunoglobulin E serum levels. Conclusion The transmission disequilibrium in unaffected sibs of otherwise multiple-affected families seem to be a powerful statistical test. A preferential transmission of vitamin D receptor variants to children with asthma could not be confirmed but raises the possibility of a protective effect for unaffected children.

  11. Human genes with a greater number of transcript variants tend to show biological features of housekeeping and essential genes

    DEFF Research Database (Denmark)

    Ryu, Jae Yong; Kim, Hyun Uk; Lee, Sang Yup

    2015-01-01

    Alternative splicing is a process observed in gene expression that results in a multi-exon gene to produce multiple mRNA variants which might have different functions and activities. Although physiologically important, many aspects of genes with different number of transcript variants (or splice...... variants) still remain to be characterized. In this study, we provide bioinformatic evidence that genes with a greater number of transcript variants are more likely to play functionally important roles in cells, compared with those having fewer transcript variants. Among 21 983 human genes, 3728 genes were...... 64 vertebrate species as orthologs, subjected to regulations by transcription factors and microRNAs, and showed hub node-like properties in the human protein-protein interaction network. These findings were also confirmed by metabolic simulations of 60 cancer metabolic models. All these results...

  12. Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology.

    Science.gov (United States)

    Crabb, David W; Matsumoto, Michinaga; Chang, David; You, Min

    2004-02-01

    Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations. PMID:15099407

  13. A systematic survey of loss-of-function variants in human protein-coding genes

    OpenAIRE

    MacArthur, Daniel G; Balasubramanian, Suganthi; Frankish, Adam; Huang, Ni; Morris, James; Walter, Klaudia; Jostins, Luke; Habegger, Lukas; Pickrell, Joseph K.; Montgomery, Stephen; Albers, Cornelis A.; Zhang, Zhengdong D.; Conrad, Donald F.; Lunter, Gerton; Zheng, Hancheng

    2012-01-01

    Genome sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2,951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterio...

  14. IL18 Gene Variants Influence the Susceptibility to Chagas Disease

    Science.gov (United States)

    Leon Rodriguez, Daniel A; Carmona, F. David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-01-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control. PMID:27027876

  15. Loss aversion and 5HTT gene variants in adolescent anxiety

    Directory of Open Access Journals (Sweden)

    Monique Ernst

    2014-04-01

    Full Text Available Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR in healthy and clinically anxious adolescents. Findings show that loss aversion (1 does manifest in adolescents, (2 does not differ between healthy and clinically anxious participants, and (3, when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents.

  16. Characterization of a novel splicing variant in the RAPTOR gene

    International Nuclear Information System (INIS)

    The mammalian target of rapamycin (mTOR) plays an essential role in the regulation of cell growth, proliferation and apoptosis. Raptor, the regulatory associated protein of mTOR, is an important member in this signaling pathway. In the present report, we identified and characterized a novel splicing variant of this gene, RAPTORv2, in which exons 14-17, 474 bp in total, are omitted from the mRNA. This deletion does not change the open reading frame, but causes a nearly complete absence of HEAT repeats, which were shown to be involved in the binding of mTOR substrates. Real time PCR performed on 48 different human tissues demonstrated the ubiquitous presence of this splice variant. Quantification of mRNA levels in lymphoblastoid cell lines (LCL) from 56 unrelated HapMap individuals revealed that the expression of this splicing form is quite variable. One synonymous SNP, rs2289759 in exon 14, was predicted by ESEfinder to cause a significant gain/loss of SRp55 and/or SF2/ASF binding sites, and thus potentially influence splicing. This prediction was confirmed by linear regression analysis between the ratio of RAPTORv2 to total RAPTOR mRNA levels and the SNP genotype in the above 56 individuals (r = 0.281 and P = 0.036). Moreover, the functional evaluation indicated that this splicing isoform is expected to retain the ability to bind mTOR, but is unlikely to bind mTOR substrates, hence affecting signal transduction and further cell proliferation

  17. Novel genetic variants in miR-191 gene and familial ovarian cancer

    International Nuclear Information System (INIS)

    Half of the familial aggregation of ovarian cancer can't be explained by any known risk genes, suggesting the existence of other genetic risk factors. Some of these unknown factors may not be traditional protein encoding genes. MicroRNA (miRNA) plays a critical role in tumorigenesis, but it is still unknown if variants in miRNA genes lead to predisposition to cancer. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis in familial ovarian cancer, we screened for genetic variants in thirty selected miRNA genes, which are predicted to regulate key ovarian cancer genes and are reported to be misexpressed in ovarian tumor tissues, in eighty-three patients with familial ovarian cancer. All of the patients are non-carriers of any known BRCA1/2 or mismatch repair (MMR) gene mutations. Seven novel genetic variants were observed in four primary or precursor miRNA genes. Among them, three rare variants were found in the precursor or primary precursor of the miR-191 gene. In functional assays, the one variant located in the precursor of miR-191 resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-191. In further analysis, we found that this particular variant exists in five family members who had ovarian cancer. Our findings suggest that there are novel genetic variants in miRNA genes, and those certain genetic variants in miRNA genes can affect the expression of mature miRNAs and, consequently, might alter the regulation of TSGs or oncogenes. Additionally, the variant might be potentially associated with the development of familial ovarian cancer

  18. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    OpenAIRE

    Touraj Mahmoudi; Keivan Majidzadeh-A; Hamid Farahani; Mojgan Mirakhorli; Reza Dabiri; Hossein Nobakht; Asadollah Asadi

    2015-01-01

    Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS), and therefore vitamin D receptor (VDR), parathyroid hormone (PTH), and insulin receptor (INSR) gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genoty...

  19. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    OpenAIRE

    Mahmoudi, Touraj; Majidzadeh-A, Keivan; Farahani, Hamid; Mirakhorli, Mojgan; Dabiri, Reza; Nobakht, Hossein; Asadi, Asadollah

    2015-01-01

    Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS), and therefore vitamin D receptor (VDR), parathyroid hormone (PTH), and insulin receptor (INSR) gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genotyped in ...

  20. Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

    DEFF Research Database (Denmark)

    Kästner, Anne; Grube, Sabrina; El-Kordi, Ahmed;

    2012-01-01

    ) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short...

  1. Analysis of stop-gain and frameshift variants in human innate immunity genes.

    Directory of Open Access Journals (Sweden)

    Antonio Rausell

    2014-07-01

    Full Text Available Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.

  2. Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice

    International Nuclear Information System (INIS)

    The nucleotide sequence of the human growth hormone variant gene, one of the five members of the growth hormone gene family, predicts that it encodes a growth hormone-like protein. As a first step in determining whether this gene is functional in humans, the authors have expressed a mouse methallothionein I/human growth hormone variant fusion gene in mouse L cells and in transgenic mice. The growth hormone variant protein expressed in transiently transfected L cells is distinct from growth hormone itself with respect to reactivity with anti-growth hormone monoclonal antibodies, behavior during column chromatography, and isoelectric point. Transgenic mice expressing the growth hormone variant protein are 1.4- to 1.9-fold larger than nontransgenic controls, suggesting that the protein has growth-promoting properties

  3. Sexually dimorphic effects of oxytocin receptor gene (OXTR ) variants on Harm Avoidance

    OpenAIRE

    Stankova Trayana; Eichhammer Peter; Langguth Berthold; Sand Philipp G

    2012-01-01

    Abstract Background Recent research has suggested that oxytocin receptor gene (OXTR) variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. Methods We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. Results When sex was controlled...

  4. Notch Signaling Is Associated With ALDH Activity And An Aggressive Metastatic Phenotype In Murine Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Xiaodong eMu

    2013-06-01

    Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone, and pulmonary metastatic disease accounts for nearly all mortality. However, little is known about the biochemical signaling alterations that drive the progression of metastatic disease. Two murine OS cell populations, K7M2 and K12, are clonally related but differ significantly in their metastatic phenotypes and therefore represent excellent tools for studying metastatic OS molecular biology. K7M2 cells are highly metastatic, whereas K12 cells display limited metastatic potential. Here we report that the expression of Notch genes (Notch1, 2, 4 are up-regulated, including downstream targets Hes1 and Stat3, in the highly metastatic K7M2 cells compared to the less metastatic K12 cells, indicating that the Notch signaling pathway is more active in K7M2 cells. We have previously described that K7M2 cells exhibit higher levels of aldehyde dehydrogenase (ALDH activity. Here we report that K7M2 cell ALDH activity is reduced with Notch inhibition, suggesting that ALDH activity may be regulated in part by the Notch pathway. Notch signaling is also associated with increased resistance to oxidative stress, migration, invasion, and VEGF expression in vitro. However, Notch inhibition did not significantly alter K7M2 cell proliferation. In conclusion, we provide evidence that Notch signaling is associated with ALDH activity and increased metastatic behavior in OS cells. Both Notch and ALDH are putative molecular targets for the treatment and prevention of OS metastasis.

  5. FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

    Science.gov (United States)

    Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

    2016-09-01

    Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. PMID:27325607

  6. Msx1 Gene Variant - Its Presence in Tooth Absence - A Case Control Genetic Study

    OpenAIRE

    Reddy, Naveen Admala; Adusumilli, Gopinath; Devanna, Raghu; Pichai, Saravanan; Rohra, Mayur Gobindram; Arjunan, Sharmila

    2013-01-01

    Background: Non Syndromic tooth agenesis is a congenital anomaly with significant medical, psychological and social ramifications. There is sufficient evidence to hypothesize that locus for this condition can be identified by candidate genes. The aim of this study was to test whether MSX1 671 T>C gene variant was involved in etiology of Non Syndromic tooth agenesis in Raichur Patients.

  7. Genome-wide identification of structural variants in genes encoding drug targets

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Berg; Dahmcke, Christina Mackeprang

    2012-01-01

    The objective of the present study was to identify structural variants of drug target-encoding genes on a genome-wide scale. We also aimed at identifying drugs that are potentially amenable for individualization of treatments based on knowledge about structural variation in the genes encoding the...

  8. Identification of sequence variants in genetic disease-causing genes using targeted next-generation sequencing.

    Directory of Open Access Journals (Sweden)

    Xiaoming Wei

    Full Text Available BACKGROUND: Identification of gene variants plays an important role in research on and diagnosis of genetic diseases. A combination of enrichment of targeted genes and next-generation sequencing (targeted DNA-HiSeq results in both high efficiency and low cost for targeted sequencing of genes of interest. METHODOLOGY/PRINCIPAL FINDINGS: To identify mutations associated with genetic diseases, we designed an array-based gene chip to capture all of the exons of 193 genes involved in 103 genetic diseases. To evaluate this technology, we selected 7 samples from seven patients with six different genetic diseases resulting from six disease-causing genes and 100 samples from normal human adults as controls. The data obtained showed that on average, 99.14% of 3,382 exons with more than 30-fold coverage were successfully detected using Targeted DNA-HiSeq technology, and we found six known variants in four disease-causing genes and two novel mutations in two other disease-causing genes (the STS gene for XLI and the FBN1 gene for MFS as well as one exon deletion mutation in the DMD gene. These results were confirmed in their entirety using either the Sanger sequencing method or real-time PCR. CONCLUSIONS/SIGNIFICANCE: Targeted DNA-HiSeq combines next-generation sequencing with the capture of sequences from a relevant subset of high-interest genes. This method was tested by capturing sequences from a DNA library through hybridization to oligonucleotide probes specific for genetic disorder-related genes and was found to show high selectivity, improve the detection of mutations, enabling the discovery of novel variants, and provide additional indel data. Thus, targeted DNA-HiSeq can be used to analyze the gene variant profiles of monogenic diseases with high sensitivity, fidelity, throughput and speed.

  9. Haplotype-Based Study of the Association of Alcohol Metabolizing Genes with Alcohol Dependence in Four Independent Populations

    Science.gov (United States)

    Liu, Jixia; Zhou, Zhifeng; Hodgkinson, Colin A.; Yuan, Qiaoping; Shen, Pei-Hong; Mulligan, Connie J.; Wang, Alex; Gray, Rebecca R.; Roy, Alec; Virkkunen, Matti; Goldman, David; Enoch, Mary-Anne

    2010-01-01

    Background Ethanol is metabolized by two rate limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde, subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non-East Asian populations by performing systematic haplotype association analyses in order to maximize the chances of capturing functional variation. Methods Haplotype-tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case, control sample sizes were: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; Southwestern American (SW) Indians: 317, 72. Results In all four populations, as well as HapMap populations, five haplotype blocks were identified across the ADH gene cluster: (1) ADH5-ADH4; (2) ADH6-ADH1A-ADH1B; (3) ADH1C; (4) intergenic; (5) ADH7. The ALDH1A1 gene was defined by four blocks and ALDH2 by one block. No haplotype or SNP association results were significant after correction for multiple comparisons; however several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3′ UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317 respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians. Conclusions The systematic evaluation of

  10. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

    DEFF Research Database (Denmark)

    Mills, Philippa B; Footitt, Emma J; Mills, Kevin A;

    2010-01-01

    of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary L-alpha-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the...... normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on...

  11. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

    Directory of Open Access Journals (Sweden)

    Siew Mei Joyce-Tan

    2016-01-01

    Full Text Available Genome-wide association studies (GWAS have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM. However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE, angiotensinogen (AGT, and angiotensin II type 1 receptor (AGTR1. There were significant differences in allele frequencies between cases and controls for AGT variants (P=0.05 but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P=0.012; however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

  12. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen.

    Science.gov (United States)

    Joyce-Tan, Siew Mei; Zain, Shamsul Mohd; Abdul Sattar, Munavvar Zubaid; Abdullah, Nor Azizan

    2016-01-01

    Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk. PMID:26682227

  13. Novel splicing variant of the human orphan nuclear receptor Nurr1 gene

    Institute of Scientific and Technical Information of China (English)

    徐评议; 乐卫东

    2004-01-01

    Background Nurr1 is a member of the nuclear receptor superfamily of transcription factors. The objective of the present study was to identify novel splicing variants of the gene in neuronal and non-neuronal tissues and determine their functions. Methods Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to screen for Nurr1 splice variants in the adult human central nervous system (CNS) and in other tissues such as lymphocytes, and liver, muscle, and kidney cells. Functional assays of the variants were performed by measuring Nurr1 response element (NuRE) transcriptional activity in vitro. Results In this study, the authors identified a novel splicing variant of Nurr1 within exon 5, found in multiple adult human tissues, including lymphocytes, and liver, muscle, and kidney cells, but not in the brain or spinal cord. Sequencing analysis showed the variant has a 75 bp deletion between nucleotides 1402 and 1476. A functional assay of the Nurr1-c splicing variant, performed by measuring NuRE transcriptional activity in vitro, detected a 39% lower level of luciferase (LUC) activity (P<0.05).Conclusion A novel splicing variant of Nurr1 exists in human non-neuronal tissues and functional assays suggest that the variant may act as an alternate transcription regulator.

  14. Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate.

    Science.gov (United States)

    Aylward, Alana; Cai, Yi; Lee, Andrew; Blue, Elizabeth; Rabinowitz, Daniel; Haddad, Joseph

    2016-07-01

    Studies suggest that nonsyndromic cleft lip and palate (NSCLP) is polygenic with variable penetrance, presenting a challenge in identifying all causal genetic variants. Despite relatively high prevalence of NSCLP among Amerindian populations, no large whole exome sequencing (WES) studies have been completed in this population. Our goal was to identify candidate genes with rare genetic variants for NSCLP in a Honduran population using WES. WES was performed on two to four members of 27 multiplex Honduran families. Genetic variants with a minor allele frequency > 1% in reference databases were removed. Heterozygous variants consistent with dominant disease with incomplete penetrance were ascertained, and variants with predicted functional consequence were prioritized for analysis. Pedigree-specific P-values were calculated as the probability of all affected members in the pedigree being carriers, given that at least one is a carrier. Preliminary results identified 3,727 heterozygous rare variants; 1,282 were predicted to be functionally consequential. Twenty-three genes had variants of interest in ≥3 families, where some genes had different variants in each family, giving a total of 50 variants. Variant validation via Sanger sequencing of the families and unrelated unaffected controls excluded variants that were sequencing errors or common variants not in databases, leaving four genes with candidate variants in ≥3 families. Of these, candidate variants in two genes consistently segregate with NSCLP as a dominant variant with incomplete penetrance: ACSS2 and PHYH. Rare variants found at the same gene in all affected individuals in several families are likely to be directly related to NSCLP. PMID:27229527

  15. FTO gene variants are associated with growth and carcass traits in cattle.

    Science.gov (United States)

    Jevsinek Skok, D; Kunej, T; Kovac, M; Malovrh, S; Potocnik, K; Petric, N; Zgur, S; Dovc, P; Horvat, S

    2016-04-01

    An important aim in animal breeding is the improvement of growth and meat quality traits. Previous studies have demonstrated that genetic variants in the fat mass and obesity associated (FTO) gene have a relatively large effect on human obesity as well as on body composition in rodents and, more recently, in livestock. Here, we examined the effects of the FTO gene variants on growth and carcass traits in the Slovenian population of Simmental (SS) and Brown (SB) cattle. To validate and identify new polymorphisms, we used sequencing, PCR-RFLP analysis and TaqMan assays in the SS breed and FTO gene variants data from the Illumina BovineSNP50 v1 array for the SB breed. Sequencing of the eight samples of progeny-tested SS sires detected 108 single nucleotide polymorphisms (SNPs) in the bovine FTO gene. Statistical analyses between growth and carcass traits and 34 FTO polymorphisms revealed significant association of FTO variants with lean meat percentage in both breeds. Additionally, FTO SNPs analyzed in SS cattle were associated with fat percentage, bone weight and live weight at slaughter. The FTO gene can thus be regarded as a candidate gene for the marker-assisted selection programs in our and possibly other populations of cattle. Future studies in cattle might reveal novel roles for the FTO gene in shaping carcass traits in livestock species as well as body composition control in other mammals. PMID:26708680

  16. C-Reactive protein gene variants are associated with postoperative C-reactive protein levels after coronary artery bypass surgery

    OpenAIRE

    Collard Charles D; Fox Amanda A; Liu Kuang-Yu; Muehlschlegel Jochen D; Perry Tjörvi E; Body Simon C; Shernan Stanton K

    2009-01-01

    Abstract Background Elevated baseline C-reactive protein (CRP) levels are associated with increased risk for developing cardiovascular disease. Several CRP gene variants have been associated with altered baseline CRP levels in ambulatory populations. However, the influence of CRP gene variants on CRP levels during inflammatory states, such as surgery, is largely unexplored. We describe the association between candidate CRP gene variants and postoperative plasma CRP levels in patients undergoi...

  17. A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

    DEFF Research Database (Denmark)

    Roos, L; Fang, M; Dali, C; Jensen, H; Christoffersen, N; Wu, B; Zhang, J; Xu, R; Harris, P; Xu, X; Grønskov, K; Tümer, Z

    2013-01-01

    identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where...

  18. An abundance of rare functional variants in 202 drug target genes sequenced in 14.002 people

    DEFF Research Database (Denmark)

    Nelson, Matthew R.; Wegmann, Daniel; Ehm, Margaret G.;

    2012-01-01

    Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases)...

  19. Association between neuromedin U gene variants and overweight and obesity

    DEFF Research Database (Denmark)

    Hainerová, Irena; Torekov, Signe S; Ek, Jakob;

    2006-01-01

    Neuromedin U (NMU) is an anorexic neuropeptide expressed in the hypothalamus. Mice lacking the NmU gene are hyperphagic and obese, whereas mice overexpressing Nmu are hypophagic and lean.......Neuromedin U (NMU) is an anorexic neuropeptide expressed in the hypothalamus. Mice lacking the NmU gene are hyperphagic and obese, whereas mice overexpressing Nmu are hypophagic and lean....

  20. Identification of Novel Milk Protein Gene Variants in Sahiwal Cattle Breed of Pakistan

    OpenAIRE

    Shahlla N. Mir; Tahir, Mohammad A.; Riazuddin Sheikh

    2013-01-01

    This novel study was aimed at identification of new genetic variants in Sahiwal cattle breed of Pakistan and determined the effects of these variants on milk yield. Five major milk protein genes in Sahiwal cattle were analyzed and two single nucleotide polymorphisms identified through bi-directional sequencing. These include A to T in exon XI at position 11462 of the alpha s1 casein gene; resulting in a Glutamic Acid (GAA) to Aspartic acid (GAU) substitution at position 84 of alpha s1 casein ...

  1. Characterization and histologic localization of human growth hormone-variant gene expression in the placenta.

    OpenAIRE

    Liebhaber, S A; Urbanek, M; Ray, J.; Tuan, R.S.; Cooke, N E

    1989-01-01

    The human growth hormone-variant (hGH-V) gene is one of five highly similar growth hormone-related genes clustered on the short arm of chromosome 17. Although the pattern of expression of the adjacent normal growth hormone (hGH-N) and chorionic somatomammotropin (hCS) genes in this cluster are well characterized, the expression of the hGH-V gene remains to be defined. In previous studies, we have demonstrated that the hGH-V gene is transcribed in the term placenta and expressed as two alterna...

  2. BRONCO: Biomedical entity Relation ONcology COrpus for extracting gene-variant-disease-drug relations

    Science.gov (United States)

    Lee, Kyubum; Lee, Sunwon; Park, Sungjoon; Kim, Sunkyu; Kim, Suhkyung; Choi, Kwanghun; Tan, Aik Choon; Kang, Jaewoo

    2016-01-01

    Comprehensive knowledge of genomic variants in a biological context is key for precision medicine. As next-generation sequencing technologies improve, the amount of literature containing genomic variant data, such as new functions or related phenotypes, rapidly increases. Because numerous articles are published every day, it is almost impossible to manually curate all the variant information from the literature. Many researchers focus on creating an improved automated biomedical natural language processing (BioNLP) method that extracts useful variants and their functional information from the literature. However, there is no gold-standard data set that contains texts annotated with variants and their related functions. To overcome these limitations, we introduce a Biomedical entity Relation ONcology COrpus (BRONCO) that contains more than 400 variants and their relations with genes, diseases, drugs and cell lines in the context of cancer and anti-tumor drug screening research. The variants and their relations were manually extracted from 108 full-text articles. BRONCO can be utilized to evaluate and train new methods used for extracting biomedical entity relations from full-text publications, and thus be a valuable resource to the biomedical text mining research community. Using BRONCO, we quantitatively and qualitatively evaluated the performance of three state-of-the-art BioNLP methods. We also identified their shortcomings, and suggested remedies for each method. We implemented post-processing modules for the three BioNLP methods, which improved their performance. Database URL: http://infos.korea.ac.kr/bronco PMID:27074804

  3. BRONCO: Biomedical entity Relation ONcology COrpus for extracting gene-variant-disease-drug relations.

    Science.gov (United States)

    Lee, Kyubum; Lee, Sunwon; Park, Sungjoon; Kim, Sunkyu; Kim, Suhkyung; Choi, Kwanghun; Tan, Aik Choon; Kang, Jaewoo

    2016-01-01

    Comprehensive knowledge of genomic variants in a biological context is key for precision medicine. As next-generation sequencing technologies improve, the amount of literature containing genomic variant data, such as new functions or related phenotypes, rapidly increases. Because numerous articles are published every day, it is almost impossible to manually curate all the variant information from the literature. Many researchers focus on creating an improved automated biomedical natural language processing (BioNLP) method that extracts useful variants and their functional information from the literature. However, there is no gold-standard data set that contains texts annotated with variants and their related functions. To overcome these limitations, we introduce a Biomedical entity Relation ONcology COrpus (BRONCO) that contains more than 400 variants and their relations with genes, diseases, drugs and cell lines in the context of cancer and anti-tumor drug screening research. The variants and their relations were manually extracted from 108 full-text articles. BRONCO can be utilized to evaluate and train new methods used for extracting biomedical entity relations from full-text publications, and thus be a valuable resource to the biomedical text mining research community. Using BRONCO, we quantitatively and qualitatively evaluated the performance of three state-of-the-art BioNLP methods. We also identified their shortcomings, and suggested remedies for each method. We implemented post-processing modules for the three BioNLP methods, which improved their performance.Database URL:http://infos.korea.ac.kr/bronco. PMID:27074804

  4. Alternative splice variants of the human PD-1 gene

    DEFF Research Database (Denmark)

    Nielsen, Christian; Ohm-Laursen, Line; Barington, Torben;

    2005-01-01

    PD-1 is an immunoregulatory receptor expressed on the surface of activated T cells, B cells, and monocytes. We describe four alternatively spliced PD-1 mRNA transcripts (PD-1Deltaex2, PD-1Deltaex3, PD-1Deltaex2,3, and PD-1Deltaex2,3,4) in addition to the full length isoform. PD-1Deltaex2 and PD-1......Deltaex3 are generated by alternative splicing where exon 2 (extracellular IgV-like domain) and exon 3 (transmembrane domain) respectively are spliced out. PD-1Deltaex3 is therefore likely to encode a soluble form of PD-1. PD-1Deltaex2,3 lacks exon 2 and 3. These three variants have unaffected open...

  5. Targeted next-generation sequencing reveals multiple deleterious variants in OPLL-associated genes.

    Science.gov (United States)

    Chen, Xin; Guo, Jun; Cai, Tao; Zhang, Fengshan; Pan, Shengfa; Zhang, Li; Wang, Shaobo; Zhou, Feifei; Diao, Yinze; Zhao, Yanbin; Chen, Zhen; Liu, Xiaoguang; Chen, Zhongqiang; Liu, Zhongjun; Sun, Yu; Du, Jie

    2016-01-01

    Ossification of the posterior longitudinal ligament of the spine (OPLL), which is characterized by ectopic bone formation in the spinal ligaments, can cause spinal-cord compression. To date, at least 11 susceptibility genes have been genetically linked to OPLL. In order to identify potential deleterious alleles in these OPLL-associated genes, we designed a capture array encompassing all coding regions of the target genes for next-generation sequencing (NGS) in a cohort of 55 unrelated patients with OPLL. By bioinformatics analyses, we successfully identified three novel and five extremely rare variants (MAF < 0.005). These variants were predicted to be deleterious by commonly used various algorithms, thereby resulting in missense mutations in four OPLL-associated genes (i.e., COL6A1, COL11A2, FGFR1, and BMP2). Furthermore, potential effects of the patient with p.Q89E of BMP2 were confirmed by a markedly increased BMP2 level in peripheral blood samples. Notably, seven of the variants were found to be associated with the patients with continuous subtype changes by cervical spinal radiological analyses. Taken together, our findings revealed for the first time that deleterious coding variants of the four OPLL-associated genes are potentially pathogenic in the patients with OPLL. PMID:27246988

  6. Targeted next-generation sequencing reveals multiple deleterious variants in OPLL-associated genes

    Science.gov (United States)

    Chen, Xin; Guo, Jun; Cai, Tao; Zhang, Fengshan; Pan, Shengfa; Zhang, Li; Wang, Shaobo; Zhou, Feifei; Diao, Yinze; Zhao, Yanbin; Chen, Zhen; Liu, Xiaoguang; Chen, Zhongqiang; Liu, Zhongjun; Sun, Yu; Du, Jie

    2016-01-01

    Ossification of the posterior longitudinal ligament of the spine (OPLL), which is characterized by ectopic bone formation in the spinal ligaments, can cause spinal-cord compression. To date, at least 11 susceptibility genes have been genetically linked to OPLL. In order to identify potential deleterious alleles in these OPLL-associated genes, we designed a capture array encompassing all coding regions of the target genes for next-generation sequencing (NGS) in a cohort of 55 unrelated patients with OPLL. By bioinformatics analyses, we successfully identified three novel and five extremely rare variants (MAF < 0.005). These variants were predicted to be deleterious by commonly used various algorithms, thereby resulting in missense mutations in four OPLL-associated genes (i.e., COL6A1, COL11A2, FGFR1, and BMP2). Furthermore, potential effects of the patient with p.Q89E of BMP2 were confirmed by a markedly increased BMP2 level in peripheral blood samples. Notably, seven of the variants were found to be associated with the patients with continuous subtype changes by cervical spinal radiological analyses. Taken together, our findings revealed for the first time that deleterious coding variants of the four OPLL-associated genes are potentially pathogenic in the patients with OPLL. PMID:27246988

  7. Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat.

    Science.gov (United States)

    Mizukami, Keijiro; Raj, Karthik; Osborne, Carl; Giger, Urs

    2016-01-01

    Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA) reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus) with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn) from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu) in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met) from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats. PMID:27404572

  8. Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat

    Science.gov (United States)

    Raj, Karthik; Osborne, Carl; Giger, Urs

    2016-01-01

    Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA) reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus) with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn) from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu) in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met) from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats. PMID:27404572

  9. FOXC2 and FLT4 Gene Variants in Lymphatic Filariasis.

    Science.gov (United States)

    Sheik, Yasmeen; Qureshi, Sameera Fatima; Mohhammed, Basheeruddin; Nallari, Pratibha

    2015-06-01

    Lymphatic filariasis is the leading cause of secondary lymphedema wherein lymph transport is impaired due to lymphatic damage. FLT4 signaling and transcription factors such as FOXC2 play an important role in this type of lymphangiogenesis process induced by filarial parasites. The present study aims to assess the association of FLT4 and FOXC2 genes in lymphatic development/remodeling in lymphatic filariasis. A total of 118 lymphatic filariasis patients and 100 non-endemic and 50 endemic healthy subjects were enrolled for the present study. Allele-specific PCR and PCR-RFLP were adopted for the genotyping, and screening of FLT4 and FOXC2 genes was carried out by PCR-SSCP, followed by in-silico and statistical analysis. A novel variation (G357A SNP) was identified on FOXC2 gene screening that may have an effect on codon usage frequency during translational process. In FLT4, A3123G mutation was found in 3.39% of the case subjects but the functional role of this mutation, along with subject's clinical presentations and patient's age, emphasize its pathogenic role in lymphedema development. Two of the subjects exhibit compound heterozygosity (A3123G FLT4 mutation and G357A SNP of FOXC2 gene). As these two genes share a common pathway, we hypothesise a synergistic interaction of these two SNPs in inhibiting the downstream signaling resulting in lymphedema progression. PMID:26091406

  10. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.

    Science.gov (United States)

    Fairfax, Benjamin P; Humburg, Peter; Makino, Seiko; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C

    2014-03-01

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants. PMID:24604202

  11. Identification and characterization of the genes encoding the core histones and histone variants of Neurospora crassa.

    OpenAIRE

    Hays, Shan M.; Swanson, Johanna; Eric U Selker

    2002-01-01

    We have identified and characterized the complete complement of genes encoding the core histones of Neurospora crassa. In addition to the previously identified pair of genes that encode histones H3 and H4 (hH3 and hH4-1), we identified a second histone H4 gene (hH4-2), a divergently transcribed pair of genes that encode H2A and H2B (hH2A and hH2B), a homolog of the F/Z family of H2A variants (hH2Az), a homolog of the H3 variant CSE4 from Saccharomyces cerevisiae (hH3v), and a highly diverged ...

  12. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

    DEFF Research Database (Denmark)

    Amankwah, Ernest K.; Lin, Hui-Yi; Tyrer, Jonathan P.;

    2015-01-01

    Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants co...

  13. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

    NARCIS (Netherlands)

    Butterworth, A.S.; Braund, P.S.; Hardwick, R.J.; Saleheen, D.; Peden, J.F.; Soranzo, N.; Chambers, J.C.; Kleber, M.E.; Keating, B.; Qasim, A.; Klopp, N.; Erdmann, J.; Basart, H.; Baumert, J.H.; Bezzina, C.R.; Boehm, B.O.; Brocheton, J.; Bugert, P.; Cambien, F.; Collins, R.; Couper, D.; Jong, J.S. de; Diemert, P.; Ejebe, K.; Elbers, C.C.; Elliott, P.; Fornage, M.; Frossard, P.; Garner, S.; Hunt, S.E.; Kastelein, J.J.; Klungel, O.H.; Kluter, H.; Koch, K.; Konig, I.R.; Kooner, A.S.; Liu, K.; McPherson, R.; Musameh, M.D.; Musani, S.; Papanicolaou, G.; Peters, A.; Peters, B.J.; Potter, S.; Psaty, B.M.; Rasheed, A.; Scott, J.; Seedorf, U.; Sehmi, J.S.; Sotoodehnia, N.; Stark, K.; Stephens, J.; Schoot, C.E. van der; Schouw, Y.T. van der; Harst, P. van der; Vasan, R.S.; Wilde, A.A.; Willenborg, C.; Winkelmann, B.R.; Zaidi, M.; Zhang, W.; Ziegler, A.; Koenig, W.; Matz, W.; Trip, M.D.; Reilly, M.P.; Kathiresan, S.; Schunkert, H.; Hamsten, A.; Hall, A.S.; Kooner, J.S.; Thompson, S.G.; Thompson, J.R.; Watkins, H.; Danesh, J.; Barnes, T.; Rafelt, S.; Codd, V.; Bruinsma, N.; Dekker, L.R.; Henriques, J.P.; Koch, K.T.; Winter, R.J. de; Alings, M.; Allaart, C.F.; Gorgels, A.P.; Verheugt, F.W.A.; Mueller, M.; Meisinger, C.; DerOhannessian, S.; Mehta, N.N.; Ferguson, J.; Hakonarson, H.; Matthai, W.; Wilensky, R.; Hopewell, J.C.; Parish, S.; Linksted, P.; Notman, J.; Gonzalez, H.; Young, A.; Ostley, T.; Munday, A.; Goodwin, N.; Verdon, V.; Shah, S.; Edwards, C.; Mathews, C.; Gunter, R.; Benham, J.; Davies, C.; Cobb, M.; Cobb, L.; Crowther, J.; Richards, A.; Silver, M.; Tochlin, S.; Mozley, S.; Clark, S.; Radley, M.; Kourellias, K.; Olsson, P.; Barlera, S.; Tognoni, G.; Rust, S.; Assmann, G.; Heath, S.; Zelenika, D.; Gut, I.; Green, F.; Farrall, M.; Peden, J.; Goel, A.; Ongen, H.; Franzosi, M.G.; Lathrop, M.; Clarke, R.; Aly, A.; Anner, K.; Bjorklund, K.; Blomgren, G.; Cederschiold, B.; Danell-Toverud, K.; Eriksson, P.; Grundstedt, U.; Heinonen, M.; Hellenius, M.L.; Hooft, F. van 't; Husman, K.; Lagercrantz, J.; Larsson, A.; Larsson, M.; Mossfeldt, M.; Malarstig, A.; Olsson, G.; Sabater-Lleal, M.; Sennblad, B.; Silveira, A.; Strawbridge, R.; Soderholm, B.; Ohrvik, J.; Zaman, K.S.; Mallick, N.H.; Azhar, M.; Samad, A.; Ishaq, M.; Shah, N.; Samuel, M.; Kathiresan, S.C.; Reilly, M.; Assimes, T.L.; Holm, H.; Preuss, M.; Stewart, A.F.; Barbalic, M.; Gieger, C.; Absher, D.; Aherrahrou, Z.; Allayee, H.; Altshuler, D.; Anand, S.; Andersen, K.; Anderson, J.L.; Ardissino, D.; Ball, S.G.; Balmforth, A.J.; Barnes, T.A.; Becker, L.C.; Becker, D.M.; Berger, K.; Bis, J.C.; Boekholdt, S.M.; Boerwinkle, E.; Brown, M.J.; Burnett, M.S.; Buysschaert, I.; Carlquist, J.F.; Chen, L.; Davies, R.W.; Dedoussis, G.; Dehghan, A.; Demissie, S.; Devaney, J.; Do, R.; Doering, A.; El Mokhtari, N.E.; Ellis, S.G.; Elosua, R.; Engert, J.C.; Epstein, S.; Faire, U. de; Fischer, M.; Folsom, A.R.; Freyer, J.; Gigante, B.; Girelli, D.; Gretarsdottir, S.; Gudnason, V.; Gulcher, J.R.; Tennstedt, S.; Halperin, E.; Hammond, N.; Hazen, S.L.; Hofman, A.; Horne, B.D.; Illig, T.; Iribarren, C.; Jones, G.T.; Jukema, J.W.; Kaiser, M.A.; Kaplan, L.M.; Khaw, K.T.; Knowles, J.W.; Kolovou, G.; Kong, A.; Laaksonen, R.; Lambrechts, D.; Leander, K.; Li, M.; Lieb, W.; Lettre, G.; Loley, C.; Lotery, A.J.; Mannucci, P.M.; Martinelli, N.; McKeown, P.P.; Meitinger, T.; Melander, O.; Merlini, P.A.; Mooser, V.; Morgan, T.; Muhleisen T.W., .; Muhlestein, J.B.; Musunuru, K.; Nahrstaedt, J.; Nothen, M.M.; Olivieri, O.; Peyvandi, F.; Patel, R.S.; Patterson, C.C.; Qu, L.; Quyyumi, A.A.; Rader, D.J.; Rallidis, L.S.; Rice, C.; Roosendaal, F.R.; Rubin, D.; Salomaa, V.; Sampietro, M.L.; Sandhu, M.S.; Schadt, E.; Schafer, A.; Schillert, A.; Schreiber, S.; Schrezenmeir, J.; Schwartz, S.M.; Siscovick, D.S.; Sivananthan, M.; Sivapalaratnam, S.; Smith, A.V.; Smith, T.B.; Snoep, J.D.; Spertus, J.A.; Stefansson, K.; Stirrups, K.; Stoll, M.; Tang, W.H.; Thorgeirsson, G.; Thorleifsson, G.; Tomaszewski, M.; Uitterlinden, A.G.; Rij, A.M. van; Voight, B.F.; Wareham, N.J.; AWells, G.; Wichmann, H.E.; Witteman, J.C.; Wright, B.J.; Ye, S.; Cupples, L.A.; Quertermous, T.; Marz, W.; Blankenberg, S.; Thorsteinsdottir, U.; Roberts, R.; O'Donnell, C.J.; Onland-Moret, N.C.; Setten, J. van; Bakker, P.I. de; Verschuren, W.M.; Boer, J.M.; Wijmenga, C.; Hofker, M.H.; Maitland-van der Zee, A.H.; Boer, A. de; Grobbee, D.E.; Attwood, T.; Belz, S.; Cooper, J.; Crisp-Hihn, A.; Deloukas, P.; Foad, N.; Goodall, A.H.; Gracey, J.; Gray, E.; Gwilliams, R.; Heimerl, S.; Hengstenberg, C.; Jolley, J.; Krishnan, U.; Lloyd-Jones, H.; Lugauer, I.; Lundmark, P.; Maouche, S.; Moore, J.S.; Muir, D.; Murray, E.; Nelson, C.P.; Neudert, J.; Niblett, D.; O'Leary, K.; Ouwehand, W.H.; Pollard, H.; Rankin, A.; Rice, C.M.; Sager, H.; Samani, N.J.; Sambrook, J.; Schmitz, G.; Scholz, M.; Schroeder, L.; Syvannen, A.C.; Wallace, C.

    2011-01-01

    Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. W

  14. The histone variant macroH2A is an epigenetic regulator of key developmental genes

    DEFF Research Database (Denmark)

    Buschbeck, Marcus; Uribesalgo, Iris; Wibowo, Indra; Rué, Pau; Martin, David; Gutierrez, Arantxa; Morey, Lluís; Guigó, Roderic; López-Schier, Hernán; Di Croce, Luciano

    2009-01-01

    activation of HOXA cluster genes during neuronal differentiation. Furthermore, elimination of macroH2A2 function in zebrafish embryos produced severe but specific phenotypes. Taken together, our data demonstrate that macroH2A variants constitute an important epigenetic mark involved in the concerted...

  15. Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity

    DEFF Research Database (Denmark)

    L. Santos, José; De la Cruz, Rolando; Holst, Claus;

    2011-01-01

    The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 recep...

  16. Genetic variants in the choline acetyltransferase (ChAT) gene are modestly associated with normal cognitive function in the elderly

    DEFF Research Database (Denmark)

    Mengel-From, J; Christensen, K; Thinggaard, M; McGue, M; Christiansen, L

    2011-01-01

    Genetic variants in the choline acetyltransferase (ChAT) gene have been suggested as risk factors for neurodegenerative Alzheimer's disease (AD). Here we tested the importance of genetic variants in the ChAT gene in normal cognitive function of elderly in a study sample of Danish twins and single...

  17. The promoter for a variant surface glycoprotein gene expression site in Trypanosoma brucei.

    OpenAIRE

    Zomerdijk, J C; Ouellette, M; ten Asbroek, A L; Kieft, R.; Bommer, A M; Clayton, C E; Borst, P

    1990-01-01

    The variant-specific surface glycoprotein (VSG) gene 221 of Trypanosoma brucei is transcribed as part of a 60 kb expression site (ES). We have identified the promoter controlling this multigene transcription unit by the use of 221 chromosome-enriched DNA libraries and VSG gene 221 expression site specific transcripts. The start of transcription was determined by hybridization and RNase protection analysis of nascent RNA. The 5' ends of the major transcripts coming from the initiation region m...

  18. Msx1 Gene Variant - its Association in Isolated Hypodontia: A Case Control Genetic study!!!

    OpenAIRE

    Naveen Admala Reddy; Gopinath Adusumilli; Raghu Devanna; Rohra G Mayur; Saravanan Pichai; Sharmila Arujnan

    2013-01-01

    Introduction: Non-syndromic tooth agenesis is a congenital anomaly with significant medical, psychological, and social ramifications. There is sufficient evidence to hypothesize that locus for this condition can be identified by candidate genes. Aim of the Study: The aim of this study was to test whether MSX1 671 T > C gene variant was involved in etiology of non-syndromic tooth agenesis in Raichur patients. Materials and Methods: Blood samples were collected with informed consent fro...

  19. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

    OpenAIRE

    Sosnay, Patrick R.; Siklosi, Karen R; Van Goor, Fredrick; Kaniecki, Kyle; Yu, Haihui; Sharma, Neeraj; Ramalho, Anabela S; Amaral, Margarida D.; Dorfman, Ruslan; Zielenski, Julian; Masica, David L.; Karchin, Rachel; Millen, Linda; Thomas, Philip J.; George P. Patrinos

    2013-01-01

    Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation to clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 cystic fibrosis patients in registries and clinics in North America and Europe. Among these patients, 159 CFTR varia...

  20. Destabilized eYFP variants for dynamic gene expression studies in Corynebacterium glutamicum

    OpenAIRE

    Hentschel, Eva; Will, Cornelia; Mustafi, Nurije; Burkovski, Andreas; Rehm, Nadine; Frunzke, Julia

    2013-01-01

    Fluorescent reporter proteins are widely used for the non-invasive monitoring of gene expression patterns, but dynamic measurements are hampered by the extremely high stability of GFP and homologue proteins. In this study, we used SsrA-mediated peptide tagging for the construction of unstable variants of the GFP derivative eYFP (enhanced yellow fluorescent protein) and applied those for transient gene expression analysis in the industrial platform organism Corynebacterium glutamicum.

  1. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

    Directory of Open Access Journals (Sweden)

    Esther Erdei

    Full Text Available OBJECTIVES: A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR. MATERIALS AND METHODS: Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia, or oral squamous cell carcinoma (SCCA were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption. RESULTS: Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70. The transforming growth factor beta-1 (TGFβ-1 -509 C/T polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79. The matrix metalloproteinase gene (MMP-1 variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53 compared to people with ancestral alleles. CONCLUSION: Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

  2. Surface gene variants of hepatitis B Virus in Saudi Patients

    Directory of Open Access Journals (Sweden)

    Ahmed Y Al-Qudari

    2016-01-01

    Full Text Available Background/Aims: Hepatitis B virus (HBV continues to be one of the most important viral pathogens in humans. Surface (S protein is the major HBV antigen that mediates virus attachment and entry and determines the virus subtype. Mutations in S gene, particularly in the “a” determinant, can influence virus detection by ELISA and may generate escape mutants. Since no records have documented the S gene mutations in HBV strains circulating in Saudi Arabia, the current study was designed to study sequence variation of S gene in strains circulating in Saudi Arabia and its correlation with clinical and risk factors. Patients and Methods: A total of 123 HBV-infected patients were recruited for this study. Clinical and biochemical parameters, serological markers, and viral load were determined in all patients. The entire S gene sequence of samples with viral load exceeding 2000 IU/mL was retrieved and exploited in sequence and phylogenetic analysis. Results: A total of 48 mutations (21 unique were recorded in viral strains in Saudi Arabia, among which 24 (11 unique changed their respective amino acids. Two amino acid changes were recorded in “a” determinant, including F130L and S135F with no evidence of the vaccine escape mutant G145R in any of the samples. No specific relationship was recognized between the mutation/amino acid change record of HBsAg in strains in Saudi Arabia and clinical or laboratory data. Phylogenetic analysis categorized HBV viral strains in Saudi Arabia as members of subgenotypes D1 and D3. Conclusion: The present report is the first that describes mutation analysis of HBsAg in strains in Saudi Arabia on both nucleotide and amino acid levels. Different substitutions, particularly in major hydrophilic region, may have a potential influence on disease diagnosis, vaccination strategy, and antiviral chemotherapy.

  3. A novel porcine bocavirus harbors a variant NP gene

    OpenAIRE

    Yoo, Sung J; Sunwoo, Sun Young; Ko, Seong Sik; Je, Sang H; Lee, Dong Uk; Lyoo, Young S

    2015-01-01

    Background Porcine bocavirus is classified within the genus Bocaparvovirus, family Parvoviridae. Unlike other parvoviruses, the members of genus Bocaparvovirus (bocaparvoviruses) encode an additional open reading frame (NP1). Many strains of PBoVs have been identified in domestic pigs and recognized as a potential emerging pathogen causing respiratory and gastrointestinal disease. Findings A new strain of porcine bocavirus (PBoV) that harbored the shortest NP1 gene among all currently charact...

  4. Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma.

    Directory of Open Access Journals (Sweden)

    Ondrej Havranek

    Full Text Available The checkpoint kinase 2 gene (CHEK2 codes for the CHK2 protein, an important mediator of the DNA damage response pathway. The CHEK2 gene has been recognized as a multi-cancer susceptibility gene; however, its role in non-Hodgkin lymphoma (NHL remains unclear. We performed mutation analysis of the entire CHEK2 coding sequence in 340 NHL patients using denaturing high-performance liquid chromatography (DHPLC and multiplex ligation-dependent probe amplification (MLPA. Identified hereditary variants were genotyped in 445 non-cancer controls. The influence of CHEK2 variants on disease risk was statistically evaluated. Identified CHEK2 germline variants included four truncating mutations (found in five patients and no control; P = 0.02 and nine missense variants (found in 21 patients and 12 controls; P = 0.02. Carriers of non-synonymous variants had an increased risk of NHL development [odds ratio (OR 2.86; 95% confidence interval (CI 1.42-5.79] and an unfavorable prognosis [hazard ratio (HR of progression-free survival (PFS 2.1; 95% CI 1.12-4.05]. In contrast, the most frequent intronic variant c.319+43dupA (identified in 22% of patients and 31% of controls was associated with a decreased NHL risk (OR = 0.62; 95% CI 0.45-0.86, but its positive prognostic effect was limited to NHL patients with diffuse large B-cell lymphoma (DLBCL treated by conventional chemotherapy without rituximab (HR-PFS 0.4; 94% CI 0.17-0.74. Our results show that germ-line CHEK2 mutations affecting protein coding sequence confer a moderately-increased risk of NHL, they are associated with an unfavorable NHL prognosis, and they may represent a valuable predictive biomarker for patients with DLBCL.

  5. Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits.

    Science.gov (United States)

    Corradin, Olivia; Saiakhova, Alina; Akhtar-Zaidi, Batool; Myeroff, Lois; Willis, Joseph; Cowper-Sal lari, Richard; Lupien, Mathieu; Markowitz, Sanford; Scacheri, Peter C

    2014-01-01

    DNA variants (SNPs) that predispose to common traits often localize within noncoding regulatory elements such as enhancers. Moreover, loci identified by genome-wide association studies (GWAS) often contain multiple SNPs in linkage disequilibrium (LD), any of which may be causal. Thus, determining the effect of these multiple variant SNPs on target transcript levels has been a major challenge. Here, we provide evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the GWAS association arises from multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type. This finding suggests a "multiple enhancer variant" hypothesis for common traits, where several variants in LD impact multiple enhancers and cooperatively affect gene expression. Using a novel method to delineate enhancer-gene interactions, we show that multiple enhancer variants within a given locus typically target the same gene. Using available data from HapMap and B lymphoblasts as a model system, we provide evidence at numerous loci that multiple enhancer variants cooperatively contribute to altered expression of their gene targets. The effects on target transcript levels tend to be modest and can be either gain- or loss-of-function. Additionally, the genes associated with multiple enhancer variants encode proteins that are often functionally related and enriched in common pathways. Overall, the multiple enhancer variant hypothesis offers a new paradigm by which noncoding variants can confer susceptibility to common traits. PMID:24196873

  6. MTP Gene Variants and Response to Lomitapide in Patients with Homozygous Familial Hypercholesterolemia.

    Science.gov (United States)

    Kolovou, Genovefa D; Kolovou, Vana; Papadopoulou, Anna; Watts, Gerald F

    2016-07-01

    Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder, which leads to premature cardiovascular diseases. Microsomal triglyceride transport protein (MTP) inhibitors, such as lomitapide, offer a new therapeutic approach for treating these patients. We evaluated the lipid lowering (LL) efficacy of lomitapide according to several gene variants in MTP. Four clinically and/or molecularly defined HoFH patients were treated with lomitapide in addition to conventional high intensity LL therapy and regular lipoprotein apheresis. Two patients responded to the therapy, with a significant reduction of LDL cholesterol (LDL-C>50%, hyper-responders). Sequencing of all exonic and intronic flanking regions of the MTP gene in all patients revealed 36 different variants. The hyper-responders to lomitapide shared six common variants: rs17533489, rs79194015, rs745075, rs41275715, rs1491246, and rs17533517, which were not seen in hypo-responders (reduction in LDL-C<50%). We suggest that in HoFH variants in the MTP gene may impact on the therapeutic response to lomitapide, but this requires further investigation. PMID:27170061

  7. Identification of Novel Milk Protein Gene Variants in Sahiwal Cattle Breed of Pakistan

    Directory of Open Access Journals (Sweden)

    Shahlla N. Mir

    2013-02-01

    Full Text Available This novel study was aimed at identification of new genetic variants in Sahiwal cattle breed of Pakistan and determined the effects of these variants on milk yield. Five major milk protein genes in Sahiwal cattle were analyzed and two single nucleotide polymorphisms identified through bi-directional sequencing. These include A to T in exon XI at position 11462 of the alpha s1 casein gene; resulting in a Glutamic Acid (GAA to Aspartic acid (GAU substitution at position 84 of alpha s1 casein protein and T to C change at position 8491 of the exon VII in beta-casein gene resulting in a Valine to Alanine substitution at position 197 of beta casein protein. Amplification Refractory Mutation System (ARMS and SNaPshot genotyping protocols were optimized for genotyping new genetic variants. The genotypes in both the alpha-s1 casein and beta casein genes were found associated with milk yield but their influence was not statistically significant. However, the least square means of milk yield for TT genotypes of alpha s1 casein and of beta casein genes were higher compared to other genotypes.

  8. A common variant associated with dyslexia reduces expression of the KIAA0319 gene.

    Directory of Open Access Journals (Sweden)

    Megan Y Dennis

    2009-03-01

    Full Text Available Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s remains unknown but may modulate gene expression, given that (1 a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2 the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001, confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits.

  9. Variant surface antigens, virulence genes and the pathogenesis of malaria

    DEFF Research Database (Denmark)

    Deitsch, Kirk W; Hviid, Lars

    2004-01-01

    The first Molecular Approaches to Malaria meeting was held 2-5 February 2000 in Lorne, Australia. Following the meeting, Brian Cooke, Mats Wahlgren and Ross Coppel predicted that research into the molecular details of the mechanisms behind sequestration of parasitized erythrocytes would "become...... increasingly more complicated, with further interactions, receptors, ligands and functional domains". Furthermore, they cautioned that "the challenge will be not to lose ourselves in the molecular detail, but remain focused on the role of [the var genes and other multigene families] in pathogenesis of malaria......". We contemplate on these statements, following the recent second Molecular Approaches to Malaria meeting, which was held at the same venue on 2-5 February 2004....

  10. Comprehensive analysis of DNA repair gene variants and risk of meningioma

    DEFF Research Database (Denmark)

    Bethke, L.; Murray, A.; Webb, E.;

    2008-01-01

    meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility. METHODS: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA...... repair genes in five case-control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided. RESULTS: The SNP rs4968451, which maps to intron 4...

  11. Association of an ACSL1 gene variant with polyunsaturated fatty acids in bovine skeletal muscle

    Directory of Open Access Journals (Sweden)

    Widmann Philipp

    2011-11-01

    Full Text Available Abstract Background The intramuscular fat deposition and the fatty acid profiles of beef affect meat quality. High proportions of unsaturated fatty acids are related to beef flavor and are beneficial for the nutritional value of meat. Moreover, a variety of clinical and epidemiologic studies showed that particularly long-chain omega-3 fatty acids from animal sources have a positive impact on human health and disease. Results To screen for genetic factors affecting fatty acid profiles in beef, we initially performed a microsatellite-based genome scan in a F2 Charolais × German Holstein resource population and identified a quantitative trait locus (QTL for fatty acid composition in a region on bovine chromosome 27 where previously QTL affecting marbling score had been detected in beef cattle populations. The long-chain acyl-CoA synthetase 1 (ACSL1 gene was identified as the most plausible functional and positional candidate gene in the QTL interval due to its direct impact on fatty acid metabolism and its position in the QTL interval. ACSL1 is necessary for synthesis of long-chain acyl-CoA esters, fatty acid degradation and phospholipid remodeling. We validated the genomic annotation of the bovine ACSL1 gene by in silico comparative sequence analysis and experimental verification. Re-sequencing of the complete coding, exon-flanking intronic sequences, 3' untranslated region (3'UTR and partial promoter region of the ACSL1 gene revealed three synonymous mutations in exons 6, 7, and 20, six noncoding intronic gene variants, six polymorphisms in the promoter region, and four variants in the 3' UTR region. The association analysis identified the gene variant in intron 5 of the ACSL1 gene (c.481-233A>G to be significantly associated with the relative content of distinct fractions and ratios of fatty acids (e.g., n-3 fatty acids, polyunsaturated, n-3 long-chain polyunsaturated fatty acids, trans vaccenic acid in skeletal muscle. A tentative association

  12. A variant in the fat mass and obesity-associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) do not influence dietary intake

    DEFF Research Database (Denmark)

    Hasselbalch, Ann L; Angquist, Lars; Christiansen, Lene;

    2010-01-01

    a population-based sample of 756 healthy adult twin pairs, we studied associations between FTO rs9939609, near-MC4R rs12970134, rs17700633, and rs17782313 single nucleotide polymorphisms (SNP) and habitual dietary intake. Habitual dietary intake was assessed by a 247-question FFQ. Nontransformed......We investigated the role of the fat mass and obesity associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) in modulating habitual intake of total energy and macronutrients, glycemic index, glycemic load, dietary energy density, and energy from 20 food groups in adults. In...... variables and variables transformed by natural logarithm were analyzed by linear regression and dichotomized variables were analyzed by logistic regression. FTO SNP rs9939609 was not associated with habitual dietary intake. For the near-MC4R SNP rs12970134 and rs17700633, we found significant positive...

  13. Msx1 Gene Variant - its Association in Isolated Hypodontia: A Case Control Genetic study!!!

    Directory of Open Access Journals (Sweden)

    Naveen Admala Reddy

    2013-01-01

    Full Text Available Introduction: Non-syndromic tooth agenesis is a congenital anomaly with significant medical, psychological, and social ramifications. There is sufficient evidence to hypothesize that locus for this condition can be identified by candidate genes. Aim of the Study: The aim of this study was to test whether MSX1 671 T > C gene variant was involved in etiology of non-syndromic tooth agenesis in Raichur patients. Materials and Methods: Blood samples were collected with informed consent from 50 subjects having non-syndromic tooth agenesis and 50 controls. Genomic deoxyribonucleic acid (DNA was extracted from the blood samples, polymerase chain reaction (PCR was performed, and restriction fragment length polymorphism (RFLP was performed for digestion products that were evaluated. Results: The results showed positive correlation between MSX1671 T > C gene variant and non-syndromic tooth agenesis in Raichur patients. Conclusion: MSX1 671 T > C gene variant may be a good screening marker for non-syndromic tooth agenesis in Raichur patients.

  14. Reliable and rapid characterization of functional FCN2 gene variants reveals diverse geographical patterns

    Directory of Open Access Journals (Sweden)

    Ojurongbe Olusola

    2012-05-01

    Full Text Available Abstract Background Ficolin-2 coded by FCN2 gene is a soluble serum protein and an innate immune recognition element of the complement system. FCN2 gene polymorphisms reveal distinct geographical patterns and are documented to alter serum ficolin levels and modulate disease susceptibility. Methods We employed a real-time PCR based on Fluorescence Resonance Energy Transfer (FRET method to genotype four functional SNPs including -986 G > A (#rs3124952, -602 G > A (#rs3124953, -4A > G (#rs17514136 and +6424 G > T (#rs7851696 in the ficolin-2 (FCN2 gene. We characterized the FCN2 variants in individuals representing Brazilian (n = 176, Nigerian (n = 180, Vietnamese (n = 172 and European Caucasian ethnicity (n = 165. Results We observed that the genotype distribution of three functional SNP variants (−986 G > A, -602 G > A and -4A > G differ significantly between the populations investigated (p p  Conclusions The observed distribution of the FCN2 functional SNP variants may likely contribute to altered serum ficolin levels and this may depend on the different disease settings in world populations. To conclude, the use of FRET based real-time PCR especially for FCN2 gene will benefit a larger scientific community who extensively depend on rapid, reliable method for FCN2 genotyping.

  15. Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women

    Directory of Open Access Journals (Sweden)

    Do Kyeong Song

    2014-08-01

    Full Text Available BackgroundThe fat mass and obesity-associated (FTO gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS. Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters.MethodsWe recruited 432 women with PCOS (24±5 years and 927 healthy women with regular menstrual cycles (27±5 years and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements.ResultsLogistic regression revealed that the G/G genotype (rs1421085, 1.6%, the C/C genotype (rs17817449, 1.6%, and the A/A genotype (rs8050136, 1.6% were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05. The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05 and higher free testosterone levels (P=0.053 to 0.063 compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI. When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants.ConclusionThe rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

  16. Variants in the Dopamine-4-Receptor Gene Promoter Are Not Associated with Sensation Seeking in Skiers

    OpenAIRE

    Thomson, Cynthia J.; Amelia K Rajala; Scott R Carlson; Jim L Rupert

    2014-01-01

    Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regio...

  17. Detection of GSTM1, GSTT1 and the Ile105Val GSTP1 gene variants

    DEFF Research Database (Denmark)

    Buchard, Anders; Sanchez, Juan J.; Dalhoff, Kim;

    2008-01-01

    We have developed a PCR multiplex method that in a fast, inexpensive and reliable manner can detect if a person has two, one or no GSTM1 and GSTT1 genes and which at the same time can detect the allelic status of the GSTP1 Ile105Val genetic variant. A total of 200 Danes, 100 Somalis and 100 Green...... Greenlanders were genotyped. This multiplex PCR assay enables future large-scale studies to investigate the role of GSTs...

  18. HFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease

    OpenAIRE

    FatimaAli-Rahmani

    2014-01-01

    Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epide...

  19. HFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease

    OpenAIRE

    Ali-Rahmani, Fatima; Schengrund, Cara-Lynne; Connor, James R.

    2014-01-01

    Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiolo...

  20. Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression

    OpenAIRE

    Fairfax, B. P.; Humburg, P.; Makino, S.; Naranbhai, V; Wong, D.; Lau, E; Jostins, L; Plant, K.; Andrews, R; McGee, C.; Knight, J.C.

    2014-01-01

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTL...

  1. Genetic variants of the FADS gene cluster and ELOVL gene family, colostrums LC-PUFA levels, breastfeeding, and child cognition

    OpenAIRE

    Morales, Eva; Bustamante Pineda, Mariona; Gonz??lez, Juan Ram??n; Guxens, M??nica; Torrent Quetglas, Maties; Mendez, Michelle A; Garc??a Esteban, Raquel; J??lvez Calvo, Jordi; Forns i Guzman, Joan, 1981-; Vrijheid, Martine; Molto Puigmarti, Carolina; L??pez Sabater, M. Carmen; Estivill, Xavier; Sunyer Deu, Jordi

    2011-01-01

    Introduction: Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs), but controversy persists. Genetic variation in fatty acid desaturase (FADS) and elongase (ELOVL) enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1) to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2) to analyze whether these maternal v...

  2. Targeted deep resequencing identifies coding variants in the PEAR1 gene that play a role in platelet aggregation.

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    Yoonhee Kim

    Full Text Available Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1 gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13 selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate. Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5% were noted in African Americans compared to European Americans (108 vs. 45. The common intronic GWAS-identified variant (rs12041331 demonstrated the most significant association signal in African Americans (p = 4.020×10(-4; no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331. Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965 supports the results noted in the sequenced discovery sample: p = 3.56×10(-4, 2.27×10(-7, 5.20×10(-5 for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans

  3. No association of primary Sjögren's syndrome with Fcγ receptor gene variants.

    Science.gov (United States)

    Haldorsen, K; Appel, S; Le Hellard, S; Bruland, O; Brun, J G; Omdal, R; Kristjansdottir, G; Theander, E; Fernandes, C P D; Kvarnström, M; Eriksson, P; Rönnblom, L; Herlenius, M W; Nordmark, G; Jonsson, R; Bolstad, A I

    2013-06-01

    The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcγ receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fcγ receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fcγ receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fcγ receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS. PMID:23552400

  4. Sexually dimorphic effects of oxytocin receptor gene (OXTR variants on Harm Avoidance

    Directory of Open Access Journals (Sweden)

    Stankova Trayana

    2012-07-01

    Full Text Available Abstract Background Recent research has suggested that oxytocin receptor gene (OXTR variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. Methods We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. Results When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p ≤ 0.01. Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant. Conclusions Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation.

  5. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    Science.gov (United States)

    Mahmoudi, Touraj; Majidzadeh-A, Keivan; Farahani, Hamid; Mirakhorli, Mojgan; Dabiri, Reza; Nobakht, Hossein; Asadi, Asadollah

    2015-01-01

    Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS), and therefore vitamin D receptor (VDR), parathyroid hormone (PTH), and insulin receptor (INSR) gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genotyped in 35 women with PCOS and 35 controls using Polymerase chain reaction – Restriction fragment length polymorphism method. Furthermore, serum levels of glucose and insulin were measured in all participants. Results: No significant differences were observed for the VDR FokI, VDR Tru9I, VDR TaqI, PTH DraII, INSR NsiI, and INSR PmlI gene polymorphisms between the women with PCOS and controls. However, after adjustment for confounding factors, the VDR BsmI “Bb” genotype and the VDR ApaI "Aa" genotype were significantly under transmitted to the patients (p= 0.016; OR= 0.250; 95% CI= 0.081-0.769, and p= 0.017; OR= 0.260; 95% CI= 0.086-0.788, respectively). Furthermore, in the women with PCOS, insulin levels were lower in the participants with the INSR NsiI "NN" genotype compared with those with the "Nn + nn" genotypes (P= 0.045). Conclusion: The results showed an association between the VDR gene BsmI and ApaI polymorphisms and PCOS risk. These data also indicated that the INSR "NN" genotype was a marker of decreased insulin in women with PCOS. Our findings, however, do not lend support to the hypothesis that PTH gene DraII variant plays a role in susceptibility to PCOS. PMID:27141540

  6. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    Directory of Open Access Journals (Sweden)

    Touraj Mahmoudi

    2015-12-01

    Full Text Available Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS, and therefore vitamin D receptor (VDR, parathyroid hormone (PTH, and insulin receptor (INSR gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genotyped in 35 women with PCOS and 35 controls using Polymerase chain reaction – Restriction fragment length polymorphism method. Furthermore, serum levels of glucose and insulin were measured in all participants. Results: No significant differences were observed for the VDR FokI, VDR Tru9I, VDR TaqI, PTH DraII, INSR NsiI, and INSR PmlI gene polymorphisms between the women with PCOS and controls. However, after adjustment for confounding factors, the VDR BsmI “Bb” genotype and the VDR ApaI "Aa" genotype were significantly under transmitted to the patients (p= 0.016; OR= 0.250; 95% CI= 0.081-0.769, and p= 0.017; OR= 0.260; 95% CI= 0.086-0.788, respectively. Furthermore, in the women with PCOS, insulin levels were lower in the participants with the INSR NsiI "NN" genotype compared with those with the "Nn + nn" genotypes (P= 0.045. Conclusion: The results showed an association between the VDR gene BsmI and ApaI polymorphisms and PCOS risk. These data also indicated that the INSR "NN" genotype was a marker of decreased insulin in women with PCOS. Our findings, however, do not lend support to the hypothesis that PTH gene DraII variant plays a role in susceptibility to PCOS.

  7. Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants

    DEFF Research Database (Denmark)

    Shi, Min; Christensen, Kaare; Weinberg, Clarice R;

    2007-01-01

    , with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples...... fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish...

  8. Variants of MicroRNA Genes: Gender-Specific Associations with Multiple Sclerosis Risk and Severity

    OpenAIRE

    Ivan Kiselev; Vitalina Bashinskaya; Olga Kulakova; Natalia Baulina; Ekaterina Popova; Alexey Boyko; Olga Favorova

    2015-01-01

    Multiple sclerosis (MS) is an autoimmune neuro-inflammatory disease arising from complex interactions of genetic, epigenetic, and environmental factors. Variations in genes of some microRNAs—key post-transcriptional regulators of many genes—can influence microRNAs expression/function and contribute to MS via expression changes of protein-coding target mRNA genes. We performed an association study of polymorphous variants of MIR146A rs2910164, MIR196A2 rs11614913, MIR499A rs3746444 MIR223 rs10...

  9. The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura

    Directory of Open Access Journals (Sweden)

    Sundholm James

    2004-02-01

    Full Text Available Abstract Background The C677T variant in the methylenetetrahydrofolate reductase (MTHFR gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Migraine, with and without aura (MA and MO, is a prevalent and complex neurovascular disorder that may also be affected by genetically influenced hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene is associated with migraine susceptibility we utilised unrelated and family-based case-control study designs. Methods A total of 652 Caucasian migraine cases were investigated in this study. The MTHFR C677T variant was genotyped in 270 unrelated migraine cases and 270 controls as well as 382 affected subjects from 92 multiplex pedigrees. Results In the unrelated case-control sample we observed an over-representation of the 677T allele in migraine patients compared to controls, specifically for the MA subtype (40% vs. 33% (χ2 = 5.70, P = 0.017. The Armitage test for trend indicated a significant dosage effect of the risk allele (T for MA (χ2 = 5.72, P = 0.017. This linear trend was also present in the independent family-based sample (χ2 = 4.25, Padjusted = 0.039. Overall, our results indicate that the T/T genotype confers a modest, yet significant, increase in risk for the MA subtype (odds ratio: 2.0 – 2.5. No increased risk for the MO subtype was observed (P > 0.05. Conclusions In Caucasians, the C677T variant in the MTHFR gene influences susceptibility to MA, but not MO. Investigation into the enzyme activity of MTHFR and the role of homocysteine in the pathophysiology of migraine is warranted.

  10. Absence of kl-vs Variant of Klotho Gene in Iranian Cardiac Patients (Comparison to the World Populations)

    OpenAIRE

    Javad Tavakkoly-Bazzaz; Ozra Tabatabaei-Malazy; Mohammad Tajmir-Riahi; Daryoosh Javidi; Manizhe Izadi; Maryam Shahrabi-Farahani; Parvin Amiri; Amoli, Mahsa M.

    2011-01-01

    Objective: Klotho has an important role in development of coronary artery (CAD) disease. A functional variant of klotho gene (kl-vs) has been found as an independent risk factor for early-onset occult coronary artery disease (CAD) in previous studies. The Frequency of this variant was not known in Iranian population. We have examined the allele frequency of the kl-vs variant in a case-control study in an Iranian population. Methods and results: Genotyping for kl-vs variant was carried out in ...

  11. The spread of alphabetical writing may have favored the latest variant of the ASPM gene.

    Science.gov (United States)

    Frost, Peter

    2008-01-01

    ASPM, a gene that regulates brain growth, has evolved considerably in the primate lineage that leads to humans. It continued to evolve even after the emergence of modern humans, with the latest ASPM variant arising about 6000 years ago somewhere in the Middle East. The new variant then proliferated within and outside this region, reaching higher incidences in the Middle East (37-52%) and in Europe (38-50%) than in East Asia (0-25%). Despite its apparent selective advantage, this variant does not seem to improve cognitive performance, at least not on standard IQ tests. At present, we can only say that it probably assists performance on a task that exhibited the same geographic expansion from a Middle Eastern origin roughly 6000 years ago. The closest match seems to be the invention of alphabetical writing, specifically the task of transcribing speech and copying texts into alphabetical script. Though more easily learned than ideographs, alphabetical characters place higher demands on mental processing, especially under premodern conditions (continuous text with little or no punctuation, real-time stenography, absence of automated assistance for publishing or copying, etc.). This task was largely delegated to scribes of various sorts who enjoyed privileged status and probably superior reproductive success. Such individuals may have served as vectors for spreading the new ASPM variant. PMID:17604569

  12. ANALYSIS OF POLYMORPHIC VARIANTS OF CYTOKINE GENES IN PATIENTS WITH HIV INFECTION

    Directory of Open Access Journals (Sweden)

    N. A. Sukhalentseva

    2011-01-01

    Full Text Available Abstract. A distribution mode for allelic variants of cytokine genes was evaluated in 184 patients with slow viral infections, including 97 patients with chronic herpetic infection and 87 HIV-infected patients. Using modern methods of immunogenetics, we have found that relative risks of recurrent course and poor outcome of infection are positively associated with AA promoter region genotype and AA promoter genotype of +874 A/T polymorphism in the IFNG gene. Immunogenetic factors associated with protective effect in slow virus infections, include G allele of TNFA gene (G-308A SNP, and T allele/TT genotype of promoter region in  the IFNG gene (+874 A/T SNP. (Med. Immunol., 2011, vol. 13, N 1, pp 79-82

  13. 'A variant of uncertain significance' and the proliferation of human disease gene databases

    Directory of Open Access Journals (Sweden)

    Nelson David R

    2005-03-01

    Full Text Available Abstract The rapid accumulation of mutation data has led to the creation of nearly 300 locus-specific mutation databases. These sites may contain a few dozen to almost 20,000 mutations for a given gene. Many of the mutations are uncharacterised and have no known effects on the gene product, the 'variant of uncertain significance'. Here, the statistics of mutation distribution are examined for six different gene databases: BRCA1 and BRCA2, haemoglobin-beta (HBB, HPRT1, CFTR and TP53. The percentage of all possible point mutations for a protein (the mutation space is calculated for each gene and the question 'How much mutation data is enough?' is raised.

  14. Polymorphic variants in hereditary pancreatic cancer genes are not associated with pancreatic cancer risk

    Science.gov (United States)

    McWilliams, Robert R.; Bamlet, William R.; de Andrade, Mariza; Rider, David N.; Couch, Fergus J.; Cunningham, Julie M.; Matsumoto, Martha E.; Rabé, Kari G.; Hammer, Traci J.; Petersen, Gloria M.

    2009-01-01

    Background Inherited risk of pancreatic cancer has been associated with mutations in several genes, including BRCA2, CDKN2A (p16), PRSS1, and PALB2. We hypothesized that common variants in these genes, single nucleotide polymorphisms (SNPs), may also influence risk for pancreatic cancer development. Methods A clinic based case-control study in non-Hispanic white persons compared 1,143 patients with pancreatic adenocarcinoma with 1,097 healthy controls. Twenty-eight genes directly and indirectly involved in the Fanconi/BRCA pathway (includes BRCA1, BRCA2, and PALB2) were identified and 248 tag-SNPs were selected. In addition, 11 SNPs in CDKN2A, PRSS1, and PRSS2 were selected. Association studies were performed at the gene level by principal components analysis, while recursive partitioning analysis was utilized to investigate pathway effects. At the individual SNP level, adjusted additive, dominant, and recessive models were investigated, and gene-environment interactions were also assessed. Results Gene level analyses showed no significant association of any genes with altered pancreatic cancer risk. Multiple single SNP analyses demonstrated associations, which will require replication. Exploratory pathway analyses by recursive partitioning demonstrated no association between SNPs and risk for pancreatic cancer. Conclusion In a candidate gene and pathway SNP association study analysis, common variations in the Fanconi/BRCA pathway and other candidate familial pancreatic cancer genes are not associated with risk for pancreatic cancer. PMID:19690177

  15. Analysis of IL12B gene variants in inflammatory bowel disease.

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    Jürgen Glas

    Full Text Available BACKGROUND: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD. However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed IL12B gene variants regarding association with Crohn's disease (CD and ulcerative colitis (UC. Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695. Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066 and UC (OR 1.18 [0.97-1.43], p = 0.092. CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10(-5; OR = 2.84, 95% CI 1.66-4.84, while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92. In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694 in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05 but there was no epistasis between IL23R and IL12B variants. CONCLUSIONS/SIGNIFICANCE: The IL12B SNP rs6887695

  16. 15q12 Variants, Sputum Gene Promoter Hypermethylation, and Lung Cancer Risk: A GWAS in Smokers

    Science.gov (United States)

    Leng, Shuguang; Liu, Yushi; Weissfeld, Joel L.; Thomas, Cynthia L.; Han, Younghun; Picchi, Maria A.; Edlund, Christopher K.; Willink, Randall P.; Gaither Davis, Autumn L.; Do, Kieu C.; Nukui, Tomoko; Zhang, Xiequn; Burki, Elizabeth A.; Van Den Berg, David; Romkes, Marjorie; Gauderman, W. James; Crowell, Richard E.; Tesfaigzi, Yohannes; Stidley, Christine A.; Amos, Christopher I.; Siegfried, Jill M.; Gilliland, Frank D.

    2015-01-01

    Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis. Methods: A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided. Results: Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10–8). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10–9). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin. Conclusions: A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing. PMID:25713168

  17. Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identified in Clinical Genetic Testing

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    Clare Brookes

    2015-05-01

    Full Text Available Objectives: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. This study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. Methods: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub for BRCA gene analysis. The analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. Results: In most of the variants, the analysis showed different in silico interpretations. This illustrates the interpretation challenges faced by diagnostic laboratories. Conclusion: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the BRCA genes. This discordance leads to complexities in interpreting and reporting these variants in a clinical context. The authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. As a consequence, the clinical value of some reports may be negligible.

  18. Association between variants in inflammation and cancer-associated genes and risk and survival of cholangiocarcinoma

    International Nuclear Information System (INIS)

    Genetic risk factors for cholangiocarcinoma (CCA) remain poorly understood. We assessed the effect of single-nucleotide polymorphisms (SNPs) of genes modulating inflammation or carcinogenesis on CCA risk and survival. We conducted a case-control, candidate gene association study of 370 CCA patients and 740 age-, sex-, and residential area-matched healthy controls. Eighteen functional or putatively functional SNPs in nine genes were genotyped. The log-additive genotype effects of SNPs on CCA risk and survival were determined using logistic regression and the log-rank test, respectively. Initial analysis identified significant associations between SNP rs2143417 and rs689466 in cyclooxygenase 2 (COX-2) and CCA risk, after adjusting for multiple comparisons (cutoff of P = 0.0028). However, these findings were not replicated in another independent cohort of 212 CCA cases and 424 matched controls. No significant association was found between any SNP and survival of CCA patients. Although COX-2 has been shown to contribute to cholangiocarcinogenesis, the COX-2 SNPs tested were not associated with risk of CCA. This study shows a lack of association between variants of genes related to inflammation and carcinogenesis and CCA risk and survival. Other factors than these genetic variants may play more important roles in CCA risk and survival

  19. Association between variants in inflammation and cancer-associated genes and risk and survival of cholangiocarcinoma.

    Science.gov (United States)

    Chaiteerakij, Roongruedee; Juran, Brian D; Aboelsoud, Mohammed M; Harmsen, William S; Moser, Catherine D; Giama, Nasra H; Allotey, Loretta K; Mettler, Teresa A; Baichoo, Esha; Zhang, Xiaodan; Therneau, Terry M; Lazaridis, Konstantinos N; Roberts, Lewis R

    2015-10-01

    Genetic risk factors for cholangiocarcinoma (CCA) remain poorly understood. We assessed the effect of single-nucleotide polymorphisms (SNPs) of genes modulating inflammation or carcinogenesis on CCA risk and survival. We conducted a case-control, candidate gene association study of 370 CCA patients and 740 age-, sex-, and residential area-matched healthy controls. Eighteen functional or putatively functional SNPs in nine genes were genotyped. The log-additive genotype effects of SNPs on CCA risk and survival were determined using logistic regression and the log-rank test, respectively. Initial analysis identified significant associations between SNP rs2143417 and rs689466 in cyclooxygenase 2 (COX-2) and CCA risk, after adjusting for multiple comparisons (cutoff of P = 0.0028). However, these findings were not replicated in another independent cohort of 212 CCA cases and 424 matched controls. No significant association was found between any SNP and survival of CCA patients. Although COX-2 has been shown to contribute to cholangiocarcinogenesis, the COX-2 SNPs tested were not associated with risk of CCA. This study shows a lack of association between variants of genes related to inflammation and carcinogenesis and CCA risk and survival. Other factors than these genetic variants may play more important roles in CCA risk and survival. PMID:26276523

  20. Mitochondrial DNA variants can mediate methylation status of inflammation, angiogenesis and signaling genes.

    Science.gov (United States)

    Atilano, Shari R; Malik, Deepika; Chwa, Marilyn; Cáceres-Del-Carpio, Javier; Nesburn, Anthony B; Boyer, David S; Kuppermann, Baruch D; Jazwinski, S Michal; Miceli, Michael V; Wallace, Douglas C; Udar, Nitin; Kenney, M Cristina

    2015-08-15

    Mitochondrial (mt) DNA can be classified into haplogroups representing different geographic and/or racial origins of populations. The H haplogroup is protective against age-related macular degeneration (AMD), while the J haplogroup is high risk for AMD. In the present study, we performed comparison analyses of human retinal cell cybrids, which possess identical nuclei, but mtDNA from subjects with either the H or J haplogroups, and demonstrate differences in total global methylation, and expression patterns for two genes related to acetylation and five genes related to methylation. Analyses revealed that untreated-H and -J cybrids have different expression levels for nuclear genes (CFH, EFEMP1, VEGFA and NFkB2). However, expression levels for these genes become equivalent after treatment with a methylation inhibitor, 5-aza-2'-deoxycytidine. Moreover, sequencing of the entire mtDNA suggests that differences in epigenetic status found in cybrids are likely due to single nucleotide polymorphisms (SNPs) within the haplogroup profiles rather than rare variants or private SNPs. In conclusion, our findings indicate that mtDNA variants can mediate methylation profiles and transcription for inflammation, angiogenesis and various signaling pathways, which are important in several common diseases. PMID:25964427

  1. An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning.

    Science.gov (United States)

    Sevgi, Meltem; Rigoux, Lionel; Kühn, Anne B; Mauer, Jan; Schilbach, Leonhard; Hess, Martin E; Gruendler, Theo O J; Ullsperger, Markus; Stephan, Klaas Enno; Brüning, Jens C; Tittgemeyer, Marc

    2015-09-01

    Variations in the fat mass and obesity-associated (FTO) gene are linked to obesity. However, the underlying neurobiological mechanisms by which these genetic variants influence obesity, behavior, and brain are unknown. Given that Fto regulates D2/3R signaling in mice, we tested in humans whether variants in FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling and is also associated with obesity. In a behavioral and fMRI study, we demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans. Furthermore, dynamic causal modeling confirmed that FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic predisposition alters reward processing not only in obesity, but also in other disorders with altered D2R-dependent impulse control, such as addiction. Significance statement: Variations in the fat mass and obesity-associated (FTO) gene are associated with obesity. Here we demonstrate that variants of FTO affect dopamine-dependent midbrain brain responses and learning from negative outcomes in humans during a reward learning task. Furthermore, FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic vulnerability in reward processing can increase predisposition to obesity. PMID:26354923

  2. Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients

    OpenAIRE

    Lohmann, Ebba; Guerreiro, Rita J.; Erginel-Unaltuna, Nihan; Gurunlian, Nicole; Bilgic, Basar; Gurvit, Hakan; Hanagasi, Hasmet A.; Luu, Nga; Emre, Murat; Singleton, Andrew

    2012-01-01

    In order to assess the frequency of mutations in the known Alzheimer's disease causative genes in Turkish dementia patients we screened amyloid precursor protein (APP), PSEN1 and PSEN2 for mutations in a cohort of 98 Turkish dementia families. Six families were found to carry PSEN1 mutations (p.H163R, p.P264L, and p.H214Y) or variants suggested to cause the disease (p.L134R, p.L262V, and p.A396T). In 4 other families, previously reported PSEN2 variants were identified (p.R62H, p.R71W, p.M174V...

  3. Epithelial-Mesenchymal Transition (EMT) gene variants and Epithelial Ovarian Cancer (EOC) risk

    Science.gov (United States)

    Amankwah, Ernest K.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chen, Zhihua; Chen, Y. Ann; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis N.; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Jim, Heather; Kellar, Melissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Lotte; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vierkant, Robert A.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Kelemen, Linda E.; Berchuck, Andrew; Schildkraut, Joellen M.; Ramus, Susan J.; Goode, Ellen L.; Monteiro, Alvaro N.A.; Gayther, Simon A.; Narod, Steven A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2016-01-01

    Introduction Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to EOC risk have been based on small sample sizes and none have sought replication in an independent population. Methods We screened 1254 SNPs in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (p<0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A p-value <0.05 and a false discovery rate (FDR) <0.2 was considered statistically significant. Results In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (OR=1.16, 95%CI=1.07–1.25, p=0.0003, FDR=0.19), while F8 rs7053448 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), F8 rs7058826 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), and CAPN13 rs1983383 (OR=0.79, 95%CI=0.69–0.90, p=0.0005, FDR=0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. Conclusion These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC. PMID:26399219

  4. Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes

    Science.gov (United States)

    Kranz, Thorsten M.; Berns, Adam; Shields, Jerry; Rothman, Karen; Walsh-Messinger, Julie; Goetz, Raymond R.; Chao, Moses V.; Malaspina, Dolores

    2016-01-01

    Background Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample. Method Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220 kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls. Findings Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n = 5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n = 4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n = 4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n = 5). Case vignettes are included in the appendix. Interpretation Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially

  5. Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence.

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    Andrea Vereczkei

    Full Text Available BACKGROUND: Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants. OBJECTIVE: To study the potential association between allelic variants of dopamine D2 receptor (DRD2, ANKK1 (ankyrin repeat and kinase domain containing 1, dopamine D4 receptor (DRD4, catechol-O-methyl transferase (COMT and dopamine transporter (SLC6A3 genes and heroin dependence in Hungarian patients. METHODS: 303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA. FINDINGS AND CONCLUSIONS: In single marker analysis the TaqIA (rs1800497 and TaqIB (rs1079597 variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955 of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462 of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955 polymorphism in the promoter.

  6. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    LENUS (Irish Health Repository)

    Pangilinan, Faith

    2012-08-02

    AbstractBackgroundNeural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate\\/B12 pathway genes contribute to NTD risk.MethodsA tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate\\/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.ResultsNearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.ConclusionsTo our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the

  7. Candidate gene linkage approach to identify DNA variants that predispose to preterm birth

    DEFF Research Database (Denmark)

    Bream, Elise N A; Leppellere, Cara R; Cooper, Margaret E;

    2013-01-01

    Background:The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach.Methods:We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were...... used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.Results:Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (P = 0.0012) and CYP2E1 (P = 0.0011). Analyses with the mother as the case identified four...... through the infant and/or the mother in the etiology of PTB....

  8. Molecular characterization of a genetic variant of the steroid hormone-binding globulin gene in heterozygous subjects

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, D.O.; Catterall, J.F. [Population Council, New York, NY (United States); Carino, C. [Instituto National de la Nutricion, Mexico City, MX (United States)] [and others

    1995-04-01

    Steroid hormone-binding globulin in human serum displays different isoelectric focusing (IEF) patterns among individuals, suggesting genetic variation in the gene for this extracellular steroid carrier protein. Analysis of allele frequencies and family studies suggested the existence of two codominant alleles of the gene. Subsequent determination of the molecular basis of a variant of the gene was carried out using DNA from homozygous individuals from a single Belgian family. It was of interest to characterize other variant individuals to determine whether all variants identified by IEF phenotyping were caused by the same mutation or whether other mutations occurred in the gene in different populations. Previous studies identified Mexican subjects who were heterozygous for the variant IEF phenotype. Denaturing gradient gel electrophoresis was used to localize the mutation in these subjects and to purify the variant allele for DNA sequence analysis. The results show that the mutation in this population is identical to that identified in the Belgian family, and no other mutations were detected in the gene. These data represent the first analysis of steroid hormone-binding globulin gene variation in heterozygous subjects and further support the conclusion of biallelism of the gene worldwide. 11 refs., 2 figs., 1 tab.

  9. ALDH1A Isozymes Are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets

    OpenAIRE

    Luo, Yuchun; Dallaglio, Katiuscia; Chen, Ying; Robinson, William A.; Robinson, Steven E.; McCarter, Martin D; Wang, Jianbin; Gonzalez, Rene; Thompson, David C.; David A Norris; Roop, Dennis R.; Vasiliou, Vasilis; Fujita, Mayumi

    2012-01-01

    Although the concept of cancer stem cells (CSCs) is well accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In the present study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into NOD/SCID mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-posi...

  10. Association study of functional genetic variants of innate immunity related genes in celiac disease

    Directory of Open Access Journals (Sweden)

    Martín J

    2005-08-01

    Full Text Available Abstract Background Recent evidence suggest that the innate immune system is implicated in the early events of celiac disease (CD pathogenesis. In this work for the first time we have assessed the relevance of different proinflammatory mediators typically related to innate immunity in CD predisposition. Methods We performed a familial study in which 105 celiac families characterized by the presence of an affected child with CD were genotyped for functional polymorphisms located at regulatory regions of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes. Familial data was analysed with a transmission disequilibrium test (TDT that revealed no statistically significant differences in the transmission pattern of the different genetic markers considered. Results The TDT analysis for IL-1α, IL-1β, IL-1RN, IL-18, and MCP-1 genes genetic variants did not reveal biased transmission to the affected offspring. Only a borderline association of RANTES promoter genetic variants with CD predisposition was observed. Conclusion Our results suggest that the analysed polymorphisms of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes do not seem to play a major role in CD genetic predisposition in our population.

  11. Variants in the dopamine-4-receptor gene promoter are not associated with sensation seeking in skiers.

    Directory of Open Access Journals (Sweden)

    Cynthia J Thomson

    Full Text Available Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4 influenced sport-specific sensation seeking, we analyzed five polymorphisms (-1106T/C, -906T/C, -809G/A, -291C/T, 120-bp duplication in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599 that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing sensation seeking between groups. There were no significant associations between genotype(s and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

  12. Haplotype analysis of common variants in the BRCA1 gene and risk of sporadic breast cancer

    International Nuclear Information System (INIS)

    Truncation mutations in the BRCA1 gene cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population and account for little of the overall incidence of sporadic breast cancer. We used whole-gene resequencing data to select haplotype tagging single nucleotide polymorphisms, and examined the association between common haplotypes of BRCA1 and breast cancer in a nested case-control study in the Nurses' Health Study (1323 cases and 1910 controls). One haplotype was associated with a slight increase in risk (odds ratio 1.18, 95% confidence interval 1.02–1.37). A significant interaction (P = 0.05) was seen between this haplotype, positive family history of breast cancer, and breast cancer risk. Although not statistically significant, similar interactions were observed with age at diagnosis and with menopausal status at diagnosis; risk tended to be higher among younger, pre-menopausal women. We have described a haplotype in the BRCA1 gene that was associated with an approximately 20% increase in risk of sporadic breast cancer in the general population. However, the functional variant(s) responsible for the association are unclear

  13. Analysis of rare variants in the C3 gene in patients with age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Maheswara R Duvvari

    Full Text Available Age-related macular degeneration (AMD is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3 gene have been associated with AMD and recently a rare C3 variant (Lys155Gln was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS, we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P=0.04, Arg735Trp (OR=17.4, 95% CI=2.2-136; P=0.0003, and Ser1619Arg (OR=5.2, 95% CI=1.0-25; P=0.05 at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.

  14. Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice.

    Science.gov (United States)

    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2013-09-15

    Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1-6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females. PMID:23810710

  15. Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function

    Energy Technology Data Exchange (ETDEWEB)

    Xi, T; Jones, I M; Mohrenweiser, H W

    2003-11-03

    Over 520 different amino acid substitution variants have been previously identified in the systematic screening of 91 human DNA repair genes for sequence variation. Two algorithms were employed to predict the impact of these amino acid substitutions on protein activity. Sorting Intolerant From Tolerant (SIFT) classified 226 of 508 variants (44%) as ''Intolerant''. Polymorphism Phenotyping (PolyPhen) classed 165 of 489 amino acid substitutions (34%) as ''Probably or Possibly Damaging''. Another 9-15% of the variants were classed as ''Potentially Intolerant or Damaging''. The results from the two algorithms are highly associated, with concordance in predicted impact observed for {approx}62% of the variants. Twenty one to thirty one percent of the variant proteins are predicted to exhibit reduced activity by both algorithms. These variants occur at slightly lower individual allele frequency than do the variants classified as ''Tolerant'' or ''Benign''. Both algorithms correctly predicted the impact of 26 functionally characterized amino acid substitutions in the APE1 protein on biochemical activity, with one exception. It is concluded that a substantial fraction of the missense variants observed in the general human population are functionally relevant. These variants are expected to be the molecular genetic and biochemical basis for the associations of reduced DNA repair capacity phenotypes with elevated cancer risk.

  16. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    Directory of Open Access Journals (Sweden)

    Pangilinan Faith

    2012-08-01

    Full Text Available Abstract Background Neural tube defects (NTDs are common birth defects (~1 in 1000 pregnancies in the US and Europe that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T and MTHFD1 rs2236225 (R653Q have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk. Methods A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents, including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. Results Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury and included the known NTD risk factor MTHFD1 R653Q (rs2236225. The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele. Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. Conclusions To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive

  17. Common variants of the vitamin D binding protein gene and adverse health outcomes

    OpenAIRE

    Malik, Suneil; Fu, Lei; Juras, David James; Karmali, Mohamed; Wong, Betty Y. L.; Gozdzik, Agnes; Cole, David E.C.

    2013-01-01

    The vitamin D binding protein (DBP) is the major plasma carrier for vitamin D and its metabolites, but it is also an actin scavenger, and is the precursor to the immunomodulatory protein, Gc-MAF. Two missense variants of the DBP gene – rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys – change the amino acid sequence and alter the protein function. They are common enough to generate population-wide constitutive differences in vitamin D status, based on assay of the serum metabolite, 25-...

  18. BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

    Science.gov (United States)

    Karamohamed, S; Latourelle, J C; Racette, B A; Perlmutter, J S; Wooten, G F; Lew, M; Klein, C; Shill, H; Golbe, L I; Mark, M H; Guttman, M; Nicholson, G; Wilk, J B; Saint-Hilaire, M; DeStefano, A L; Prakash, R; Tobin, S; Williamson, J; Suchowersky, O; Labell, N; Growdon, B N J; Singer, C; Watts, R; Goldwurm, S; Pezzoli, G; Baker, K B; Giroux, M L; Pramstaller, P P; Burn, D J; Chinnery, P; Sherman, S; Vieregge, P; Litvan, I; Gusella, J F; Myers, R H; Parsian, A

    2005-12-13

    Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age. PMID:16344533

  19. Nucleolin is required for DNA methylation state and the expression of rRNA gene variants in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Frédéric Pontvianne

    2010-11-01

    Full Text Available In eukaryotes, 45S rRNA genes are arranged in tandem arrays in copy numbers ranging from several hundred to several thousand in plants. Although it is clear that not all copies are transcribed under normal growth conditions, the molecular basis controlling the expression of specific sets of rRNA genes remains unclear. Here, we report four major rRNA gene variants in Arabidopsis thaliana. Interestingly, while transcription of one of these rRNA variants is induced, the others are either repressed or remain unaltered in A. thaliana plants with a disrupted nucleolin-like protein gene (Atnuc-L1. Remarkably, the most highly represented rRNA gene variant, which is inactive in WT plants, is reactivated in Atnuc-L1 mutants. We show that accumulated pre-rRNAs originate from RNA Pol I transcription and are processed accurately. Moreover, we show that disruption of the AtNUC-L1 gene induces loss of symmetrical DNA methylation without affecting histone epigenetic marks at rRNA genes. Collectively, these data reveal a novel mechanism for rRNA gene transcriptional regulation in which the nucleolin protein plays a major role in controlling active and repressed rRNA gene variants in Arabidopsis.

  20. Rare Variants in the TREX1 Gene and Susceptibility to Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Nadia Barizzone

    2013-01-01

    Full Text Available TREX1 (DNase III is an exonuclease involved in response to oxidative stress and apoptosis. Heterozygous mutations in TREX1 were previously observed in patients with systemic lupus erythematosus (SLE and Sjögren's syndrome (SS. We performed a mutational analysis of the TREX1 gene on three autoimmune diseases: SLE (210 patients and SS (58 patients, to confirm a TREX1 involvement in the Italian population, and systemic sclerosis (SSc, 150 patients because it shares similarities with SLE (presence of antinuclear antibodies and connective tissue damage. We observed 7 variations; two of these are novel nonsynonymous variants (p.Glu198Lys and p.Met232Val. They were detected in one SS and in one SSc patient, respectively, and in none of the 200 healthy controls typed in this study and of the 1712 published controls. In silico analysis predicts a possibly damaging role on protein function for both variants. The other 5 variations are synonymous and only one of them is novel (p.Pro48Pro. This study contributes to the demonstration that TREX1 is involved in autoimmune diseases and proposes that the spectrum of involved autoimmune diseases can be broader and includes SSc. We do not confirm a role of TREX1 variants in SLE.

  1. Rare variants in the TREX1 gene and susceptibility to autoimmune diseases.

    Science.gov (United States)

    Barizzone, Nadia; Monti, Sara; Mellone, Simona; Godi, Michela; Marchini, Maurizio; Scorza, Raffaella; Danieli, Maria G; D'Alfonso, Sandra

    2013-01-01

    TREX1 (DNase III) is an exonuclease involved in response to oxidative stress and apoptosis. Heterozygous mutations in TREX1 were previously observed in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). We performed a mutational analysis of the TREX1 gene on three autoimmune diseases: SLE (210 patients) and SS (58 patients), to confirm a TREX1 involvement in the Italian population, and systemic sclerosis (SSc, 150 patients) because it shares similarities with SLE (presence of antinuclear antibodies and connective tissue damage). We observed 7 variations; two of these are novel nonsynonymous variants (p.Glu198Lys and p.Met232Val). They were detected in one SS and in one SSc patient, respectively, and in none of the 200 healthy controls typed in this study and of the 1712 published controls. In silico analysis predicts a possibly damaging role on protein function for both variants. The other 5 variations are synonymous and only one of them is novel (p.Pro48Pro). This study contributes to the demonstration that TREX1 is involved in autoimmune diseases and proposes that the spectrum of involved autoimmune diseases can be broader and includes SSc. We do not confirm a role of TREX1 variants in SLE. PMID:24224166

  2. An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity.

    Directory of Open Access Journals (Sweden)

    Peter Kuehnen

    Full Text Available The individual risk for common diseases not only depends on genetic but also on epigenetic polymorphisms. To assess the role of epigenetic variations in the individual risk for obesity, we have determined the methylation status of two CpG islands at the POMC locus in obese and normal-weight children. We found a hypermethylation variant targeting individual CpGs at the intron 2-exon 3 boundary of the POMC gene by bisulphite sequencing that was significantly associated with obesity. POMC exon 3 hypermethylation interferes with binding of the transcription enhancer P300 and reduces expression of the POMC transcript. Since intron 2 contains Alu elements that are known to influence methylation in their genomic vicinity, the exon 3 methylation variant seems to result from an Alu element-triggered default state of methylation boundary definition. Exon 3 hypermethylation in the POMC locus represents the first identified DNA methylation variant that is associated with the individual risk for obesity.

  3. Isolation and characterization of novel RECK tumor suppressor gene splice variants

    Science.gov (United States)

    Trombetta-Lima, Marina; Winnischofer, Sheila Maria Brochado; Demasi, Marcos Angelo Almeida; Filho, Renato Astorino; Carreira, Ana Claudia Oliveira; Wei, Beiyang; de Assis Ribas, Thais; Konig, Michelle Silberspitz; Bowman-Colin, Christian; Oba-Shinjo, Sueli Mieko; Marie, Suely Kazue Nagahashi; Stetler-Stevenson, William; Sogayar, Mari Cleide

    2015-01-01

    Glioblastoma multiforme is the most common and lethal of the central nervous system glial-derived tumors. RECK suppresses tumor invasion by negatively regulating at least three members of the matrix metalloproteinase family: MMP-9, MMP-2, and MT1-MMP. A positive correlation has been observed between the abundance of RECK expression in tumor samples and a more favorable prognosis for patients with several types of tumors. In the present study, novel alternatively spliced variants of the RECK gene: RECK-B and RECK-I were isolated by RT-PCR and sequenced. The expression levels and profiles of these alternative RECK transcripts, as well as canonical RECK were determined in tissue samples of malignant astrocytomas of different grades and in a normal tissue RNA panel by qRT-PCR. Our results show that higher canonical RECK expression, accompanied by a higher canonical to alternative transcript expression ratio, positively correlates with higher overall survival rate after chemotherapeutic treatment of GBM patients. U87MG and T98G cells over-expressing the RECK-B alternative variant display higher anchorage-independent clonal growth and do not display modulation of, respectively, MMP-2 and MMP-9 expression. Our findings suggest that RECK transcript variants might have opposite roles in GBM biology and the ratio of their expression levels may be informative for the prognostic outcome of GBM patients. PMID:26431549

  4. ARNTL (BMAL1 and NPAS2 gene variants contribute to fertility and seasonality.

    Directory of Open Access Journals (Sweden)

    Leena Kovanen

    Full Text Available BACKGROUND: Circadian clocks guide the metabolic, cell-division, sleep-wake, circadian and seasonal cycles. Abnormalities in these clocks may be a health hazard. Circadian clock gene polymorphisms have been linked to sleep, mood and metabolic disorders. Our study aimed to examine polymorphisms in four key circadian clock genes in relation to seasonal variation, reproduction and well-being in a sample that was representative of the general population, aged 30 and over, living in Finland. METHODOLOGY/PRINCIPAL FINDINGS: Single-nucleotide polymorphisms in the ARNTL, ARNTL2, CLOCK and NPAS2 genes were genotyped in 511 individuals. 19 variants were analyzed in relation to 31 phenotypes that were assessed in a health interview and examination study. With respect to reproduction, women with ARNTL rs2278749 TT genotype had more miscarriages and pregnancies, while NPAS2 rs11673746 T carriers had fewer miscarriages. NPAS2 rs2305160 A allele carriers had lower Global Seasonality Scores, a sum score of six items i.e. seasonal variation of sleep length, social activity, mood, weight, appetite and energy level. Furthermore, carriers of A allele at NPAS2 rs6725296 had greater loadings on the metabolic factor (weight and appetite of the global seasonality score, whereas individuals with ARNTL rs6290035 TT genotype experienced less seasonal variation of energy level. CONCLUSIONS/SIGNIFICANCE: ARNTL and NPAS2 gene variants were associated with reproduction and with seasonal variation. Earlier findings have linked ARNTL to infertility in mice, but this is the first time when any polymorphism of these genes is linked to fertility in humans.

  5. Catecholaminergic Gene Variants: Contribution in ADHD and Associated Comorbid Attributes in the Eastern Indian Probands

    Directory of Open Access Journals (Sweden)

    Paramita Ghosh

    2013-01-01

    Full Text Available Contribution of genes in attention deficit hyperactivity disorder (ADHD has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273, DRD2 (rs1800496, rs1801028, and rs1799732, DRD4 (rs4646984 and rs4646983, and COMT (rs165599 and rs740603 in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N=170, their parents (N=310, and ethnically matched controls (n=180 was used for genotyping followed by population- and family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by case-control analysis, while DDC and COMT exhibited bias in familial transmission (P<0.05. rs3837091 “AGAG,” rs3735273 “A,” rs1799732 “C,” rs740603 “G,” rs165599 “G” and single repeat alleles of rs4646984/rs4646983 showed positive correlation with co-morbid characteristics (P<0.05. Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P<0.001, while family-based data showed interaction between DDC and DRD2 (P=0.04. This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD.

  6. Aldehyde Dehydrogenase Gene Superfamily in Populus: Organization and Expression Divergence between Paralogous Gene Pairs.

    Directory of Open Access Journals (Sweden)

    Feng-Xia Tian

    Full Text Available Aldehyde dehydrogenases (ALDHs constitute a superfamily of NAD(P+-dependent enzymes that catalyze the irreversible oxidation of a wide range of reactive aldehydes to their corresponding nontoxic carboxylic acids. ALDHs have been studied in many organisms from bacteria to mammals; however, no systematic analyses incorporating genome organization, gene structure, expression profiles, and cis-acting elements have been conducted in the model tree species Populus trichocarpa thus far. In this study, a comprehensive analysis of the Populus ALDH gene superfamily was performed. A total of 26 Populus ALDH genes were found to be distributed across 12 chromosomes. Genomic organization analysis indicated that purifying selection may have played a pivotal role in the retention and maintenance of PtALDH gene families. The exon-intron organizations of PtALDHs were highly conserved within the same family, suggesting that the members of the same family also may have conserved functionalities. Microarray data and qRT-PCR analysis indicated that most PtALDHs had distinct tissue-specific expression patterns. The specificity of cis-acting elements in the promoter regions of the PtALDHs and the divergence of expression patterns between nine paralogous PtALDH gene pairs suggested that gene duplications may have freed the duplicate genes from the functional constraints. The expression levels of some ALDHs were up- or down-regulated by various abiotic stresses, implying that the products of these genes may be involved in the adaptation of Populus to abiotic stresses. Overall, the data obtained from our investigation contribute to a better understanding of the complexity of the Populus ALDH gene superfamily and provide insights into the function and evolution of ALDH gene families in vascular plants.

  7. Association of dopamine transporter gene variants with childhood ADHD features in bipolar disorder.

    Science.gov (United States)

    Greenwood, Tiffany A; Joo, Eun-Jeong; Shekhtman, Tatyana; Sadovnick, A Dessa; Remick, Ronald A; Keck, Paul E; McElroy, Susan L; Kelsoe, John R

    2013-03-01

    Bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) exhibit remarkably high rates of comorbidity, as well as patterns of familial co-segregation. Epidemiological data suggests that these disorders either share a common genetic architecture or that ADHD features in BD may represent an etiologically distinct subtype. We previously used the Wender Utah Rating Scale (WURS) to assess ADHD features in BD families and identified three heritable factors relating to impulsivity, mood instability, and inattention. Linkage analysis revealed a LOD score of 1.33 for the inattention factor on 5p15.3 near the dopamine transporter gene (DAT1), which has been associated with both BD and ADHD. Pharmacological evidence also suggests a role for DAT in both disorders. We have now evaluated the association of ten DAT1 variants for the WURS total score and factors in an overlapping sample of 87 BD families. Significant associations for three SNPs were observed across the WURS measures, notably for a SNP in intron 8 with the WURS total score (P = 0.007) and for variants in introns 9 and 13 with mood instability (P = 0.009 and 0.004, respectively). Analysis of an independent sample of 52 BD cases and 46 healthy controls further supported association of the intron 8 variant with mood instability (P = 0.005), and a combined analysis confirmed the associations of this SNP with WURS total score. Impulsivity and mood instability (P = 0.002, 0.007, and 8 × 10(-4), respectively). These data suggest that variants within DAT1 may predispose to a subtype of BD characterized by early prodromal features that include attentional deficits. PMID:23255304

  8. Adiponectin Gene Variants are Associated with Insulin Sensitivity in Response to Dietary Fat Consumption in Caucasian Men

    Science.gov (United States)

    Adiponectin (adipoQ) gene variants have been associated with type 2 diabetes mellitus and insulin resistance. Our aim was to examine whether the presence of several polymorphisms at the adipoQ gene locus (211391 G . A, 211377C.G, 45 T.G, and 276 G.T) influences the insulin sensitivity to dietary fat...

  9. Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival.

    Science.gov (United States)

    Yadav, Anu; Gupta, Annapurna; Rastogi, Neeraj; Agrawal, Sushma; Kumar, Ashok; Kumar, Vijay; Mittal, Balraj

    2016-02-01

    Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM Ars1157Crs10511244 (P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response. PMID:26318430

  10. Circadian gene variants and susceptibility to type 2 diabetes: a pilot study.

    Directory of Open Access Journals (Sweden)

    M Ann Kelly

    Full Text Available BACKGROUND: Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. METHODOLOGY/PRINCIPAL FINDINGS: The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732 and without (N = 1780 type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium and white European cohorts (DIAGRAM+ using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 × 10(-5, while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003. Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively. CONCLUSIONS/SIGNIFICANCE: None of the selected circadian gene variants was associated with type

  11. Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways.

    Science.gov (United States)

    Howe, A S; Buttenschøn, H N; Bani-Fatemi, A; Maron, E; Otowa, T; Erhardt, A; Binder, E B; Gregersen, N O; Mors, O; Woldbye, D P; Domschke, K; Reif, A; Shlik, J; Kõks, S; Kawamura, Y; Miyashita, A; Kuwano, R; Tokunaga, K; Tanii, H; Smoller, J W; Sasaki, T; Koszycki, D; De Luca, V

    2016-05-01

    The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10(-6)), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10(-5)) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must

  12. Transcriptional regulation of the human ALDH1A1 promoter by the oncogenic homeoprotein TLX1/HOX11

    Directory of Open Access Journals (Sweden)

    Kim Rice

    2009-08-01

    Full Text Available The homeoprotein TLX1, which is essential to spleen organogenesis and oncogenic when aberrantly expressed in immature T cells, functions as a bifunctional transcriptional regulator, being capable of activation or repression depending on cell type and/or promoter context. However, the detailed mechanisms by which it regulates the transcription of target genes such as ALDH1A1 remains to be elucidated. We therefore functionally assessed the ability of TLX1 to regulate ALDH1A1 expression in two hematopoietic cell lines, PER-117 T-leukemic cells and human erythroleukemic (HEL cells, by use of luciferase reporter and mobility shift assays. We showed that TLX1 physically interacts with the general transcription factor TFIIB via its homeodomain, and identified two activities in respect to TLX1-mediated regulation of the CCAAT box-containing ALDH1A1 promoter. The first involved CCAAT-dependent transcriptional repression via perturbation of GATA factor-containing protein complexes assembled at a non-canonical TATA (GATA box. A structurally intact homeodomain was essential for repression by TLX1 although direct DNA binding was not required. The second activity, which involved CCAAT-independent transcriptional activation did not require an intact homeodomain, indicating that the activation and repression functions of TLX1 are distinct. These findings confirm ALDH1A1 gene regulation by TLX1 and support an indirect model for TLX1 function, in which protein-protein interactions, rather than DNA binding at specific sites, are crucial for its transcriptional activity.

  13. Identification of Genome-Wide Variants and Discovery of Variants Associated with Brassica rapa Clubroot Resistance Gene Rcr1 through Bulked Segregant RNA Sequencing.

    Science.gov (United States)

    Yu, Fengqun; Zhang, Xingguo; Huang, Zhen; Chu, Mingguang; Song, Tao; Falk, Kevin C; Deora, Abhinandan; Chen, Qilin; Zhang, Yan; McGregor, Linda; Gossen, Bruce D; McDonald, Mary Ruth; Peng, Gary

    2016-01-01

    Clubroot, caused by Plasmodiophora brassicae, is an important disease on Brassica species worldwide. A clubroot resistance gene, Rcr1, with efficacy against pathotype 3 of P. brassicae, was previously mapped to chromosome A03 of B. rapa in pak choy cultivar "Flower Nabana". In the current study, resistance to pathotypes 2, 5 and 6 was shown to be associated with Rcr1 region on chromosome A03. Bulked segregant RNA sequencing was performed and short read sequences were assembled into 10 chromosomes of the B. rapa reference genome v1.5. For the resistant (R) bulks, a total of 351.8 million (M) sequences, 30,836.5 million bases (Mb) in length, produced 120-fold coverage of the reference genome. For the susceptible (S) bulks, 322.9 M sequences, 28,216.6 Mb in length, produced 109-fold coverage. In total, 776.2 K single nucleotide polymorphisms (SNPs) and 122.2 K insertion / deletion (InDels) in R bulks and 762.8 K SNPs and 118.7 K InDels in S bulks were identified; each chromosome had about 87% SNPs and 13% InDels, with 78% monomorphic and 22% polymorphic variants between the R and S bulks. Polymorphic variants on each chromosome were usually below 23%, but made up 34% of the variants on chromosome A03. There were 35 genes annotated in the Rcr1 target region and variants were identified in 21 genes. The numbers of poly variants differed significantly among the genes. Four out of them encode Toll-Interleukin-1 receptor / nucleotide-binding site / leucine-rich-repeat proteins; Bra019409 and Bra019410 harbored the higher numbers of polymorphic variants, which indicates that they are more likely candidates of Rcr1. Fourteen SNP markers in the target region were genotyped using the Kompetitive Allele Specific PCR method and were confirmed to associate with Rcr1. Selected SNP markers were analyzed with 26 recombinants obtained from a segregating population consisting of 1587 plants, indicating that they were completely linked to Rcr1. Nine SNP markers were used for marker

  14. Identification of Genome-Wide Variants and Discovery of Variants Associated with Brassica rapa Clubroot Resistance Gene Rcr1 through Bulked Segregant RNA Sequencing

    Science.gov (United States)

    Yu, Fengqun; Zhang, Xingguo; Huang, Zhen; Chu, Mingguang; Song, Tao; Falk, Kevin C.; Deora, Abhinandan; Chen, Qilin; Zhang, Yan; McGregor, Linda; Gossen, Bruce D.; McDonald, Mary Ruth; Peng, Gary

    2016-01-01

    Clubroot, caused by Plasmodiophora brassicae, is an important disease on Brassica species worldwide. A clubroot resistance gene, Rcr1, with efficacy against pathotype 3 of P. brassicae, was previously mapped to chromosome A03 of B. rapa in pak choy cultivar “Flower Nabana”. In the current study, resistance to pathotypes 2, 5 and 6 was shown to be associated with Rcr1 region on chromosome A03. Bulked segregant RNA sequencing was performed and short read sequences were assembled into 10 chromosomes of the B. rapa reference genome v1.5. For the resistant (R) bulks, a total of 351.8 million (M) sequences, 30,836.5 million bases (Mb) in length, produced 120-fold coverage of the reference genome. For the susceptible (S) bulks, 322.9 M sequences, 28,216.6 Mb in length, produced 109-fold coverage. In total, 776.2 K single nucleotide polymorphisms (SNPs) and 122.2 K insertion / deletion (InDels) in R bulks and 762.8 K SNPs and 118.7 K InDels in S bulks were identified; each chromosome had about 87% SNPs and 13% InDels, with 78% monomorphic and 22% polymorphic variants between the R and S bulks. Polymorphic variants on each chromosome were usually below 23%, but made up 34% of the variants on chromosome A03. There were 35 genes annotated in the Rcr1 target region and variants were identified in 21 genes. The numbers of poly variants differed significantly among the genes. Four out of them encode Toll-Interleukin-1 receptor / nucleotide-binding site / leucine-rich-repeat proteins; Bra019409 and Bra019410 harbored the higher numbers of polymorphic variants, which indicates that they are more likely candidates of Rcr1. Fourteen SNP markers in the target region were genotyped using the Kompetitive Allele Specific PCR method and were confirmed to associate with Rcr1. Selected SNP markers were analyzed with 26 recombinants obtained from a segregating population consisting of 1587 plants, indicating that they were completely linked to Rcr1. Nine SNP markers were used for marker

  15. iFish: predicting the pathogenicity of human nonsynonymous variants using gene-specific/family-specific attributes and classifiers.

    Science.gov (United States)

    Wang, Meng; Wei, Liping

    2016-01-01

    Accurate prediction of the pathogenicity of genomic variants, especially nonsynonymous single nucleotide variants (nsSNVs), is essential in biomedical research and clinical genetics. Most current prediction methods build a generic classifier for all genes. However, different genes and gene families have different features. We investigated whether gene-specific and family-specific customized classifiers could improve prediction accuracy. Customized gene-specific and family-specific attributes were selected with AIC, BIC, and LASSO, and Support Vector Machine classifiers were generated for 254 genes and 152 gene families, covering a total of 5,985 genes. Our results showed that the customized attributes reflected key features of the genes and gene families, and the customized classifiers achieved higher prediction accuracy than the generic classifier. The customized classifiers and the generic classifier for other genes and families were integrated into a new tool named iFish (integrated Functional inference of SNVs in human, http://ifish.cbi.pku.edu.cn). iFish outperformed other methods on benchmark datasets as well as on prioritization of candidate causal variants from whole exome sequencing. iFish provides a user-friendly web-based interface and supports other functionalities such as integration of genetic evidence. iFish would facilitate high-throughput evaluation and prioritization of nsSNVs in human genetics research. PMID:27527004

  16. Identification of a splice-site mutation in the human growth hormone-variant gene.

    OpenAIRE

    MacLeod, J.N.; Liebhaber, S A; MacGillivray, M H; Cooke, N E

    1991-01-01

    The human growth-hormone-variant (hGH-V) gene normally expresses two alternatively spliced forms of mRNA--hGH-V and hGH-V2--in the placenta. hGH-V2 mRNA differs from hGH-V rDNA by the retention of intron 4 and represents approximately 15% of transcripts at term. In a survey of hGH-V gene expression in 20 placentas of gestational age 8-40 wk, we detected a single placenta that contained, in addition to the two normal hGH-V mRNA species, a set of two slightly larger hGH-V mRNAs. Sequence analys...

  17. Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays

    DEFF Research Database (Denmark)

    Heinen, Christopher D; Juel Rasmussen, Lene

    2012-01-01

    provided an important experimental tool for studying the functional consequences of VUS. However, beyond this repair assay, a number of other experimental methods have been developed that allow us to test the effect of a VUS on discrete biochemical steps or other aspects of MMR function. Here, we describe......ABSTRACT: With the discovery that the hereditary cancer susceptibility disease Lynch syndrome (LS) is caused by deleterious germline mutations in the DNA mismatch repair (MMR) genes nearly 20 years ago, genetic testing can now be used to diagnose this disorder in patients. A definitive diagnosis of...... LS can direct how clinicians manage the disease as well as prevent future cancers for the patient and their families. A challenge emerges, however, when a germline missense variant is identified in a MMR gene in a suspected LS patient. The significance of a single amino acid change in these large...

  18. Expression of Tetrahymena snRNA gene variants including a U1 gene with mutations in the 5' splice site recognition sequence

    DEFF Research Database (Denmark)

    Eugen-Olsen, J; Hagemeister, J J; Hellung-Larsen, P

    1997-01-01

    The expression of U1, U2 and U5 snRNA gene variants has been studied under different physiological states of Tetrahymena. Variants of all three snRNA genes are expressed. Among the snRNAs detected is U1-3, a variant with 66 mutations compared to the normal U1 snRNA. Three of these mutations affec...... the 5' splice site recognition sequence. The U1-3 snRNA is present in a few hundred copies per cell. The expression of Tetrahymena snRNA genes is independent of the physiological state of the cell.......The expression of U1, U2 and U5 snRNA gene variants has been studied under different physiological states of Tetrahymena. Variants of all three snRNA genes are expressed. Among the snRNAs detected is U1-3, a variant with 66 mutations compared to the normal U1 snRNA. Three of these mutations affect...

  19. Functional variants of ERAP1 gene are associated with HLA-B27 positive spondyloarthritis.

    Science.gov (United States)

    Cherciu, M; Popa, L O; Bojinca, M; Dutescu, M I; Bojinca, V; Bara, C; Popa, O M

    2013-09-01

    We investigated two nonsynonymous variants (rs30187 and rs27044) of ERAP1 gene in HLA-B27 positive individuals (150 spondyloarthritis and 108 controls) and in general ankylosing spondylitis (AS) patients (n = 137) vs random controls (n = 139). Both single nucleotide polymorphisms (SNPs) were associated with the risk of spondyloarthritis [odds ratio (OR) 1.80, 95% confidence interval (CI) 1.24-2.62, P = 0.001 for rs30187, OR 1.58, 95% CI 1.07-2.34, P = 0.02 for rs27044]. The CC haplotype was a protective factor (P = 0.002), while the TG haplotype was a risk factor (P = 0.01) for spondyloarthritis. The SNP rs30187 was also associated with the risk of HLA-B27+ AS. For the general group of AS, the carriers of minor alleles showed an increased risk for the disease (OR 1.92, 95% CI 1.17-3.13 for rs30187, OR 1.74, 95% CI 1.08-2.80 for rs27044). This is the first study that shows the association of ERAP1 gene variants and haplotypes with HLA-B27 positive spondyloarthritis. PMID:23800305

  20. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain.

    Science.gov (United States)

    Deverman, Benjamin E; Pravdo, Piers L; Simpson, Bryan P; Kumar, Sripriya Ravindra; Chan, Ken Y; Banerjee, Abhik; Wu, Wei-Li; Yang, Bin; Huber, Nina; Pasca, Sergiu P; Gradinaru, Viviana

    2016-02-01

    Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer. However, the tropism repertoire of naturally occurring AAVs is limited, prompting a search for novel AAV capsids with desired characteristics. Here we describe a capsid selection method, called Cre recombination-based AAV targeted evolution (CREATE), that enables the development of AAV capsids that more efficiently transduce defined Cre-expressing cell populations in vivo. We use CREATE to generate AAV variants that efficiently and widely transduce the adult mouse central nervous system (CNS) after intravenous injection. One variant, AAV-PHP.B, transfers genes throughout the CNS with an efficiency that is at least 40-fold greater than that of the current standard, AAV9 (refs. 14,15,16,17), and transduces the majority of astrocytes and neurons across multiple CNS regions. In vitro, it transduces human neurons and astrocytes more efficiently than does AAV9, demonstrating the potential of CREATE to produce customized AAV vectors for biomedical applications. PMID:26829320

  1. Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects

    Institute of Scientific and Technical Information of China (English)

    Ji-Ping Shan; Xiao-Li Wang; Yuan-Gang Qiao; Hong-Xin Wan Yan; Wen-Hui Huang; Shu-Chao Pang; Bo Yan

    2014-01-01

    Background: Congenital heart disease (CHD) is the most common human birth defect. Genetic causes for CHD remain largely unknown. GATA transcription factor 5 (GATA 5) is an essential regulator for the heart development. Mutations in the GATA5 gene have been reported in patients with a variety of CHD. Since misregulation of gene expression have been associated with human diseases, we speculated that changed levels of cardiac transcription factors, GATA5, may mediate the development of CHD. Methods: In this study, GATA5 gene promoter was genetically and functionally analyzed in large cohorts of patients with ventricular septal defect (VSD) (n=343) and ethnic-matched healthy controls (n=348). Results: Two novel and heterozygous DNA sequence variants (DSVs), g.61051165A>G and g.61051463delC, were identified in three VSD patients, but not in the controls. In cultured cardiomyocytes, GATA5 gene promoter activities were significantly decreased by DSV g.61051165A>G and increased by DSV g.61051463delC. Moreover, fathers of the VSD patients carrying the same DSVs had reduced diastolic function of left ventricles. Three SNPs, g.61051279C>T (rs77067995), g.61051327A>C (rs145936691) and g.61051373G>A (rs80197101), and one novel heterozygous DSV, g.61051227C>T, were found in both VSD patients and controls with similar frequencies. Conclusion: Our data suggested that the DSVs in the GATA5 gene promoter may increase the susceptibility to the development of VSD as a risk factor.

  2. Novel and Functional DNA Sequence Variants within the GATA6 Gene Promoter in Ventricular Septal Defects

    Directory of Open Access Journals (Sweden)

    Chunyu Li

    2014-07-01

    Full Text Available Congenital heart disease (CHD is the most common birth defect in humans. Genetic causes and underlying molecular mechanisms for isolated CHD remain largely unknown. Studies have demonstrated that GATA transcription factor 6 (GATA6 plays an essential role in the heart development. Mutations in GATA6 gene have been associated with diverse types of CHD. As GATA6 functions in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs within the gene regulatory regions, may mediate the CHD development. In the present study, GATA6 gene promoter was genetically and functionally analyzed in large groups of patients with ventricular septal defect (VSD (n = 359 and ethnic-matched healthy controls (n = 365. In total, 11 DSVs, including four SNPs, were identified in VSD patients and controls. Two novel and heterozygous DSVs, g.22169190A>T and g.22169311C>G, were identified in two VSD patients, but in none of controls. In cultured cardiomyocytes, the activities of the GATA6 gene promoter were significantly reduced by the DSVs g.22169190A>T and g.22169311C>G. Therefore, our findings suggested that the DSVs within the GATA6 gene promoter identified in VSD patients may change GATA6 levels, contributing to the VSD development as a risk factor.

  3. Genetic variant in DIP2A gene is associated with developmental dyslexia in Chinese population.

    Science.gov (United States)

    Kong, Rui; Shao, Shanshan; Wang, Jia; Zhang, Xiaohui; Guo, Shengnan; Zou, Li; Zhong, Rong; Lou, Jiao; Zhou, Jie; Zhang, Jiajia; Song, Ranran

    2016-03-01

    Increasing evidence suggests that there is a substantial heritable component including several risk loci and candidate genes for developmental dyslexia (DD). DIP2A has been identified to be partially deleted on chromosome region 21q22.3, which cosegregates with DD. And it fits into a theoretical molecular network of DD implicated in the development of DD. Compared with some DD candidate genes that have been extensively studied (e.g., DYX1C1, DCDC2, KIAA0319, and ROBO1), very little is known about the association between candidate gene DIP2A and DD susceptibility. And given the linguistic and genetic differences between Chinese and other Western populations, it is worthwhile validating the association of DIP2A in Chinese dyslexic children. Here, we investigated two genetic variants, selected by bioinformatics analysis, in DIP2A in a Chinese population with 409 dyslexic cases and 410 healthy controls. We observed a significantly increased DD risk associated with rs2255526 G allele (OR = 1.297, 95% CI = 1.036-1.623, Padjusted  = 0.023) and GG genotypes (OR = 1.833, 95% CI = 1.043-3.223, Padjusted  = 0.035), compared with their wild-type counterparts. In addition, it was marginally significantly associated with DD under the recessive model (OR = 1.677, 95% CI = 0.967-2.908, Padjusted  = 0.066) and the dominant model (OR = 1.314, 95% CI = 0.992-1.741, Padjusted  = 0.057). However, we found no evidence of an association of SNP rs16979358 with DD. In conclusion, this study showed that a genetic variant in the DIP2A gene was associated with increased DD risk in China. PMID:26452339

  4. Fibulin-3 negatively regulates ALDH1 via c-MET suppression and increases γ-radiation-induced sensitivity in some pancreatic cancer cell lines

    International Nuclear Information System (INIS)

    Highlights: • FBLN-3 gene was poorly expressed in some pancreatic cancer lines. • FBLN-3 promoter region was highly methylated in some pancreatic cancer cell lines. • FBLN-3 inhibited c-MET activation and expression and reduced cellular level of ALDH1. • FBLN-3/c-Met/ALDH1 axis modulates stemness and EMT in pancreatic cancer cells. - Abstract: Fibulin-3 (FBLN-3) has been postulated to be either a tumor suppressor or promoter depending on the cell type, and hypermethylation of the FBLN-3 promoter is often associated with human disease, especially cancer. We report that the promoter region of the FBLN-3 was significantly methylated (>95%) in some pancreatic cancer cell lines and thus FBLN-3 was poorly expressed in pancreatic cancer cell lines such as AsPC-1 and MiaPaCa-2. FBLN-3 overexpression significantly down-regulated the cellular level of c-MET and inhibited hepatocyte growth factor-induced c-MET activation, which were closely associated with γ-radiation resistance of cancer cells. Moreover, we also showed that c-MET suppression or inactivation decreased the cellular level of ALDH1 isozymes (ALDH1A1 or ALDH1A3), which serve as cancer stem cell markers, and subsequently induced inhibition of cell growth in pancreatic cancer cells. Therefore, forced overexpression of FBLN-3 sensitized cells to cytotoxic agents such as γ-radiation and strongly inhibited the stemness and epithelial to mesenchymal transition (EMT) property of pancreatic cancer cells. On the other hand, if FBLN3 was suppressed in FBLN-3-expressing BxPC3 cells, the results were opposite. This study provides the first demonstration that the FBLN-3/c-MET/ALDH1 axis in pancreatic cancer cells partially modulates stemness and EMT as well as sensitization of cells to the detrimental effects of γ-radiation

  5. Fibulin-3 negatively regulates ALDH1 via c-MET suppression and increases γ-radiation-induced sensitivity in some pancreatic cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Kim, In-Gyu, E-mail: igkim@kaeri.re.kr [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353 (Korea, Republic of); Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-daero, Yusong-gu, Daejeon 305-353 (Korea, Republic of); Lee, Jae-Ha [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353 (Korea, Republic of); Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-daero, Yusong-gu, Daejeon 305-353 (Korea, Republic of); Kim, Seo-Yoen; Kim, Jeong-Yul [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353 (Korea, Republic of); Cho, Eun-Wie [Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806 (Korea, Republic of)

    2014-11-21

    Highlights: • FBLN-3 gene was poorly expressed in some pancreatic cancer lines. • FBLN-3 promoter region was highly methylated in some pancreatic cancer cell lines. • FBLN-3 inhibited c-MET activation and expression and reduced cellular level of ALDH1. • FBLN-3/c-Met/ALDH1 axis modulates stemness and EMT in pancreatic cancer cells. - Abstract: Fibulin-3 (FBLN-3) has been postulated to be either a tumor suppressor or promoter depending on the cell type, and hypermethylation of the FBLN-3 promoter is often associated with human disease, especially cancer. We report that the promoter region of the FBLN-3 was significantly methylated (>95%) in some pancreatic cancer cell lines and thus FBLN-3 was poorly expressed in pancreatic cancer cell lines such as AsPC-1 and MiaPaCa-2. FBLN-3 overexpression significantly down-regulated the cellular level of c-MET and inhibited hepatocyte growth factor-induced c-MET activation, which were closely associated with γ-radiation resistance of cancer cells. Moreover, we also showed that c-MET suppression or inactivation decreased the cellular level of ALDH1 isozymes (ALDH1A1 or ALDH1A3), which serve as cancer stem cell markers, and subsequently induced inhibition of cell growth in pancreatic cancer cells. Therefore, forced overexpression of FBLN-3 sensitized cells to cytotoxic agents such as γ-radiation and strongly inhibited the stemness and epithelial to mesenchymal transition (EMT) property of pancreatic cancer cells. On the other hand, if FBLN3 was suppressed in FBLN-3-expressing BxPC3 cells, the results were opposite. This study provides the first demonstration that the FBLN-3/c-MET/ALDH1 axis in pancreatic cancer cells partially modulates stemness and EMT as well as sensitization of cells to the detrimental effects of γ-radiation.

  6. Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.

    Science.gov (United States)

    Vallée, Maxime P; Di Sera, Tonya L; Nix, David A; Paquette, Andrew M; Parsons, Michael T; Bell, Russel; Hoffman, Andrea; Hogervorst, Frans B L; Goldgar, David E; Spurdle, Amanda B; Tavtigian, Sean V

    2016-07-01

    Clinical mutation screening of the cancer susceptibility genes BRCA1 and BRCA2 generates many unclassified variants (UVs). Most of these UVs are either rare missense substitutions or nucleotide substitutions near the splice junctions of the protein coding exons. Previously, we developed a quantitative method for evaluation of BRCA gene UVs-the "integrated evaluation"-that combines a sequence analysis-based prior probability of pathogenicity with patient and/or tumor observational data to arrive at a posterior probability of pathogenicity. One limitation of the sequence analysis-based prior has been that it evaluates UVs from the perspective of missense substitution severity but not probability to disrupt normal mRNA splicing. Here, we calibrated output from the splice-site fitness program MaxEntScan to generate spliceogenicity-based prior probabilities of pathogenicity for BRCA gene variants; these range from 0.97 for variants with high probability to damage a donor or acceptor to 0.02 for exonic variants that do not impact a splice junction and are unlikely to create a de novo donor. We created a database http://priors.hci.utah.edu/PRIORS/ that provides the combined missense substitution severity and spliceogenicity-based probability of pathogenicity for BRCA gene single-nucleotide substitutions. We also updated the BRCA gene Ex-UV LOVD, available at http://hci-exlovd.hci.utah.edu, with 77 re-evaluable variants. PMID:26913838

  7. Analysis of FTO Gene Variants with Measures of Obesity and Glucose Homeostasis in the IRAS Family Study

    OpenAIRE

    Wing, Maria R; Ziegler, Julie; Langefeld, Carl D.; Ng, Maggie CY; Haffner, Steven M.; Norris, Jill M.; Goodarzi, Mark O; Donald W Bowden

    2009-01-01

    Multiple studies have identified FTO gene variants associated with measures of adiposity in European-derived populations. The study objective was to determine whether FTO variants were associated with adiposity, including visceral and subcutaneous adipose tissue (VAT; SAT), and glucose homeostasis measures in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A total of 27 SNPs in FTO intron 1, including SNPs prominent in the literature (rs9939609, rs8050136, rs1121980, rs17817449,...

  8. Functional variants of sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

    Science.gov (United States)

    Sun, Xiaoguang; Ma, Shwu-Fan; Wade, Michael S.; Flores, Carlos; Pino-Yanes, Maria; Moitra, Jaideep; Ober, Carole; Kittles, Rick; Husain, Aliya N.; Ford, Jean G.; Garcia, Joe G. N.

    2012-01-01

    Background The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma and the sphingosine-1-phosphate receptor, S1PR1, is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective We explored the contribution of polymorphisms in the S1PR1 gene (S1PR1) to asthma susceptibility. Methods A combination of gene re-sequencing for SNP discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was utilized. Results Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in asthmatic lungs compared to non-asthmatic individuals (p<0.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in three case-control cohorts from Chicago and New York totaling 1061 subjects (502 cases and 559 controls). Promoter SNP rs2038366 (−1557G/T) was found to be associated with asthma (p=0.03) in European Americans. In African Americans, an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.−164+170A/G) (p=0.006 and p=0.040, respectively) and for promoter SNP rs59317557 (−532C/G) with severe asthma (p=0.028). Consistent with predicted in silico functionality, alleles of promoter SNPs rs2038366 (−1557G/T) and rs59317557 (−532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (EGF, PDGF, VEGF) known to be increased in asthmatic airways. Conclusion These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity. Clinical Implications Our results indicate S1PR1 is a novel asthma candidate gene and an attractive target for future therapeutic strategies. Capsule summary This study

  9. Identification of novel functional sequence variants in the gene for peptidase inhibitor 3

    Directory of Open Access Journals (Sweden)

    Edwin Samuel

    2006-05-01

    Full Text Available Abstract Background Peptidase inhibitor 3 (PI3 inhibits neutrophil elastase and proteinase-3, and has a potential role in skin and lung diseases as well as in cancer. Genome-wide expression profiling of chorioamniotic membranes revealed decreased expression of PI3 in women with preterm premature rupture of membranes. To elucidate the molecular mechanisms contributing to the decreased expression in amniotic membranes, the PI3 gene was searched for sequence variations and the functional significance of the identified promoter variants was studied. Methods Single nucleotide polymorphisms (SNPs were identified by direct sequencing of PCR products spanning a region from 1,173 bp upstream to 1,266 bp downstream of the translation start site. Fourteen SNPs were genotyped from 112 and nine SNPs from 24 unrelated individuals. Putative transcription factor binding sites as detected by in silico search were verified by electrophoretic mobility shift assay (EMSA using nuclear extract from Hela and amnion cell nuclear extract. Deviation from Hardy-Weinberg equilibrium (HWE was tested by χ2 goodness-of-fit test. Haplotypes were estimated using expectation maximization (EM algorithm. Results Twenty-three sequence variations were identified by direct sequencing of polymerase chain reaction (PCR products covering 2,439 nt of the PI3 gene (-1,173 nt of promoter sequences and all three exons. Analysis of 112 unrelated individuals showed that 20 variants had minor allele frequencies (MAF ranging from 0.02 to 0.46 representing "true polymorphisms", while three had MAF ≤ 0.01. Eleven variants were in the promoter region; several putative transcription factor binding sites were found at these sites by database searches. Differential binding of transcription factors was demonstrated at two polymorphic sites by electrophoretic mobility shift assays, both in amniotic and HeLa cell nuclear extracts. Differential binding of the transcription factor GATA1 at -689C>G site

  10. Association analysis of genetic variants in the myosin IXB gene in acute pancreatitis.

    Directory of Open Access Journals (Sweden)

    Rian M Nijmeijer

    Full Text Available INTRODUCTION: Impairment of the mucosal barrier plays an important role in the pathophysiology of acute pancreatitis. The myosin IXB (MYO9B gene and the two tight-junction adaptor genes, PARD3 and MAGI2, have been linked to gastrointestinal permeability. Common variants of these genes are associated with celiac disease and inflammatory bowel disease, two other conditions in which intestinal permeability plays a role. We investigated genetic variation in MYO9B, PARD3 and MAGI2 for association with acute pancreatitis. METHODS: Five single nucleotide polymorphisms (SNPs in MYO9B, two SNPs in PARD3, and three SNPs in MAGI2 were studied in a Dutch cohort of 387 patients with acute pancreatitis and over 800 controls, and in a German cohort of 235 patients and 250 controls. RESULTS: Association to MYO9B and PARD3 was observed in the Dutch cohort, but only one SNP in MYO9B and one in MAGI2 showed association in the German cohort (p < 0.05. Joint analysis of the combined cohorts showed that, after correcting for multiple testing, only two SNPs in MYO9B remained associated (rs7259292, p = 0.0031, odds ratio (OR 1.94, 95% confidence interval (95% CI 1.35-2.78; rs1545620, p = 0.0006, OR 1.33, 95% CI 1.16-1.53. SNP rs1545620 is a non-synonymous SNP previously suspected to impact on ulcerative colitis. None of the SNPs showed association to disease severity or etiology. CONCLUSION: Variants in MYO9B may be involved in acute pancreatitis, but we found no evidence for involvement of PARD3 or MAGI2.

  11. Characterization of the antigenic and functional domains of a Mycoplasma synoviae variant vlhA gene.

    Science.gov (United States)

    Khiari, Awatef Béjaoui; Mardassi, Boutheina Ben Abdelmoumen

    2012-05-01

    The Mycoplasma synoviae haemagglutinin gene, vlhA, encodes two major immunodominant and surface-exposed membrane proteins, MSPB and MSPA. Both products are antigenically variable but only MSPA mediates binding to erythrocytes. Previously we have shown that M. synoviae type strain WVU 1853 could express a variant vlhA gene, referred to as MS2/28.1, with a considerably shorter and divergent MSPA region. A finding that prompted detailed characterization of its antigenic and functional properties. Here we mutagenized each of the six opal codons of the variant MS2/28.1 vlhA member into tryptophan, thus allowing its expression in Escherichia coli as well as its cleavage products, MSPB and MSPA. In addition, we expressed 5 contiguous regions of MS2/28.1 extending from the last part of MSPB to the C-terminus of MSPA. Colony immunostaining with region-specific antisera mapped antigenic variation to the N-terminal half of MS2/28.1 MSPA. No haemagglutinating activity was observed for MSPB, but consistent haemadsorption inhibition was mapped to the region extending from amino acid 325 to 344. Inhibition of both haemagglutination and haemadsorption activities were obtained with sera directed against the C-terminal region of MSPA, with the highest titers (1/320 and 1/160, respectively) being recorded for its last 60 residues. Importantly, antibodies to this region also yielded the highest metabolic inhibition titer of 1/1280. Overall, aside from mapping the functional domains of a M. synoviae highly divergent haemagglutinin gene, this study shows that the C-terminal half of its MSPA region induced the highest titers of antibodies inhibiting haemagglutination, haemadsorption, and metabolism. PMID:22176762

  12. FEATURES OF THE CLINICAL SIGNIFICANCE OF POLYMORPHIC VARIANTS OF ENOS AND AGTR2 GENES IN PATIENTS WITH CAD

    Directory of Open Access Journals (Sweden)

    A. L. Khokhlov

    2016-01-01

    Full Text Available Coronary heart disease (CHD is a major cause of mortality. Morphological substrate of CHD in most cases is atherosclerosis, which is based on structural genes polymorphism eNOS and AGTR2. The aim of the study was to study the prevalence of eNOS and AGTR2 genes in patients with coronary artery disease and the association of these genes with coronary heart disease. The study involved 187 patients aged 36 to 86 years (62,2±11,2 with different forms of CHD: stable and unstable angina, myocardial infarction and 45 people without CHD. Determination of gene polymorphisms was performed by real-time PCR analyzer of nucleic acids IQ 5 Bio-Rad. Statistical analysis was performed using Statistica 10.0. The study revealed a significant difference between the incidence of homozygous AA allelic variant gene AGTR2 group of patients with myocardial infarction and the comparison group; polymorphic variant AA AGTR2 gene is associated with earlier onset of coronary artery disease; It found that carriers of the polymorphic variant gene GA AGTR2 beginning statistically CHD occurred significantly later than in carriers of alleles GG and AA; age CHD debut TT allele carriers of the eNOS gene is associated with an earlier onset of the disease and statistically significantly different from the age of first CHD in carriers of alleles of polymorphic variants of GG and GT; revealed a positive correlation between the polymorphic allele AGTR2 gene with the presence of arterial hypertension in patients with coronary artery disease; It determined that the T allele carriers of the polymorphic gene eNOS is associated more early onset of hypertension, found the association of the polymorphic allele gene AGTR2 the need to use higher doses of ACE inhibitor — perindopril.

  13. A scallop IGF binding protein gene: molecular characterization and association of variants with growth traits.

    Directory of Open Access Journals (Sweden)

    Liying Feng

    Full Text Available BACKGROUND: Scallops represent economically important aquaculture shellfish. The identification of genes and genetic variants related to scallop growth could benefit high-yielding scallop breeding. The insulin-like growth factor (IGF system is essential for growth and development, with IGF binding proteins (IGFBPs serving as the major regulators of IGF actions. Although an effect of IGF on growth was detected in bivalve, IGFBP has not been reported, and members of the IGF system have not been characterized in scallop. RESULTS: We cloned and characterized an IGFBP (PyIGFBP gene from the aquaculture bivalve species, Yesso scallop (Patinopecten yessoensis, Jay, 1857. Its full-length cDNA sequence was 1,445 bp, with an open reading frame of 378 bp, encoding 125 amino acids, and its genomic sequence was 10,193 bp, consisting of three exons and two introns. The amino acid sequence exhibited the characteristics of IGFBPs, including multiple cysteine residues and relatively conserved motifs in the N-terminal and C-terminal domains. Expression analysis indicated that PyIGFBP was expressed in all the tissues and developmental stages examined, with a significantly higher level in the mantle than in other tissues and a significantly higher level in gastrulae and trochophore larvae than in other stages. Furthermore, three single nucleotide polymorphisms (SNPs were identified in this gene. SNP c.1054A>G was significantly associated with both shell and soft body traits in two populations, with the highest trait values in GG type scallops and lowest in AG type ones. CONCLUSION: We cloned and characterized an IGFBP gene in a bivalve, and this report also represents the first characterizing an IGF system gene in scallops. A SNP associated with scallop growth for both the shell and soft body was identified in this gene. In addition to providing a candidate marker for scallop breeding, our results also suggest the role of PyIGFBP in scallop growth.

  14. Diagnostic value of post-heparin lipase testing in detecting common genetic variants in the LPL and LIPC genes

    OpenAIRE

    van Hoek, Mandy; Dallinga-Thie, Geesje M.; Ewout W Steyerberg; Sijbrands, Eric J. G.

    2009-01-01

    Post-heparin lipoprotein lipase and hepatic lipase activities are used to identify primary disorders of triglyceride and HDL-cholesterol metabolism. Their ability to identify common variants in the lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes is unclear. To investigate the ability of lipase testing to detect common lipase gene variants, we included 183 patients who had undergone post-heparin lipase testing and genotyped the LPL D9N, N291S, PvuII, HindIII, and S447X and the LIPC-51...

  15. Racial Differences in DNA-Methylation of CpG Sites Within Preterm-Promoting Genes and Gene Variants.

    Science.gov (United States)

    Salihu, H M; Das, R; Morton, L; Huang, H; Paothong, A; Wilson, R E; Aliyu, M H; Salemi, J L; Marty, P J

    2016-08-01

    Objective To evaluate the role DNA methylation may play in genes associated with preterm birth for higher rates of preterm births in African-American women. Methods Fetal cord blood samples from births collected at delivery and maternal demographic and medical information were used in a cross-sectional study to examine fetal DNA methylation of genes implicated in preterm birth among black and non-black infants. Allele-specific DNA methylation analysis was performed using a methylation bead array. Targeted maximum likelihood estimation was applied to examine the relationship between race and fetal DNA methylation of candidate preterm birth genes. Receiver-operating characteristic analyses were then conducted to validate the CpG site methylation marker within the two racial groups. Bootstrapping, a method of validation and replication, was employed. Results 42 CpG sites were screened within 20 candidate gene variants reported consistently in the literature as being associated with preterm birth. Of these, three CpG sites on TNFAIP8 and PON1 genes (corresponding to: cg23917399; cg07086380; and cg07404485, respectively) were significantly differentially methylated between black and non-black individuals. The three CpG sites showed lower methylation status among infants of black women. Bootstrapping validated and replicated results. Conclusion for Practice Our study identified significant differences in levels of methylation on specific genes between black and non-black individuals. Understanding the genetic/epigenetic mechanisms that lead to preterm birth may lead to enhanced prevention strategies to reduce morbidity and mortality by eventually providing a means to identify individuals with a genetic predisposition to preterm labor. PMID:27000849

  16. Studies of metabolic phenotypic correlates of 15 obesity associated gene variants

    DEFF Research Database (Denmark)

    Sandholt, Camilla Helene; Vestmar, Marie Aare; Bille, Dorthe Sadowa; Borglykke, Anders; Almind, Katrine; Hansen, Lars; Sandbæk, Annelli; Lauritzen, Torsten; Witte, Daniel; Jørgensen, Torben; Pedersen, Oluf; Hansen, Torben

    2011-01-01

    Aims: Genome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci...... (rs10938397), MTCH2 (rs10838738), BAT2 (rs2260000), NPC1 (rs1805081), MAF (rs1424233), and PTER (rs10508503) were genotyped in 18,014 middle-aged Danes. Results: Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15–1.20 for overweight......, 1.10–1.25 for obesity, and 1.41–1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78–0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with...

  17. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    International Nuclear Information System (INIS)

    CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations

  18. Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia

    International Nuclear Information System (INIS)

    The MRE11, RAD50, and NBN genes encode proteins of the MRE11-RAD50-NBN (MRN) complex involved in cellular response to DNA damage and the maintenance of genome stability. In our previous study we showed that the germline p.I171V mutation in NBN may be considered as a risk factor in the development of childhood acute lymphoblastic leukemia (ALL) and some specific haplotypes of that gene may be associated with childhood leukemia. These findings raise important questions about the role of mutations in others genes of the MRN complex in childhood leukemia. The aim of this study was to answer the question whether MRE11 and RAD50 alterations may be associated with childhood ALL or AML. We estimated the frequency of constitutional mutations and polymorphisms in selected regions of MRE11, RAD50, and NBN in the group of 220 children diagnosed with childhood leukemias and controls (n=504/2200). The analysis was performed by specific amplification of region of interest by PCR and followed by multi-temperature single-strand conformation polymorphism (PCR-MSSCP) technique. We performed two molecular tests to examine any potential function of the detected the c.551+19G>A SNP in RAD50 gene. To our knowledge, this is the first analysis of the MRE11, RAD50 and NBN genes in childhood leukemia. The frequency of either the AA genotype or A allele of RAD50-rs17166050 were significantly different in controls compared to leukemia group (ALL+AML) (p<0.0019 and p<0.0019, respectively). The cDNA analysis of AA or GA genotypes carriers has not revealed evidence of splicing abnormality of RAD50 pre-mRNA. We measured the allelic-specific expression of G and A alleles at c.551+19G>A and the statistically significant overexpression of the G allele has been observed. Additionally we confirmed the higher incidence of the p.I171V mutation in the leukemia group (7/220) than among controls (12/2400) (p<0.0001). The formerly reported sequence variants in the RAD50 and MRE11 gene may not constitute a

  19. SAH Gene Variants Revisited in the European Project on Genes in Hypertension

    Czech Academy of Sciences Publication Activity Database

    Tikhonoff, V.; Staessen, J.A.; Kuznetsova, T.; Thijs, L.; Hasenkamp, S.; Stolarz, K.; Seidlerová, J.; Filipovský, J.; Nikitin, Y.; Peleška, Jan; Kawecka-Jaszcz, K.; Casiglia, E.; Brand-Herrmann, S.M.; Brand, E.

    2008-01-01

    Roč. 26, č. 2 (2008), s. 244-250. ISSN 0263-6352 Institutional research plan: CEZ:AV0Z10300504 Keywords : body mass index * hypertension * population study * SAH gene * serum lipids Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 5.132, year: 2008

  20. Nucleophosmin (NPM1) gene variants in Egyptian patients with acute myeloid leukemia

    International Nuclear Information System (INIS)

    To the editor Kassem et al. [1] described a novel mutational deletion [del 1178 (A)] in the 30 untranslated region of NPM1 gene detected in a heterozygous form in seven de novo acute myeloid leukemia (AML) patients of their study population. The described nucleotide deletion is an NPM1 gene polymorphism recorded in db SNP database (rs34351976; g28027: Genbank accession number NG016018.1) (http://www.ncbi.nlm.nih.gov/projects/SNP/) and was described previously by Do hner et al. [2] and Chou et al. [3]. This variant accounted for 60-70% of AML patients with normal karyotype [2]. The putative deletion was also identified in healthy volunteers and persisted at complete remission and also at relapse of AML patients [3]. This deletion had no effect on the predicted amino acid sequence and is not in linkage disequilibrium with any previously identified NPM1 mutations [2,3]. Analysis of RNA folding at the region surrounding the rs34351976 in the presence or absence of the deletion using Mfold analysis software (http://www.mfold.rna.albany.edu) revealed no RNA folding change that may alter RNA splicing and subsequently gene expression. Furthermore, splicing motifs analysis using Human Splicing Finder software version 2.4.1 showed that the presence of the deletion does not abolish any recognition site of exonic or intronic enhancers or silencer motifs. In general, it seems that the impact of NMP1 polymorphisms on the molecular pathogenesis of AML is not clear yet and needs further investigation. Kassem et al. [1] describes the molecular aspect of de novo AML in the Egyptian population. The previously known NPM1 mutations mentioned in their study are less frequent compared to the figures recorded worldwide. Moreover, the authors wondered whether the NPM1 variants identified in their patients may confer a better outcome of AML. According to the previously mentioned data, one can speculate that the presence of NPM1 gene polymorphism (rs34351976) should not be mistaken as being

  1. ALDH1A3, a metabolic target for cancer diagnosis and therapy.

    Science.gov (United States)

    Duan, Jiang-Jie; Cai, Jiao; Guo, Yu-Feng; Bian, Xiu-Wu; Yu, Shi-Cang

    2016-09-01

    Metabolism reprogramming has been linked with the initiation, metastasis, and recurrence of cancer. The aldehyde dehydrogenase (ALDH) family is the most important enzyme system for aldehyde metabolism. The human ALDH family is composed of 19 members. ALDH1A3 participates in various physiological processes in human cells by oxidizing all-trans-retinal to retinoic acid. ALDH1A3 expression is regulated by many factors, and it is associated with the development, progression, and prognosis of cancers. In addition, ALDH1A3 influences a diverse range of biological characteristics within cancer stem cells and can act as a marker for these cells. Thus, growing evidence indicates that ALDH1A3 has the potential to be used as a target for cancer diagnosis and therapy. PMID:26991532

  2. Differential expression of aldehyde dehydrogenase 1a1 (ALDH1 in normal ovary and serous ovarian tumors

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    Penumatsa Krishna

    2010-12-01

    Full Text Available Abstract Background We showed there are specific ALDH1 autoantibodies in ovarian autoimmune disease and ovarian cancer, suggesting a role for ALDH1 in ovarian pathology. However, there is little information on the ovarian expression of ALDH1. Therefore, we compared ALDH1 expression in normal ovary and benign and malignant ovarian tumors to determine if ALDH1 expression is altered in ovarian cancer. Since there is also recent interest in ALDH1 as a cancer stem cell (CSC marker, we assessed co-expression of ALDH1 with CSC markers in order to determine if ALDH1 is a potential CSC marker in ovarian cancer. Methods mRNA and protein expression were compared in normal human ovary and serous ovarian tumors using quantitative Reverse-Transcriptase PCR, Western blot (WB and semi-quantitative immunohistochemistry (IHC. ALDH1 enzyme activity was confirmed in primary ovarian cells by flow cytometry (FC using ALDEFLUOR assay. Results ALDH1 mRNA expression was significantly reduced (p Conclusions Total ALDH1 expression is significantly reduced in malignant ovarian tumors while it is relatively unchanged in benign tumors compared to normal ovary. Thus, ALDH1 expression in the ovary does not appear to be similar to breast, lung or colon cancer suggesting possible functional differences in these cancers. Significance These observations suggest that reduced ALDH1 expression is associated with malignant transformation in ovarian cancer and provides a basis for further study of the mechanism of ALDH1 in this process.

  3. Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

    International Nuclear Information System (INIS)

    The human fibroblast growth factor (FGF) and its receptor (FGFR) play an important role in tumorigenesis. Deregulation of the FGFR2 gene has been identified in a number of cancer sites. Overexpression of the FGFR4 protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the FGFR2 and FGFR4 genes and development of various cancers. We evaluated the associations of four genetic variants in the FGFR2 gene highly related to breast cancer risk and the three common tag-SNPs in the FGFR4 gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer. Given the power of this study, we did not detect any contribution of genetic variants in the FGFR2 or FGFR4 genes to inherited predisposition to skin cancer among Caucasian women

  4. The regulated secretory pathway and human disease: insights from gene variants and single nucleotide polymorphisms

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    Stephen eSalton

    2013-08-01

    Full Text Available The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs, where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs, with neuropsychiatric, endocrine and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A of the human brain-derived neurotrophic factor (BDNF gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired.

  5. A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence.

    Science.gov (United States)

    Cabana-Domínguez, Judit; Roncero, Carlos; Grau-López, Lara; Rodríguez-Cintas, Laia; Barral, Carmen; Abad, Alfonso C; Erikson, Galina; Wineinger, Nathan E; Torrico, Bàrbara; Arenas, Concepció; Casas, Miquel; Ribasés, Marta; Cormand, Bru; Fernàndez-Castillo, Noèlia

    2016-01-01

    Cocaine dependence is a complex psychiatric disorder involving both genetic and environmental factors. Several neurotransmitter systems mediate cocaine's effects, dependence and relapse, being the components of the neurotransmitter release machinery good candidates for the disorder. Previously, we identified a risk haplotype for cocaine dependence in the NSF gene, encoding the protein N-Ethylmaleimide-Sensitive Factor essential for synaptic vesicle turnover. Here we examined the possible contribution to cocaine dependence of a large copy number variant (CNV) that encompasses part of the NSF gene. We performed a case-control association study in a discovery sample (359 cases and 356 controls) and identified an association between cocaine dependence and the CNV (P = 0.013), that was confirmed in the replication sample (508 cases and 569 controls, P = 7.1e-03) and in a pooled analysis (P = 1.8e-04), with an over-representation of low number of copies in cases. Subsequently, we studied the functional impact of the CNV on gene expression and found that the levels of two NSF transcripts were significantly increased in peripheral blood mononuclear cells (PBMC) along with the number of copies of the CNV. These results, together with a previous study from our group, support the role of NSF in the susceptibility to cocaine dependence. PMID:27498889

  6. Genetic variants of the FADS gene cluster and ELOVL gene family, colostrums LC-PUFA levels, breastfeeding, and child cognition.

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    Eva Morales

    Full Text Available INTRODUCTION: Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs, but controversy persists. Genetic variation in fatty acid desaturase (FADS and elongase (ELOVL enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1 to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2 to analyze whether these maternal variants are related to child cognition; and 3 to assess whether children's variants modify breastfeeding effects on cognition. METHODS: Data come from two population-based birth cohorts (n = 400 mother-child pairs from INMA-Sabadell; and n = 340 children from INMA-Menorca. LC-PUFAs were measured in 270 colostrum samples from INMA-Sabadell. Tag SNPs were genotyped both in mothers and children (13 in the FADS cluster, 6 in ELOVL2, and 7 in ELOVL5. Child cognition was assessed at 14 mo and 4 y using the Bayley Scales of Infant Development and the McCarthy Scales of Children's Abilities, respectively. RESULTS: Children of mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis, higher FADS2 activity (regulating DHA synthesis, and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 mo (3.5 to 5.3 points. Not being breastfed conferred an 8- to 9-point disadvantage in cognition among children GG homozygote for rs174468 (low FADS1 activity but not among those with the A allele. Moreover, not being breastfed resulted in a disadvantage in cognition (5 to 8 points among children CC homozygote for rs2397142 (low ELOVL5 activity, but not among those carrying the G allele. CONCLUSION: Genetically determined maternal supplies of LC-PUFAs during pregnancy and lactation appear to be crucial for child cognition. Breastfeeding effects on cognition are modified by child genetic

  7. A Functional Variant of the Dimethylarginine Dimethylaminohydrolase-2 Gene Is Associated with Insulin Sensitivity

    Science.gov (United States)

    Andreozzi, Francesco; Presta, Ivan; Mannino, Gaia Chiara; Scarpelli, Daniela; Di Silvestre, Sara; Di Pietro, Natalia; Succurro, Elena; Sciacqua, Angela; Pandolfi, Assunta; Consoli, Agostino; Hribal, Marta Letizia; Perticone, Francesco; Sesti, Giorgio

    2012-01-01

    Background Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH) is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis), we identified a variant (rs9267551) in the DDAH2 gene nominally associated with type 2 diabetes (P = 3×10−5). Methodology/Principal Findings initially, we assessed the functional impact of rs9267551 in human endothelial cells (HUVECs), observing that the G allele had a lower transcriptional activity resulting in reduced expression of DDAH2 and decreased NO production in primary HUVECs naturally carrying it. We then proceeded to investigate whether this variant is associated with insulin sensitivity in vivo. To this end, two cohorts of nondiabetic subjects of European ancestry were studied. In sample 1 (n = 958) insulin sensitivity was determined by the insulin sensitivity index (ISI), while in sample 2 (n = 527) it was measured with a euglycemic-hyperinsulinemic clamp. In sample 1, carriers of the GG genotype had lower ISI than carriers of the C allele (67±33 vs.79±44; P = 0.003 after adjusting for age, gender, and BMI). ADMA levels were higher in subjects carrying the GG genotype than in carriers of the C allele (0.68±0.14 vs. 0.57±0.14 µmol/l; P = 0.04). In sample 2, glucose disposal was lower in GG carriers as compared with C carriers (9.3±4.1 vs. 11.0±4.2 mg×Kg−1 free fat mass×min−1; P = 0.009). Conclusions/Significance A functional polymorphism of the DDAH2 gene may confer increased risk for type 2 diabetes by affecting insulin sensitivity throughout increased ADMA levels. PMID:22558392

  8. A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Francesco Andreozzi

    Full Text Available BACKGROUND: Asymmetric dimethylarginine (ADMA is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis, we identified a variant (rs9267551 in the DDAH2 gene nominally associated with type 2 diabetes (P = 3 × 10(-5. METHODOLOGY/PRINCIPAL FINDINGS: initially, we assessed the functional impact of rs9267551 in human endothelial cells (HUVECs, observing that the G allele had a lower transcriptional activity resulting in reduced expression of DDAH2 and decreased NO production in primary HUVECs naturally carrying it. We then proceeded to investigate whether this variant is associated with insulin sensitivity in vivo. To this end, two cohorts of nondiabetic subjects of European ancestry were studied. In sample 1 (n = 958 insulin sensitivity was determined by the insulin sensitivity index (ISI, while in sample 2 (n = 527 it was measured with a euglycemic-hyperinsulinemic clamp. In sample 1, carriers of the GG genotype had lower ISI than carriers of the C allele (67 ± 33 vs.79 ± 44; P = 0.003 after adjusting for age, gender, and BMI. ADMA levels were higher in subjects carrying the GG genotype than in carriers of the C allele (0.68 ± 0.14 vs. 0.57 ± 0.14 µmol/l; P = 0.04. In sample 2, glucose disposal was lower in GG carriers as compared with C carriers (9.3 ± 4.1 vs. 11.0 ± 4.2 mg × Kg(-1 free fat mass × min(-1; P = 0.009. CONCLUSIONS/SIGNIFICANCE: A functional polymorphism of the DDAH2 gene may confer increased risk for type 2 diabetes by affecting insulin sensitivity throughout increased ADMA levels.

  9. Galiellalactone Inhibits Stem Cell-Like ALDH-Positive Prostate Cancer Cells

    OpenAIRE

    Hellsten, Rebecka; Johansson, Martin; Dahlman, Anna; Sterner, Olov; Bjartell, Anders

    2011-01-01

    Galiellalactone is a potent and specific inhibitor of STAT3 signaling which has been shown to possess growth inhibitory effects on prostate cancer cells expressing active STAT3. In this study we aimed to investigate the effect of galiellalactone on prostate cancer stem cell-like cells. We explored the expression of aldehyde dehydrogenase (ALDH) as a marker for cancer stem cell-like cells in different human prostate cancer cell lines and the effects of galiellalactone on ALDH expressing (ALDH+...

  10. Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.

    Science.gov (United States)

    Visschedijk, Marijn C; Alberts, Rudi; Mucha, Soren; Deelen, Patrick; de Jong, Dirk J; Pierik, Marieke; Spekhorst, Lieke M; Imhann, Floris; van der Meulen-de Jong, Andrea E; van der Woude, C Janneke; van Bodegraven, Adriaan A; Oldenburg, Bas; Löwenberg, Mark; Dijkstra, Gerard; Ellinghaus, David; Schreiber, Stefan; Wijmenga, Cisca; Rivas, Manuel A; Franke, Andre; van Diemen, Cleo C; Weersma, Rinse K

    2016-01-01

    Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC. PMID:27490946

  11. Evaluation of variants in the selectin genes in age-related macular degeneration

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    Wang Kai

    2011-04-01

    Full Text Available Abstract Background Age-related macular degeneration (AMD is a common disease of the elderly that leads to loss of the central visual field due to atrophic or neovascular events. Evidence from human eyes and animal models suggests an important role for macrophages and endothelial cell activation in the pathogenesis of AMD. We sought to determine whether common ancestral variants in genes encoding the selectin family of proteins are associated with AMD. Methods Expression of E-selectin, L-selectin and P-selectin was examined in choroid and retina by quantitative PCR and immunofluorescence. Samples from patients with AMD (n = 341 and controls (n = 400 were genotyped at a total of 34 SNPs in the SELE, SELL and SELP genes. Allele and genotype frequencies at these SNPs were compared between AMD patients and controls as well as between subtypes of AMD (dry, geographic atrophy, and wet and controls. Results High expression of all three selectin genes was observed in the choroid as compared to the retina. Some selectin labeling of retinal microglia, drusen cores and the choroidal vasculature was observed. In the genetic screen of AMD versus controls, no positive associations were observed for SELE or SELL. One SNP in SELP (rs3917751 produced p-values SELE, two in SELL, and three in SELP produced p-values SELP (rs3917751 produced a statistically significant p-value (p = 0.0029. Conclusions This genetic screen did not detect any SNPs that were highly associated with AMD affection status overall. However, subtype analysis showed that a single SNP located within an intron of SELP (rs3917751 is statistically associated with dry AMD in our cohort. Future studies with additional cohorts and functional assays will clarify the biological significance of this discovery. Based on our findings, it is unlikely that common ancestral variants in the other selectin genes (SELE and SELL are risk factors for AMD. Finally, it remains possible that sporadic or rare

  12. Gene expression, single nucleotide variant and fusion transcript discovery in archival material from breast tumors.

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    Nadine Norton

    Full Text Available Advantages of RNA-Seq over array based platforms are quantitative gene expression and discovery of expressed single nucleotide variants (eSNVs and fusion transcripts from a single platform, but the sensitivity for each of these characteristics is unknown. We measured gene expression in a set of manually degraded RNAs, nine pairs of matched fresh-frozen, and FFPE RNA isolated from breast tumor with the hybridization based, NanoString nCounter (226 gene panel and with whole transcriptome RNA-Seq using RiboZeroGold ScriptSeq V2 library preparation kits. We performed correlation analyses of gene expression between samples and across platforms. We then specifically assessed whole transcriptome expression of lincRNA and discovery of eSNVs and fusion transcripts in the FFPE RNA-Seq data. For gene expression in the manually degraded samples, we observed Pearson correlations of >0.94 and >0.80 with NanoString and ScriptSeq protocols, respectively. Gene expression data for matched fresh-frozen and FFPE samples yielded mean Pearson correlations of 0.874 and 0.783 for NanoString (226 genes and ScriptSeq whole transcriptome protocols respectively, p<2x10(-16. Specifically for lincRNAs, we observed superb Pearson correlation (0.988 between matched fresh-frozen and FFPE pairs. FFPE samples across NanoString and RNA-Seq platforms gave a mean Pearson correlation of 0.838. In FFPE libraries, we detected 53.4% of high confidence SNVs and 24% of high confidence fusion transcripts. Sensitivity of fusion transcript detection was not overcome by an increase in depth of sequencing up to 3-fold (increase from ~56 to ~159 million reads. Both NanoString and ScriptSeq RNA-Seq technologies yield reliable gene expression data for degraded and FFPE material. The high degree of correlation between NanoString and RNA-Seq platforms suggests discovery based whole transcriptome studies from FFPE material will produce reliable expression data. The RiboZeroGold ScriptSeq protocol

  13. Characterization of the rat Class 3 aldehyde dehydrogenase gene promoter.

    OpenAIRE

    Xie, Y Q; Takimoto, K; Pitot, H. C.; Miskimins, W K; Lindahl, R

    1996-01-01

    The Class 3 aldehyde dehydrogenase gene (ALDH-3) is differentially expressed. Expression is either constitutive or xenobiotic inducible via an aromatic hydrocarbon (Ah) receptor-mediated pathway, depending upon the tissue. A series of studies were performed to examine the regulation of rat ALDH-3 basal expression. DNase I footprint analysis identified four DNA regions within the proximal 1 kb of the 5' flanking region of rat ALDH-3 which interact with regulatory proteins. Reporter gene and ge...

  14. Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2 genes in yeast

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    Hudler Petra

    2009-10-01

    Full Text Available Abstract Background Loss of DNA mismatch repair (MMR in humans, mainly due to mutations in the hMLH1 gene, is linked to hereditary nonpolyposis colorectal cancer (HNPCC. Because not all MLH1 alterations result in loss of MMR function, accurate characterization of variants and their classification in terms of their effect on MMR function is essential for reliable genetic testing and effective treatment. To date, in vivo assays for functional characterization of MLH1 mutations performed in various model systems have used episomal expression of the modified MMR genes. We describe here a novel approach to determine accurately the functional significance of hMLH1 mutations in vivo, based on co-expression of human MLH1 and PMS2 in yeast cells. Methods Yeast MLH1 and PMS1 genes, whose protein products form the MutLα complex, were replaced by human orthologs directly on yeast chromosomes by homologous recombination, and the resulting MMR activity was tested. Results The yeast strain co-expressing hMLH1 and hPMS2 exhibited the same mutation rate as the wild-type. Eight cancer-related MLH1 variants were introduced, using the same approach, into the prepared yeast model, and their effect on MMR function was determined. Five variants (A92P, S93G, I219V, K618R and K618T were classified as non-pathogenic, whereas variants T117M, Y646C and R659Q were characterized as pathogenic. Conclusion Results of our in vivo yeast-based approach correlate well with clinical data in five out of seven hMLH1 variants and the described model was thus shown to be useful for functional characterization of MLH1 variants in cancer patients found throughout the entire coding region of the gene.

  15. Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2 genes in yeast

    International Nuclear Information System (INIS)

    Loss of DNA mismatch repair (MMR) in humans, mainly due to mutations in the hMLH1 gene, is linked to hereditary nonpolyposis colorectal cancer (HNPCC). Because not all MLH1 alterations result in loss of MMR function, accurate characterization of variants and their classification in terms of their effect on MMR function is essential for reliable genetic testing and effective treatment. To date, in vivo assays for functional characterization of MLH1 mutations performed in various model systems have used episomal expression of the modified MMR genes. We describe here a novel approach to determine accurately the functional significance of hMLH1 mutations in vivo, based on co-expression of human MLH1 and PMS2 in yeast cells. Yeast MLH1 and PMS1 genes, whose protein products form the MutLα complex, were replaced by human orthologs directly on yeast chromosomes by homologous recombination, and the resulting MMR activity was tested. The yeast strain co-expressing hMLH1 and hPMS2 exhibited the same mutation rate as the wild-type. Eight cancer-related MLH1 variants were introduced, using the same approach, into the prepared yeast model, and their effect on MMR function was determined. Five variants (A92P, S93G, I219V, K618R and K618T) were classified as non-pathogenic, whereas variants T117M, Y646C and R659Q were characterized as pathogenic. Results of our in vivo yeast-based approach correlate well with clinical data in five out of seven hMLH1 variants and the described model was thus shown to be useful for functional characterization of MLH1 variants in cancer patients found throughout the entire coding region of the gene

  16. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

    DEFF Research Database (Denmark)

    Helgason, Agnar; Pálsson, Snaebjörn; Thorleifsson, Gudmar;

    2007-01-01

    We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2di...

  17. Calling genotypes from public RNA-sequencing data enables identification of genetic variants that affect gene-expression levels

    NARCIS (Netherlands)

    Deelen, Patrick; Zhernakova, Daria V.; de Haan, Mark; van der Sijde, Marijke; Bonder, Marc Jan; Karjalainen, Juha; van der Velde, K. Joeri; Abbott, Kristin M.; Fu, Jingyuan; Wijmenga, Cisca; Sinke, Richard J.; Swertz, Morris A.; Franke, Lude

    2015-01-01

    Background: RNA-sequencing (RNA-seq) is a powerful technique for the identification of genetic variants that affect gene-expression levels, either through expression quantitative trait locus (eQTL) mapping or through allele-specific expression (ASE) analysis. Given increasing numbers of RNA-seq samp

  18. New variant of TEM-10 beta-lactamase gene produced by a clinical isolate of proteus mirabilis.

    OpenAIRE

    Palzkill, T.; Thomson, K S; Sanders, C C; Moland, E S; Huang, W.; Milligan, T W

    1995-01-01

    A clinical isolate of Proteus mirabilis was found to produce a new variant of the TEM-10 beta-lactamase gene. This is the first report of TEM-10 production by P. mirabilis and the first report of extended-spectrum beta-lactamase production by an isolate of this species recovered in the United States.

  19. COMT Val[superscript 108/158] Met Gene Variant, Birth Weight, and Conduct Disorder in Children with ADHD

    Science.gov (United States)

    Sengupta, Sarojini M.; Grizenko, Natalie; Schmitz, Norbert; Schwartz, George; Amor, Leila Ben; Bellingham, Johanne; de Guzman, Rosherrie; Polotskaia, Anna; Stepanian, Marina Ter; Thakur, Geeta; Joober, Ridha

    2006-01-01

    Objective: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design. Method: Children (n = 191) between 6 and…

  20. Association of adiponectin receptor 1 gene −106 C > T variant with susceptibility to colorectal cancer

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    Touraj Mahmoudi

    2016-09-01

    Conclusions: Our findings suggest for the first time that the −106 C > T (rs2275738 variant of ADIPOR1 gene may be a genetic contributor to CRC and obesity risk in the cases with CRC. However, further studies with bigger sample size are needed to validate these findings.

  1. IDENTIFICATION AND HORMONE INDUCTION OF PUTATIVE CHITIN SYNTHASE GENES AND SPLICE VARIANTS IN Leptinotarsa decemlineata (SAY).

    Science.gov (United States)

    Shi, Ji-Feng; Mu, Li-Li; Guo, Wen-Chao; Li, Guo-Qing

    2016-08-01

    Chitin synthase (ChS) plays a critical role in chitin synthesis and excretion. In this study, two ChS genes (LdChSA and LdChSB) were identified in Leptinotarsa decemlineata. LdChSA contains two splicing variants, LdChSAa and LdChSAb. Within the first, second, and third larval instars, the mRNA levels of LdChSAa, LdChSAb, and LdChSB coincide with the peaks of circulating 20-hydroxyecdysone (20E) and juvenile hormone (JH). In vitro culture of midguts and an in vivo bioassay revealed that 20E and an ecdysteroid agonist halofenozide stimulated the expression of the three LdChSs. Conversely, a reduction of 20E by RNA interference (RNAi) of an ecdysteroidogenesis gene LdSHD repressed the expression of these LdChSs, and ingestion of halofenozide by LdSHD RNAi larvae rescued the repression. Moreover, disruption of 20E signaling by RNAi of LdEcR, LdE75, LdHR3, and LdFTZ-F1 reduced the expression levels of these genes. Similarly, in vitro culture and an in vivo bioassay showed that exogenous JH and a JH analog methoprene activated the expression of the three LdChSs, whereas a decrease in JH by RNAi of a JH biosynthesis gene LdJHAMT downregulated these LdChSs. It seems that JH upregulates LdChSs at the early stage of each instar, whereas a 20E pulse triggers the transcription of LdChSs during molting in L. decemlineata. PMID:27030662

  2. The Porcine TSPY Gene Is Tricopy but Not a Copy Number Variant.

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    Anh T Quach

    Full Text Available The testis-specific protein Y-encoded (TSPY gene is situated on the mammalian Y-chromosome and exhibits some remarkable biological characteristics. It has the highest known copy number (CN of all protein coding genes in the human and bovine genomes (up to 74 and 200, respectively and also shows high individual variability. Although the biological function of TSPY has not yet been elucidated, its specific expression in the testis and several identified binding domains within the protein suggests roles in male reproduction. Here we describe the porcine TSPY, as a multicopy gene with three copies located on the short arm of the Y-chromosome with no variation at three exon loci among 20 animals of normal reproductive health from four breeds of domestic pigs (Piétrain, Landrace, Duroc and Yorkshire. To further investigate the speculation that porcine TSPY is not a copy number variant, we have included five Low-fertility boars and five boars with exceptional High-fertility records. Interestingly, there was no difference between the High- and Low-fertile groups, but we detected slightly lower TSPY CN at all three exons (2.56-2.85 in both groups, as compared to normal animals, which could be attributed to technical variability or somatic mosaicism. The results are based on both relative quantitative real-time PCR (qPCR and droplet digital PCR (ddPCR. Chromosomal localization of the porcine TSPY was done using fluorescence in situ hybridization (FISH with gene specific PCR probes.

  3. Genetic Variants in Matrix Metalloproteinase Genes as Disposition Factors for Ovarian Cancer Risk, Survival, and Clinical Outcome

    OpenAIRE

    Yan WANG; Ye, Yuanqing; Lin, Jie; Meyer, Larissa; Wu, Xifeng; Lu, Karen; Liang, Dong

    2013-01-01

    Ovarian cancer is one of the leading female cancers in the United States. Challenges remain in early diagnosis of this deadly disease. Matrix metalloproteinases (MMPs) family genes are paradoxically involved in cancer promotion and suppression. We hypothesize that genetic variants in MMP genes are associated with ovarian cancer development, so they could be potential markers for ovarian cancer diagnosis and prognosis. In this study of 417 ovarian cancer cases and 417 healthy controls, we geno...

  4. Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign

    OpenAIRE

    Strom, Samuel P.; Gorin, Michael B.

    2013-01-01

    Background Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced. Methods Publicly available data from the Exome Variant Project were analyzed, focusing on 3...

  5. Detection of copy number variants reveals association of cilia genes with neural tube defects.

    Directory of Open Access Journals (Sweden)

    Xiaoli Chen

    Full Text Available BACKGROUND: Neural tube defects (NTDs are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs. METHODS: The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined. RESULTS: Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV. Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05. Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87. Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05, corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01. Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways. CONCLUSIONS: Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.

  6. Characterization of the Ubiquitin E2 Enzyme Variant Gene Family in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Yu Zhang; Pei Wen; On-Sun Lau; Xing-Wang Deng

    2007-01-01

    Ubiquitin E2 enzyme variant (UEV) proteins are similar to ubiquitin-conjugating enzyme (E2) in both sequence and structure, but the lack of a catalytic cysteine residue renders them incapable of forming a thiolester linkage with ubiquitin. While the functional roles of several UEVs have been defined in yeast and animal systems, Arabidopsis COP10, a photomorphogenesis repressor, is the only UEV characterized in plants. Phylogenetic analysis revealed that the eight Arabidopsis UEV genes belong to three subfamilies.The expression of those genes is supported by either the presence of ESTs or RT-PCR analysis. We also characterized the other members of the COP10 subfamily, UEV2. Semi-quantitative RT-PCR analysis indicated that the UEV2 transcripts can be detected in most organs of Arabidopsis. Analysis of UEV2::GUS transgenic lines also showed its ubiquitous expression in nearly all the developmental stages of Arabidopsis.Transient expression analysis indicated that the sGFP-UEV2 fusion protein can localize to both the cytoplasm and nucleus. A T-DNA insertion mutant, uev2-1, which abolished the transcription of UEV2, displays no visible phenotype. Further, the cop10-4 uev2-1 double mutant exhibits the same phenotype as the cop10-4mutant in darkness. UEV2 is therefore not functionally redundant with COP10.

  7. ASSOCIATION OF ANGIOTENSINOGEN GENE M235T VARIANT IN PRE-ECLAMPSIA

    International Nuclear Information System (INIS)

    Pre-eclampsia (PE) is multisystem and multifactorial complication of pregnancy. The precise cause of pre-eclampsia has not been determined but mal adoption of the rennin and angiotensinogen (AGT) system may play a role. The products of genes involving the components of this system may be potential candidates for pre-eclampsia and hypertension related to pregnancy. This study was designed to determine whether the M235T variants of AGT gene were associated with the prevalence of pre-eclampsia and also to evaluate the role of plasma AGT in the development of the disease. Hence, developed, rapid and reliable PCR based assay was used to screen individuals for the M235T alleles. This assay was also used to genotype prospectively both recruited pregnant women with pre-eclampsia (n=24) and controls (n=11). Plasma AGT was determined by radioimmunoassay (RIA). The results of the PCR based assay revealed a significant association of 235T allele with the prevalence of all pre-eclamptic patients, Chi-square (x2) = 3.714, P0.05). Also, pre-eclamptic women exhibited significant higher levels of plasma AGT (52.15 ± 1.63) versus controls (44.76 ± 4.6) with P value < 0.001. This gave clear evidence that T235T allele and plasma AGT contributed to the development of pre-eclampsia with pregnancy and correlated with severity of the disease

  8. Gene transfer and expression of enhanced green fluorescent protein in variant HT-29c cells

    Institute of Scientific and Technical Information of China (English)

    Min Wang; Lars Boenicke; Bradley D. Howard; Ilka Vogel; Hoiger Kalthoff

    2003-01-01

    AIM: To study the expression of enhanced green fluorescent protein (EGFP) gene in retrovirally transduced variant HT29 cells.METHODS: The retroviral vector prkat EGFP/neo was constructed and transfected into the 293T cell using a standard calcium phosphate precipitation method. HT-29c cells (selected from HT-29 cells) were transduced by a retroviral vector encoding the GEFP gene. The fluorescence intensity of colorectal carcinoma HT-29c cells after transduced with the EGFP bearing retrovirus was visualized using fluorescence microscope and fluorescence activated cell sorter (FACS) analysis. Multiple biological behaviors of transduced cells such as the proliferating potential and the expression of various antigens were comparatively analyzed between untransduced and transduced cells in vitro. EGFP expression of the fresh tumor tissue was assessed in vivo.RESULTS: After transduced, HT-29c cells displayed a stable and long-term EGFP expression under the nonselective conditionsin vitro. After cells were successively cultured to passage 50 in vitro, EGFP expression was still at a high level. Their biological behaviors, such as expression of tumor antigens, proliferation rate and aggregation capability were not different compared to untransduced parental cells in vitro. In subcutaneous tumors, EGFP was stable and highly expressed.CONCLUSION: An EGFP expressing retroviral vector was used to transduce HT-29c cells. The transduced cells show a stable and long-term EGFP expression in vitro and in vivo.These cells with EGFP are a valuable tool forin vivo research of tumor metastatic spread.

  9. Association of NPRA and NPRC gene variants and hypertension in Mongolian population.

    Science.gov (United States)

    Chang, P Y; Liu, Z Y; Qin, L; Zhao, P

    2015-01-01

    NPRA and NPRC are candidate susceptibility genes for essential hypertension (EH) and play a key role in the regulation of plasma levels and biological effects of natriuretic peptides. The aims of the present study were to find new genetic markers in the NPRA and NPRC genes and to assess relationships between variants and EH. A total of 797 unrelated Mongolian herdsmen were enrolled, including 389 EH patients and 408 normotensive controls. Genotyping was performed using the polymerase chain reaction/ligase detection reaction assay. The distribution of the T-allele frequency of rs1847018 in NPRC differed significantly between hypertensive subjects and controls. There was an association between rs1847018 and EH in the additive model in NPRC (P TCG was significantly higher in the EH group than in controls; Individuals who possessed the TCA haplotype had a significantly lower risk of EH, whereas the presence of haplotype TCG was significantly associated with a higher risk of EH. However, there was no significant difference between the EH group and controls in any of the 8 haplotypes in NPRC. Rs1847018 is a genetic marker of EH in NPRC, and the frequency of haplotype TCA and TCG in NPRA is associated with EH in the Mongolian population. PMID:26782497

  10. Characterization of nodal/TGF-lefty signaling pathway gene variants for possible roles in congenital heart diseases.

    Directory of Open Access Journals (Sweden)

    Xia Deng

    Full Text Available BACKGROUND: Nodal/TGF-Lefty signaling pathway has important effects at early stages of differentiation of human embryonic stem cells in directing them to differentiate into different embryonic lineages. LEFTY, one of transforming growth factors in the Nodal/TGF-Lefty signaling pathway, plays an important role in the development of heart. The aim of this work was to find evidence on whether Lefty variations are associated with congenital heart diseases (CHD. METHODS: We sequenced the Lefty gene for 230 Chinese Han CHD patients and evaluated SNPs rs2295418, rs360057 and g.G169A, which are located within the translated regions of the genes. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0. The Hardy-Weinberg equilibrium test of the population was carried out using online software OEGE, and multiple-sequence alignments of LEFTY proteins were carried out using the Vector NTI software. RESULTS: Two heterozygous variants in Lefty1 gene, g.G169A and g.A1035C, and one heterozygous variant in Lefty2 gene, g.C925A, were identified. Statistical analyses showed that the rs2295418 (g.C925A variant in Lefty2 gene was obviously associated with the risk of CHD (P value = 0.0160.05. CONCLUSIONS: The SNP rs2295418 in the Lefty2 gene is associated with CHD in Chinese Han populations.

  11. Assessment of pathogenicity of natural IGFALS gene variants by in silico bioinformatics tools and in vitro functional studies.

    Science.gov (United States)

    Martucci, Lucía C; Gutiérrez, Mariana L; Karabatas, Liliana M; Scaglia, Paula A; Rey, Rodolfo A; Domené, Horacio M; Jasper, Héctor G; Domené, Sabina

    2016-07-01

    Acid-labile subunit (ALS) is essential for stabilization of IGF-I and IGFBP-3 in ternary complexes within the vascular system. ALS deficient (ALS-D) patients and a subset of children with idiopathic short stature (ISS), presenting IGFALS gene variants, show variable degree of growth retardation associated to IGF-I and IGFBP-3 deficiencies. The aim of this study was to evaluate the potential pathogenicity of eleven IGFALS variants identified in ALS-D and ISS children using in silico and in vitro approaches. We were able to classify seven of these variants as pathogenic since they present impaired synthesis (p.Glu35Lysfs*87, p.Glu35Glyfs*17, p.Asn276Ser, p.Leu409Phe, p.Ser490Trp and p.Cys540Arg), or partial impairment of synthesis and lack of secretion (p.Leu213Phe). We also observed significant reduction of secreted protein for variants p.Ala330Asp, Ala475Val and p.Arg548Trp, while still retaining their ability to form ternary complexes. These findings provide an approach to test the pathogenicity of IGFALS gene variants. PMID:27018247

  12. No significant impact of IFN-γ pathway gene variants on tuberculosis susceptibility in a West African population.

    Science.gov (United States)

    Meyer, Christian G; Intemann, Christopher D; Förster, Birgit; Owusu-Dabo, Ellis; Franke, Andre; Horstmann, Rolf D; Thye, Thorsten

    2016-05-01

    The concept of interferon-γ (IFN-γ) having a central role in cell-mediated immune defence to Mycobacterium tuberculosis has long been proposed. Observations made through early candidate gene studies of constituents of the IFN-γ pathway have identified moderately associated variants associated with resistance or susceptibility to tuberculosis (TB). By analysing 20 major genes whose proteins contribute to IFN-γ signalling we have assessed a large fraction of the variability in genes that might contribute to susceptibility to TB. Genetic variants were identified by sequencing the promoter regions and all exons of IFNG, IFNGR1, IFNGR2, IRF1, IL12A, IL12B, IL12RB1, IL12RB2, IL23A, IL23R, IL27, EBI3, IL27RA, IL6ST, SOCS1, STAT1, STAT4, JAK2, TYK2 and TBX21 in 69 DNA samples from Ghana. In addition, we screened all exons of IFNGR1 in a Ghanaian study group comprising 1999 TB cases and 2589 controls by high-resolution melting point analysis. The fine-mapping approach allows for a detailed screening of all variants, common and rare. Statistical comparisons of cases and controls, however, did not yield significant results after correction for multiple testing with any of the 246 variants selected for genotyping in this investigation. Gene-wise haplotype tests and analysis of rare variants did not reveal any significant association with susceptibility to TB in our investigation as well. Although this analysis was applied on a plausible set of IFN-γ pathway genes in the largest African TB cohort available so far, the lack of significant results challenges the view that genetic marker of the IFN-γ pathway have an important impact on susceptibility to TB. PMID:26242990

  13. Meiotic Interactors of a Mitotic Gene TAO3 Revealed by Functional Analysis of its Rare Variant.

    Science.gov (United States)

    Gupta, Saumya; Radhakrishnan, Aparna; Nitin, Rachana; Raharja-Liu, Pandu; Lin, Gen; Steinmetz, Lars M; Gagneur, Julien; Sinha, Himanshu

    2016-01-01

    Studying the molecular consequences of rare genetic variants has the potential to identify novel and hitherto uncharacterized pathways causally contributing to phenotypic variation. Here, we characterize the functional consequences of a rare coding variant of TAO3, previously reported to contribute significantly to sporulation efficiency variation in Saccharomyces cerevisiae During mitosis, the common TAO3 allele interacts with CBK1-a conserved NDR kinase. Both TAO3 and CBK1 are components of the RAM signaling network that regulates cell separation and polarization during mitosis. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2-a RAM network target gene. By quantitatively measuring cell morphological dynamics, and expressing the TAO3(4477C) allele conditionally during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation identified regulators of carbon and lipid metabolic pathways as candidate mediators. We show experimentally that, during sporulation, the TAO3(4477C) allele interacts genetically with ERT1 and PIP2, regulators of the tricarboxylic acid cycle and gluconeogenesis metabolic pathways, respectively. We thus uncover a meiotic functional role for TAO3, and identify ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that studying the causal effects of genetic variation on the underlying molecular network has the potential to provide a more extensive understanding of the pathways driving a complex trait. PMID:27317780

  14. Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine.

    Science.gov (United States)

    Anil Yağcioğlu, A Elif; Yoca, Gökhan; Ayhan, Yavuz; Karaca, R Özgür; Çevik, Lokman; Müderrisoğlu, Ahmet; Göktaş, Mustafa T; Eni, Nurhayat; Yazici, M Kâzim; Bozkurt, Atilla; Babaoğlu, Melih O

    2016-06-01

    Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event. PMID:27043126

  15. Prevalence of the prion protein gene E211K variant in U.S. cattle

    Directory of Open Access Journals (Sweden)

    Chase Chad C

    2008-07-01

    Full Text Available Abstract Background In 2006, an atypical U.S. case of bovine spongiform encephalopathy (BSE was discovered in Alabama and later reported to be polymorphic for glutamate (E and lysine (K codons at position 211 in the bovine prion protein gene (Prnp coding sequence. A bovine E211K mutation is important because it is analogous to the most common pathogenic mutation in humans (E200K which causes hereditary Creutzfeldt – Jakob disease, an autosomal dominant form of prion disease. The present report describes a high-throughput matrix-associated laser desorption/ionization-time-of-flight mass spectrometry assay for scoring the Prnp E211K variant and its use to determine an upper limit for the K211 allele frequency in U.S. cattle. Results The K211 allele was not detected in 6062 cattle, including those from five commercial beef processing plants (3892 carcasses and 2170 registered cattle from 42 breeds. Multiple nearby polymorphisms in Prnp coding sequence of 1456 diverse purebred cattle (42 breeds did not interfere with scoring E211 or K211 alleles. Based on these results, the upper bounds for prevalence of the E211K variant was estimated to be extremely low, less than 1 in 2000 cattle (Bayesian analysis based on 95% quantile of the posterior distribution with a uniform prior. Conclusion No groups or breeds of U.S. cattle are presently known to harbor the Prnp K211 allele. Because a carrier was not detected, the number of additional atypical BSE cases with K211 will also be vanishingly low.

  16. Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2.

    Science.gov (United States)

    Tee, Meng Kian; Speek, Mart; Legeza, Balázs; Modi, Bhavi; Teves, Maria Eugenia; McAllister, Janette M; Strauss, Jerome F; Miller, Walter L

    2016-10-15

    Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterized by hyperandrogenism and metabolic disorders. The excess androgens may be of both ovarian and adrenal origin. PCOS has a strong genetic component, and genome-wide association studies have identified several candidate genes, notably DENND1A, which encodes connecdenn 1, involved in trafficking of endosomes. DENND1A encodes two principal variants, V1 (1009 amino acids) and V2 (559 amino acids). The androgen-producing ovarian theca cells of PCOS women over-express V2. Knockdown of V2 in these cells reduces androgen production, and overexpression of V2 in normal theca cells confers upon them a PCOS phenotype of increased androgen synthesis. We report that human adrenal NCI-H295A cells express V1 and V2 mRNA and that the V2 isoform is produced by exonization of sequences in intron 20, which generates a unique exon 20A, encoding the C-terminus of V2. As in human theca cells from normal women, forced expression of V2 in NCI-H295A cells resulted in increased abundance of CYP17A1 and CYP11A1 mRNAs. We also found genetic variation in the intronic region 330 bp upstream from exon 20A, which could have the potential to drive the selective expression of V2. There was no clear association with these variants with PCOS when we analyzed genomc DNA from normal women and women with PCOS. Using minigene expression vectors in NCI-H295A cells, this variable region did not consistently favor splicing of the V2 transcript. These findings suggest increased V2 expression in PCOS theca cells is not the result of genomic sequence variation in intron 20. PMID:27297658

  17. Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy.

    Directory of Open Access Journals (Sweden)

    Dara G Torgerson

    Full Text Available Severe infection with respiratory syncytial virus (RSV during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20 at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively, and NOS1 in African Americans (p = 2.3x10-11. One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888, which was also nominally associated with asthma (p = 0.027 and active asthma (p = 0.013 among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.

  18. Identification of polymorphic variants of modifier gene B2AR (ADRB2 in patients with cystic fibrosis

    Directory of Open Access Journals (Sweden)

    ENILDA RRAPAJ

    2014-06-01

    Full Text Available Mutations of CFTR gene are identified as the molecular basis of cystic fibrosis (CF disease, but there are also other "modifier" genes, that influence the pathogenesis of the patients with CF. One such modifier genes is β2-adrenoreceptor gene (ADRB2. The aim of this study is the identification of polymorphic variants of this gene, in the locus Gln27Glu, in Albanian CF patients, in order to elucidate possible relations with clinical signs of the patients. We analyzed 47 patients with CF, which have the same genotype for CFTR gene, delF508 homozygous. DNA was extracted using standard methods from 5 ml of blood samples with EDTA. To identify genetic variants of this gene we used AS-PCR method and gel electrophoresis. Calculation of allele frequencies was done according to formulas in genetics of population.The method used for this study (AS - PCR was very effective, with high sensitivity and low cost. We found out that in Gln27Glu locus, the frequency of Gln27 and Glu27 alleles were 0,62 and 0,38 respectivily.After genotyping ADRB2 gene in locus 27 for each patient, we defined groups of patients with the same genotype. In future, we will use subgroups of CF patients with the same genotypes for ADBR2 gene, in order to analyze the relationship between genotypes Gln27Glu and clinical parameters of CF disease. Identification of polymorphic variants of B2AR modifier gene in CF patients, could be useful in predicting clinical status of the patients and can help to perform differentiated treatments.

  19. Multiplex PCR detection of GSTM1, GSTT1, and GSTP1 gene variants: simultaneously detecting GSTM1 and GSTT1 gene copy number and the allelic status of the GSTP1 Ile105Val genetic variant

    DEFF Research Database (Denmark)

    Buchard, Anders; Sanchez Sanchez, Juan Jose; Dalhoff, Kim;

    2007-01-01

    The glutathione S-transferase (GST) genes GSTM1, GSTT1, and GSTP1 are involved in the detoxification of a broad range of toxic substances. Genetic polymorphisms in these genes have been studied intensively for their potential role in cancer susceptibility and drug response. In Caucasians, the...... none, one, or two copies of the GSTM1 and GSTT1 genes and simultaneously detects the allelic status of the GSTP1 Ile105Val genetic variant. A total of 200 Danes, 100 Somalis, and 100 Greenlanders were genotyped. This multiplex PCR assay enables future large-scale studies to investigate the role of GSTs....

  20. Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

    Directory of Open Access Journals (Sweden)

    Natalie J Prescott

    2015-02-01

    Full Text Available The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04], but was independent of the known common associated CD and UC variants at this locus. Rare (T or decreased risk (IL12B p.V298F, and NICN p.H191R of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

  1. Copy number variants including RAS pathway genes-How much RASopathy is in the phenotype?

    Science.gov (United States)

    Lissewski, Christina; Kant, Sarina G; Stark, Zornitza; Schanze, Ina; Zenker, Martin

    2015-11-01

    The RASopathies comprise a group of clinically overlapping developmental syndromes the common pathogenetic basis of which is dysregulated signal flow through the RAS-MAPK pathway. Mutations in several components or modifiers of the pathway have been identified in Noonan syndrome and related disorders. Over the past years copy number variants (CNVs) encompassing RAS pathway genes (PTPN11, RAF1, MEK2, or SHOC2) have been reported in children with developmental syndromes. These observations raised speculations that the associated phenotypes represent RASopathies, implying that the increased or reduced expression of the respective RAS pathway component and a consecutive dysregulation of RAS pathway signalling is responsible for the clinical picture. Herein, we present two individuals and three of their relatives harboring duplications of either 3p25.2 including the RAF1 locus or 19p13.3 including the MEK2 locus. Duplication carriers exhibited variable clinical phenotypes including non-specific facial dysmorphism, short stature, and learning difficulties. A careful review of the literature supported the impression that phenotypes associated with CNVs including RAS pathway genes commonly share non-specific symptoms with RASopathies, while the characteristic "gestalt" is lacking. Considering the known molecular pathogenesis of RASopathies, it is questionable that a modest increase in the expression of a functionally normal signaling component can mimic the effects of a qualitatively abnormal (hyperactive) mutant protein. We thus argue that current empirical and biological evidence is still insufficient to allow the conclusion that an altered copy number of a RAS pathway component is indeed the mechanism that is critical for the phenotype associated with CNVs including RASopathy genes. PMID:25974318

  2. Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

    DEFF Research Database (Denmark)

    Druley, Todd E; Wang, Lihua; Lin, Shiow J;

    2016-01-01

    BACKGROUND: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. METHODS...... was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). CONCLUSIONS: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants....

  3. lambda altSF: a phage variant that acquired the ability to substitute specific sets of genes at high frequency.

    OpenAIRE

    Friedman, D.; Tomich, P; Parsons, C; Olson, E; Deans, R; Flamm, E

    1981-01-01

    We report the isolation of lambda altSF, a variant of Escherichia coli phage lambda that substitutes sets of genes at high frequency. Two forms of the variant phage have been studied: lambda altSF lambda, which exhibits the immunity (repressor recognition) of phage lambda, and lambda altSF22, which exhibits the immunity of Salmonella phage P22. Lysates made from single plaques of lambda altSF lambda contain 10-30% phage of the P22 form. Similarly, lysates from single plaques of lambda altSF22...

  4. Variant forms of the binary toxin CDT locus and tcdC gene in Clostridium difficile strains.

    Science.gov (United States)

    Stare, Barbara Geric; Delmée, Michel; Rupnik, Maja

    2007-03-01

    Variability in the genes for toxin A, toxin B and other pathogenicity locus regions is well known and is the basis for the distribution of Clostridium difficile strains into variant toxinotypes. Previous data have indicated that some C. difficile strains have a non-functional truncated form of the binary toxin (CDT) locus. This study analysed variability in the CDT locus and the presence of deleted tcdC genes in C. difficile strains. A total of 146 strains were screened, including known variant toxinotypes and non-variant A+B+ (toxinotype 0) and A-B- C. difficile strains. In all of the strains studied, only two forms of the CDT locus were found: a full-length 4.3 kb fragment encoding the functional binary toxin or a truncated 2.3 kb fragment. Whilst the full-length CDT locus was found almost exclusively in variant toxinotypes, the truncated form was detected in 79% of toxinotype 0 strains. Non-toxinogenic A-B- strains with a truncated version were not found and only rarely possessed the full-length CDT locus (A-B-CDT+ strains). Four different forms of the tcdC gene were found; three represented deleted versions and typically were found in toxinotypes III-VII, XI, XIV-XVI and XXIV. PMID:17314362

  5. Identification of rare high-risk copy number variants affecting the dopamine transporter gene in mental disorders

    DEFF Research Database (Denmark)

    Hoeffding, Louise K; Duong, Linh T T; Ingason, Andrés;

    2015-01-01

    rare high-risk variants of psychiatric disorders. METHODS: We performed a systematic screening for CNVs affecting SLC6A3 in 761 healthy controls, 672 schizophrenia patients, and 194 patients with bipolar disorder in addition to 253 family members from six large pedigrees affected by mental disorders...... affective disorders. Recently, copy number variants (CNVs) in SLC6A3 have been identified in healthy subjects but so far, the implication of CNVs affecting this gene in psychiatric diseases has not been addressed. AIMS: In the present study, we aimed to investigate whether CNVs affecting SLC6A3 represent...... sizes and two affected several genes in addition to SLC6A3. CONCLUSION: Our findings suggest that rare high-risk CNVs affecting the gene encoding the dopamine transporter contribute to the pathogenesis of schizophrenia and affective disorders....

  6. The effect of BCMO1 gene variants on macular pigment optical density in young healthy Caucasians

    Directory of Open Access Journals (Sweden)

    Zachary eKyle-Little

    2014-12-01

    Full Text Available Background: Serum lutein (L and zeaxanthin (Z positively correlate with macular pigment optical density (MPOD, hence the latter is a valuable indirect tool for measuring L and Z content in the macula. L and Z have been attributed antioxidant capacity and protection from certain retinal diseases but their uptake within the eye is thought to depend on genetic, age and environmental factors. In particular gene variants within beta-carotene monooxygenase (BCMO1 are thought to modulate MPOD in the macula.Objectives: To determine the effect of BCMO1 single nucleotide polymorphisms (SNPs rs11645428, rs6420424 and rs6464851 on macular pigment optical density (MPOD in a cohort of young healthy participants of Caucasian origin with normal ocular health.Design: In this cohort study, MPOD was assessed in 46 healthy participants (22 male and 24 female with a mean age of 24 ± 4.0 years (range 19-33. The three SNPs, rs11645428, rs6420424, rs6564851 that have established associations with MPOD were determined using MassEXTEND (hME Sequenom assay. One-way analysis of variance (ANOVA was performed on groups segregated into homozygous and heterozygous BCMO1 genotypes. Correlations between body mass index (BMI, iris colour, gender, central retinal thickness (CRT, diet and MPOD were investigated.Results: MPOD did not significantly vary with BCMO1 rs11645428 (F2,41 = 0.700, p = 0.503, rs6420424 (F2,41 = 0.210, p = 0.801 nor rs6464851 homozygous or heterozygous genotypes (F2,41 = 0,13, p = 0.88, in this young healthy cohort. The combination of these three SNPs into triple genotypes based on plasma conversion efficiency did not affect MPOD (F2,41 = 0.07, p = 0.9. There was a significant negative correlation with MPOD and central retinal thickness (r = - 0.39, p = 0.01 but no significant correlation between BMI, iris colour, gender and MPOD. Conclusion: Our results indicate that macular pigment deposition within the central retina is not dependent on BCMO1 gene variant

  7. Complex Behavior of ALDH1A1 and IGFBP1 in Liver Metastasis from a Colorectal Cancer

    Science.gov (United States)

    Kim, Jin Cheon; Ha, Ye Jin; Tak, Ka Hee; Roh, Seon Ae; Kim, Chan Wook; Kim, Tae Won; Kim, Seon-Kyu; Kim, Seon-Young; Cho, Dong-Hyung; Kim, Yong Sung

    2016-01-01

    Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p ≤ 0.001–0.003) and suppressed invasiveness by ≥3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of β-catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1

  8. Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects

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    Matimba Alice

    2009-01-01

    Full Text Available Abstract Pharmacogenetics enables personalised therapy based on genetic profiling and is increasingly applied in drug discovery. Medicines are developed and used together with pharmacodiagnostic tools to achieve desired drug efficacy and safety margins. Genetic polymorphism of drug-metabolising enzymes such as cytochrome P450s (CYPs and N-acetyltransferases (NATs has been widely studied in Caucasian and Asian populations, yet studies on African variants have been less extensive. The aim of the present study was to search for novel variants of CYP2C9, CYP2C19, CYP2D6 and NAT2 genes in Africans, with a particular focus on their prevalence in different populations, their relevance to enzyme functionality and their potential for personalised therapy. Blood samples from various ethnic groups were obtained from the AiBST Biobank of African Populations. The nine exons and exon-intron junctions of the CYP genes and exon 2 of NAT2 were analysed by direct DNA sequencing. Computational tools were used for the identification, haplotype analysis and prediction of functional effects of novel single nucleotide polymorphisms (SNPs. Novel SNPs were discovered in all four genes, grouped to existing haplotypes or assigned new allele names, if possible. The functional effects of non-synonymous SNPs were predicted and known African-specific variants were confirmed, but no significant differences were found in the frequencies of SNPs between African ethnicities. The low prevalence of our novel variants and most known functional alleles is consistent with the generally high level of diversity in gene loci of African populations. This indicates that profiles of rare variants reflecting interindividual variability might become the most relevant pharmacodiagnostic tools explaining Africans' diversity in drug response.

  9. Association of Transforming Growth Factor Alpha and Methylenetetrahydrofolate reductase gene variants with nonsyndromic cleft lip and palate in the Indian population

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    Asavari L Desai

    2014-01-01

    Full Text Available Objectives: The aim was to evaluate the relationship of the K-primer variant of the transforming growth factor-alpha (TGF-α gene and C677T variant of the methylenetetrahydrofolate reductase (MTHFR gene with nonsyndromic cleft lip and palate (CL/P in the Indian population. Setting and Sample Population: The study group consisted of DNA samples of 25 subjects with nonsyndromic CL with or without cleft palate and 25 unrelated controls, already existing in the Department of Orthodontics, D.A.P.M.R.V. Dental College, Bengaluru, Karnataka, India. Materials and Methods: The DNA samples were divided into two categories: Group A which included the 25 subjects with nonsyndromic CL/P; and Group B, which consisted of the 25 unrelated controls. The polymerase chain reaction (PCR test was done for amplification of the region of interest from the DNA samples. Restriction digestion was then performed on the amplified product using the restriction enzyme HinfI, separately for each of the variants. The digested PCR products were separated into channels on a 1.5% agarose gel containing ethidium bromide in an electrophoretic chamber. A U.V. transilluminator was used to see the specific bands of base pairs of the digested PCR products. Results: In Group A, the TGF-α gene variant was present in 16 subjects (P = 0.001 and MTHFR gene variant was present in 8 subjects (P = 0.185. A combination of both gene variants were present in seven subjects, which was an interesting finding. In Group B, four subjects tested positive for the TGF-α and MTHFR gene variants. Conclusions: The TGF-α gene variant and a combination of TGF-α + MTHFR gene variants significantly contribute to the development of nonsyndromic CL/P and can be considered as genetic markers for Indian population. The MTHFR gene variant, though a minor risk factor, cannot be considered as a genetic marker.

  10. Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke.

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    Stephen R Williams

    2014-03-01

    Full Text Available Circulating homocysteine levels (tHcy, a product of the folate one carbon metabolism pathway (FOCM through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD, cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia, dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 × 10(-63], CBS [p = 3.15 × 10(-26], CPS1 [p = 9.10 × 10(-13], ALDH1L1 [p = 7.3 × 10(-13] and PSPH [p = 1.17 × 10(-16] were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST. Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.

  11. Genes of nuclear encoded mitochondrial proteins: evidence for a variant of the 3' splice-site consensus sequence.

    OpenAIRE

    Juretić, N; Jaussi, R; Mattes, U; Christen, P

    1987-01-01

    The introns of animal nuclear genes and of viral genes encoding protein possess at their 3' splice-site the consensus sequence (CT)11NTCAG (Mount, S.M. (1982) Nucl. Acids Res. 10, 459-472; Green, M.R. (1986) Ann. Rev. Genet. 20, 671-708). However, the total 39 introns of the 5 imported mitochondrial proteins of higher eucaryotes whose gene structure has been determined to date show a predominance of 44% for base T at position -4. Apparently, a variant consensus sequence, i.e. (CT)11TTCAG, cha...

  12. Nucleotide Variants of the BH4 Biosynthesis Pathway Gene GCH1 and the Risk of Orofacial Clefts

    OpenAIRE

    Hozyasz, Kamil K.; Mostowska, Adrianna; Wójcicki, Piotr; Lasota, Agnieszka; Zadurska, Małgorzata; Dunin-Wilczyńska, Izabela; Jagodziński, Paweł P.

    2015-01-01

    A deficiency of GTP cyclohydrolase, encoded by the GCH1 gene, results in two neurological diseases: hyperphenylalaninaemia type HPABH4B and DOPA-responsive dystonia. Genes involved in neurotransmitter metabolism and motor systems may contribute to palatogenesis. The purpose of the study was to analyse polymorphic variants of the GCH1 gene as risk factors for non-syndromic cleft lip with or without cleft palate (NSCL/P). Genotyping of nine polymorphisms was conducted in a group of 281 NSCL/P p...

  13. Variant at position 10,055 in mitochondrial tRNA(Gly) gene has a negative association with aplastic anemia.

    Science.gov (United States)

    Jiang, Zhongxing; Wu, Xinai; Zhu, Yanan

    2016-09-01

    Recently, a growing number of reports had shown the association between mitochondrial DNA (mtDNA) sequence variants and aplastic anemia (AA). Owing to its high mutation rate, mtDNA variant had become biomarker for clinical and molecular diagnosis for AA. However, the relationship between mtDNA variant and AA was largely unknown. In this study, we reanalyzed the possible association between a "pathogenic" mutation A10055G in mt-tRNA(Gly) gene and AA, through the application of bioinformatics tool, we found that this mutation did not alter the secondary structure of tRNA(Gly), the pathogenicity scoring system indicated that the score of this mutation was only two points and belonged to a "neutral polymorphism", suggested that the role of A10055G mutation in clinical expression in AA needed to be further experimentally addressed. PMID:25629498

  14. Rare Variants in Genes Encoding MuRF1 and MuRF2 Are Modifiers of Hypertrophic Cardiomyopathy

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    Ming Su

    2014-05-01

    Full Text Available Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM, but are still largely unknown. Muscle ring finger (MuRF proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2% vs. 1/307 (0.3%, p = 0.04; MuRF2 22/594 (3.7% vs. 2/307 (0.7%; p = 0.007. Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04 and had greater maximum left ventricular wall thickness (p = 0.006 than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9% of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.

  15. Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis.

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    Anil K Giri

    Full Text Available A recent genome-wide association study (GWAS identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525-OR 1.71, P = 1.38 x 10-09; rs12008279-OR 1.56, P = 1.53 x 10-04 and 2 variants in MORC4 gene (rs12688220-OR 1.72, P = 9.20 x 10-09; rs6622126-OR 1.75, P = 4.04x10-05 in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06 and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31-0.78], P = 0.0027. A variant in the gene MORC4 (rs12688220 showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068 suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14. Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.

  16. Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis.

    Science.gov (United States)

    Giri, Anil K; Midha, Shallu; Banerjee, Priyanka; Agrawal, Ankita; Mehdi, Syed Jafar; Dhingra, Rajan; Kaur, Ismeet; G, Ramesh Kumar; Lakhotia, Ritika; Ghosh, Saurabh; Das, Kshaunish; Mohindra, Samir; Rana, Surinder; Bhasin, Deepak K; Garg, Pramod K; Bharadwaj, Dwaipayan

    2016-01-01

    A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525-OR 1.71, P = 1.38 x 10-09; rs12008279-OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220-OR 1.72, P = 9.20 x 10-09; rs6622126-OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31-0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients. PMID:26820620

  17. Functional Analysis of Missense Variants in the Putative Breast Cancer Susceptibility Gene XRCC2.

    Science.gov (United States)

    Hilbers, Florentine S; Luijsterburg, Martijn S; Wiegant, Wouter W; Meijers, Caro M; Völker-Albert, Moritz; Boonen, Rick A; van Asperen, Christi J; Devilee, Peter; van Attikum, Haico

    2016-09-01

    XRCC2 genetic variants have been associated with breast cancer susceptibility. However, association studies have been complicated because XRCC2 variants are extremely rare and consist mainly of amino acid substitutions whose grouping is sensitive to misclassification by the predictive algorithms. We therefore functionally characterized variants in XRCC2 by testing their ability to restore XRCC2-DNA repair deficient phenotypes using a cDNA-based complementation approach. While the protein-truncating variants p.Leu117fs, p.Arg215*, and p.Cys217* were unable to restore XRCC2 deficiency, 19 out of 23 missense variants showed no or just a minor (<25%) reduction in XRCC2 function. The remaining four (p.Cys120Tyr, p.Arg91Trp, p.Leu133Pro, and p.Ile95Leu) had a moderate effect. Overall, measured functional effects correlated poorly with those predicted by in silico analysis. After regrouping variants from published case-control studies based on the functional effect found in this study and reanalysis of the prevalence data, there was no longer evidence for an association with breast cancer. This suggests that if breast cancer susceptibility alleles of XRCC2 exist, they are likely restricted to protein-truncating variants and a minority of missense changes. Our study emphasizes the use of functional analyses of missense variants to support variant classification in association studies. PMID:27233470

  18. Rare Syndromes and Common Variants of the Brain-Derived Neurotrophic Factor Gene in Human Obesity.

    Science.gov (United States)

    Han, J C

    2016-01-01

    Rare genetic disorders that cause BDNF haploinsufficiency, such as WAGR syndrome, 11p deletion, and 11p inversion, serve as models for understanding the role of BDNF in human energy balance and neurocognition. Patients with BDNF haploinsufficiency or inactivating mutations of the BDNF receptor exhibit hyperphagia, childhood-onset obesity, intellectual disability, and impaired nociception. Prader-Willi, Smith-Magenis, and ROHHAD syndromes are separate genetic disorders that do not directly affect the BDNF locus but share many similar clinical features with BDNF haploinsufficiency, and BDNF insufficiency is believed to possibly contribute to the pathophysiology of each of these conditions. In the general population, common variants of BDNF that affect BDNF gene expression or BDNF protein processing have also been associated with modest alterations in energy balance and cognitive functioning. Thus, variable degrees of BDNF insufficiency appear to contribute to a spectrum of excess weight gain and cognitive impairment that ranges in phenotypic severity. In this modern era of precision medicine, genotype-specific therapies aimed at increasing BDNF signaling in patients with rare and common disorders associated with BDNF insufficiency could serve as useful approaches for treating obesity and neurodevelopmental disorders. PMID:27288826

  19. Synchronous expression of individual metacyclic variant surface glycoprotein genes in Trypanosoma brucei.

    Science.gov (United States)

    Ramey-Butler, Kiantra; Ullu, Elisabetta; Kolev, Nikolay G; Tschudi, Christian

    2015-01-01

    One distinctive feature of the Trypanosoma brucei life cycle is the presence of two discrete populations that are based on differential expression of variant surface glycoproteins (VSGs). Both are adapted to the environmental pressures they face and more importantly, both contribute directly to transmission. Metacyclics in the tsetse fly enable transmission to a new mammalian host, whereas bloodstream trypanosomes must avoid immune destruction to the extent that sufficient numbers are available for transmission, when the insect vector takes a blood meal. At present, there are few investigations on the molecular aspects of parasite biology in the tsetse vector and specifically about the activation of metacyclic VSG gene expression. Here we used an established in vitro differentiation system based on the overexpression of the RNA-binding protein 6 (RBP6), to monitor two metacyclic VSGs (VSG 397 and VSG 653) during development from procyclics to infectious metacyclic forms. We observed that activation of these two mVSGs was simultaneous both at the transcript and protein level, and manifested by the appearance of only one of the mVSGs in individual cells. PMID:25896436

  20. Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD.

    Science.gov (United States)

    Arcos-Burgos, Mauricio; Muenke, Maximilian

    2010-11-01

    During the past 15 years, an impressive amount of genetic information has become available in the research field of psychiatry, particularly as it relates to attention-deficit/hyperactivity disorder (ADHD). However, the classical clinical approach to ADHD has minimally affected and not significantly been improved by this genetic revolution. It is difficult to predict how long it will take for genetic findings to alter the way clinicians treat patients with ADHD. New medications or treatment protocols may take years to become routine clinical practice. However, when taken together, recent successes in genomics, pharmacogenomics, and genetic epidemiology have the potential (1) to prevent comorbid consequences of ADHD, (2) to individualize therapies for patients with ADHD, and (3) to define new epidemiological policies to aid with the impact of ADHD on society. Here, we present an overview of how genetic research may affect and improve the quality of life of patients with ADHD: as an example, we use the discovery of LPHN3, a new gene in which variants have recently been shown to be associated with ADHD. PMID:21432600

  1. RBP4 Gene Variants Are Associated with Insulin Resistance in Women with Previous Gestational Diabetes

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    Renata Saucedo

    2014-01-01

    Full Text Available Objective. This study aimed to examine possible genetic effects of some retinol binding protein-4 (RBP4 single nucleotide polymorphisms (SNPs on the risk of gestational diabetes mellitus (GDM. In addition, the SNPs were examined for their possible association with insulin resistance at 6 weeks after delivery. Methods. This was a prospective study of 100 women with GDM and 100 participants with normal gestation who were evaluated at gestational week 30 and 6 weeks postpartum. Three SNPs of RBP4 (rs3758539, rs116736522, and rs34571439 were genotyped using TaqMan assay. The genotype distributions between GDM patients and normal controls were analyzed using logistic regression models. In addition, differences in clinical characteristics among subjects grouped by genotype were assessed using the analysis of covariance test. Results. The frequencies of the rare alleles were not significantly different between GDM patients and controls. However, we identified two variants rs3758539 and rs34571439 associated with insulin levels and insulin resistance in women with previous GDM. Conclusion. Noncoding SNPs of the RBP4 gene are not associated with GDM, but two SNPs showed associations with insulin resistance and insulin levels in women with prior GDM. Additional studies with increased sample size will be necessary in other GDM cohorts.

  2. The c.657del5 variant in the NBN gene predisposes to pancreatic cancer.

    Science.gov (United States)

    Borecka, Marianna; Zemankova, Petra; Lhota, Filip; Soukupova, Jana; Kleiblova, Petra; Vocka, Michal; Soucek, Pavel; Ticha, Ivana; Kleibl, Zdenek; Janatova, Marketa

    2016-08-10

    Pancreatic ductal adenocarcinoma (PDAC) is the sixth most frequent cancer type in the Czech Republic with a poor prognosis that could be improved by an early detection and subsequent surgical treatment combined with chemotherapy. Genetic factors play an important role in PDAC risk. We previously identified one PDAC patient harboring the Slavic founder deleterious mutation c.657del5 in the NBN gene, using a panel next-generation sequencing (NGS). A subsequent analysis of 241 unselected PDAC patients revealed other mutation carriers. The overall frequency of c.657del5 in unselected PDAC patients (5/241; 2.07%) significantly differed from that in non-cancer controls (2/915; 0.2%; P=0.006). The result indicates that the NBN c.657del5 variant represents a novel PDAC-susceptibility allele increasing PDAC risk (OR=9.7; 95% CI: 1.9 to 50.2). The increased risk of PDAC in follow-up recommendations for NBN mutation carriers should be considered if other studies also confirm an increased frequency of c.657del5 carriers in PDAC patients from other populations. PMID:27150568

  3. Correlation of a set of gene variants, life events and personality features on adult ADHD severity.

    Science.gov (United States)

    Müller, Daniel J; Chiesa, Alberto; Mandelli, Laura; De Luca, Vincenzo; De Ronchi, Diana; Jain, Umesh; Serretti, Alessandro; Kennedy, James L

    2010-07-01

    Increasing evidence suggests that symptoms of attention deficit hyperactivity disorder (ADHD) could persist into adult life in a substantial proportion of cases. The aim of the present study was to investigate the impact of (1) adverse events, (2) personality traits and (3) genetic variants chosen on the basis of previous findings and (4) their possible interactions on adult ADHD severity. One hundred and ten individuals diagnosed with adult ADHD were evaluated for occurrence of adverse events in childhood and adulthood, and personality traits by the Temperament and Character Inventory (TCI). Common polymorphisms within a set of nine important candidate genes (SLC6A3, DBH, DRD4, DRD5, HTR2A, CHRNA7, BDNF, PRKG1 and TAAR9) were genotyped for each subject. Life events, personality traits and genetic variations were analyzed in relationship to severity of current symptoms, according to the Brown Attention Deficit Disorder Scale (BADDS). Genetic variations were not significantly associated with severity of ADHD symptoms. Life stressors displayed only a minor effect as compared to personality traits. Indeed, symptoms' severity was significantly correlated with the temperamental trait of Harm avoidance and the character trait of Self directedness. The results of the present work are in line with previous evidence of a significant correlation between some personality traits and adult ADHD. However, several limitations such as the small sample size and the exclusion of patients with other severe comorbid psychiatric disorders could have influenced the significance of present findings. PMID:20006992

  4. Genetic Variants in the FADS Gene: Implications for Dietary Recommendations for Fatty Acid Intake.

    Science.gov (United States)

    Mathias, Rasika A; Pani, Vrindarani; Chilton, Floyd H

    2014-06-01

    Unequivocally, genetic variants within the fatty acid desaturase (FADS) cluster are determinants of long chain polyunsaturated fatty acid (LC-PUFA) levels in circulation, cells and tissues. A recent series of papers have addressed these associations in the context of ancestry; evidence clearly supports that the associations are robust to ethnicity. However ∼80% of African Americans carry two copies of the alleles associated with increased levels of arachidonic acid, compared to only ∼45% of European Americans raising important questions of whether gene-PUFA interactions induced by a modern western diet are differentially driving the risk of diseases of inflammation in diverse populations, and are these interactions leading to health disparities. We highlight an important aspect thus far missing in the debate regarding dietary recommendations; we content that current evidence from genetics strongly suggest that an individual's, or at the very least the population from which an individual is sampled, genetic architecture must be factored into dietary recommendations currently in place. PMID:24977108

  5. Corticotropin-releasing hormone receptor 1 gene variants in irritable bowel syndrome.

    Directory of Open Access Journals (Sweden)

    Naoko Sato

    Full Text Available BACKGROUND: Corticotropin-releasing hormone (CRH acts mainly via the CRH receptor 1 (CRH-R1 and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS. Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients. METHODS: A total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402 were genotyped. Subjects' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale. RESULTS: The TT genotype of rs7209436 (P = 0.01 and rs242924 (P = 0.02 was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms and the T allele of rs7209436 (P = 0.008, T allele of rs242924 (P = 0.019, A allele of rs110402 (P = 0.047, and TAT haplocopies (P = 0.048. Negative emotion was not associated with the examined CRH-R1 SNPs. CONCLUSION: These findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.

  6. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, G.M.; Wasserman, C.R.; O`Malley, C.D. [California Birth Defects Monitoring Program, Emeryville, CA (United States)] [and others

    1996-03-01

    Results of studies determine whether women who smoke during early pregnancy are at increased risk of delivering infants with orofacial clefts have been mixed, and recently a gene-environment interaction between maternal smoking, transforming growth factor-alpha (TGFa), and clefting has been reported. Using a large population-based case-control study, we investigated whether parental periconceptional cigarette smoking was associated with an increased risk for having offspring with orofacial clefts. We also investigated the influence of genetic variation of the TGFa locus on the relation between smoking and clefting. Parental smoking information was obtained from telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening blood spots and genotyped for the allelic variants of TGFa. We found that risks associated with maternal smoking were most elevated for isolated cleft lip with or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked {ge} 20 cigarrettes/d. These risks for white infants ranged from 3-fold to 11-fold across phenotypic groups. Paternal smoking was not associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly increased risks. This study offers evidence that the risk for orofacial clefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the presence of the uncommon TGFa allele. 56 refs., 5 tabs.

  7. EDN1 Gene Variant is Associated with Neonatal Persistent Pulmonary Hypertension

    Science.gov (United States)

    Mei, Mei; Cheng, Guoqiang; Sun, Bijun; Yang, Lin; Wang, Huijun; Sun, Jinqiao; Zhou, Wenhao

    2016-01-01

    Recent studies have suggested associations between certain genetic variants and susceptibility to persistent pulmonary hypertension of the newborn (PPHN). The aim of the study was to evaluate the association of EDN1, NOS3, ACE and VEGFA genes with PPHN. Neonates with respiratory distress were enrolled in the study, whose gestational age ≥34 weeks, age ≤3 days. They were divided into PPHN and non-PPHN group. The EDN1, NOS3, ACE and VEGFA genes were detected by next-generation sequencing, and the results were validated by Sanger sequencing. Serum endothelin-1 (ET-1) levels were quantified by ELISA. A total of 112 neonates were enrolled (n = 55 in PPHN group; n = 57 in non-PPHN group). There is a significantly difference in the genotype distribution of EDN1 rs2070699 between the PPHN and non-PPHN group (P = 0). A higher frequency of the rs2070699 T allele was observed in the PPHN group (54.5% vs 27.2%; OR = 3.89; 95%CI 1.96–7.72). The rs2070699 T allele was associated with higher ET-1 levels (3.333 ± 2.517 pg/mL vs 1.223 ± 0.856 pg/mL; P = 0.002) and a longer ventilation period (5.8 ± 2.6 days vs 3.6 ± 3.3 days; P = 0). The results suggest there is an association between EDN1 and PPHN. The presence of the rs2070699 T allele increased the risk of PPHN in neonates with respiratory distress. PMID:27425626

  8. Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

    International Nuclear Information System (INIS)

    MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls) to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH). Using unconditional logistic regression we found that MLH3 (L844P, G>A) polymorphism GA (Leu/Pro) and AA (Pro/Pro) genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95) (p = 0.03) and OR = 0.62 (0.41-0.94) (p = 0.03), respectively. Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83), p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49), p = 0.01], GG/AA [OR = 2.11 (1.12-3,98), p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15), p = 0.02] all associated with an increased risk for breast cancer. It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results

  9. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1, in human epithelial cancers.

    Directory of Open Access Journals (Sweden)

    Shan Deng

    Full Text Available Aldehyde dehydrogenase isoform 1 (ALDH1 has been proved useful for the identification of cancer stem cells. However, our knowledge of the expression and activity of ALDH1 in common epithelial cancers and their corresponding normal tissues is still largely absent. Therefore, we characterized ALDH1 expression in 24 types of normal tissues and a large collection of epithelial tumor specimens (six cancer types, n = 792 by immunohistochemical staining. Using the ALDEFUOR assay, ALDH1 activity was also examined in 16 primary tumor specimens and 43 established epithelial cancer cell lines. In addition, an ovarian cancer transgenic mouse model and 7 murine ovarian cancer cell lines were analyzed. We found that the expression levels and patterns of ALDH1 in epithelial cancers are remarkably distinct, and they correlate with their corresponding normal tissues. ALDH1 protein expression levels are positively correlated with ALDH1 enzymatic activity measured by ALDEFLUOR assay. Long-term in vitro culture doesn't significantly affect ALDH1 activity in epithelial tumor cells. Consistent with research on other cancers, we found that high ALDH1 expression is significantly associated with poor clinical outcomes in serous ovarian cancer patients (n = 439, p = 0.0036. Finally, ALDH(br tumor cells exhibit cancer stem cell properties and are resistant to chemotherapy. As a novel cancer stem cell marker, ALDH1 can be used for tumors whose corresponding normal tissues express ALDH1 in relatively restricted or limited levels such as breast, lung, ovarian or colon cancer.

  10. Allelic variants of XRCC1 and XRCC3 repair genes and susceptibility of oral cancer in Brazilian patients

    DEFF Research Database (Denmark)

    Dos Reis, Mariana Bisarro; Losi-Guembarovski, Roberta; de Souza Fonseca Ribeiro, Enilze Maria; Cavalli, Iglenir João; Morita, Maria Celeste; Ramos, Gyl Henrique Albrecht; de Oliveira, Benedito Valdecir; Mizuno, Lauro Toyoshi; Rogatto, Silvia Regina; de Syllos Cólus, Ilce Mara

    2013-01-01

    genes have been found to be associated with oral cancer. The aim of this study was to investigate the relationship between the presence of allelic variants Arg194Trp (rs:1799782) and Arg399Gln (rs: 25487) of XRCC1 gene and Thr241Met (rs: 861539) of XRCC3 gene and susceptibility to oral cancer. We also...... variants of the XRCC1 gene within codon 194 (OR 0.82, 95% CI: 0.44-1.51) and codon 399 (OR 0.94, 95% CI: 0.59-1.50) and within the XRCC3 gene (OR 0.72; 95% CI: 0.45-1.16) were not associated with an increased risk of oral cancer. A combinational analysis of SNPs in both genes indicated no association. The......BACKGROUND: The capacity for DNA repair is essential in maintaining cellular functions and homeostasis; however, this capacity can be altered based on DNA sequence variations in DNA repair genes, which may contribute to the onset of cancer. Many single-nucleotide polymorphisms (SNPs) in repair...

  11. [Lack of association between the S447X variant of the lipoprotein lipase gene and plasma lipids. A preliminary study].

    Science.gov (United States)

    Zambrano Morales, Mariana; Fernández Salgado, Erika; Balzán Urdaneta, Ligia; Labastidas, Neila; Aranguren-Méndez, José; Connell, Lissette; Molero Paredes, Tania; Rojas, Alicia; Panunzio, Amelia

    2014-06-01

    The increase in lipid plasma values is an important cardiovascular risk factor. Lipoprotein lipase (LPL) plays an important role in the lipoprotein metabolism and metabolic and genetic factors may influence its levels and functions. The S447X variant of the lipoprotein lipase gene is associated with changes in plasma lipids in different populations. The objective of this research was to analyze the S447X variant of the LPL gene and its relation with plasma lipids of individuals in Zulia state, Venezuela. With this purpose, we studied 75 individuals (34 men and 41 women) between 20 and 60 years of age. Each subject had a medical history which included family history, anthropometric characteristics, nutritional status evaluation and biochemical tests. Genomic DNA was extracted for the molecular study and the polymerase chain reaction was used, followed by enzyme digestion, for restriction fragments length polymorphisms using the Hinf I enzyme. The individuals studied had normal levels of blood glucose, triglycerides, total cholesterol and low density lipoproteins (LDL-C) and slightly decreased levels of high density lipoproteins (HDL-C). The genotypic distribution of the LPL gene S447X variant in the studied population was 90.6% for the homozygous genotype SS447 and 9.4% for the heterozygote SX447. The genotype 447XX was not identified. The population was found in Hardy Weinberg genetic equilibrium. No association between the S447X polymorphism of lipoprotein lipase gene and plasma lipids was observed. PMID:24974629

  12. Genetic polymorphisms of ADH2 and ALDH2 association with esophageal cancer risk in southwest China

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To evaluate the impact of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2)polymorphisms on esophageal cancer risk.METHODS: One hundred and ninety-one esophageal cancer patients and 198 healthy controls from Yanting County were enrolled in this study. ADH2 and ALDH2genotypes were examined by polymerase-chain-reaction with the confronting-two-pair-primer (PCR-CTPP)method. Unconditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence interval (95% CI).RESULTS: Both ,ADH2*1 allele and ,ALDH2*1/*2 allele showed an increased risk of developing esophageal cancer. The adjusted OR (95% CI) for ,ADH2*1allele compared with ,ADH2*2/*2 was 1.65 (95%CI= 1.02-2.68) and 1.67 (95% CI= 1.02-2.72) for ,ALDH2*1/*2 compared with ALDH2*1/*1. A significant interaction between ,ALDH2 and drinking was detected regarding esophageal cancer risk, the OR was 1.83(95% CI = 1.13-2.95). Furthermore, when compared with ADH2*2/*2 and ALDH2*1/*1 carriers, ADH2*1 and ALDH2*2 carriers showed an elevated risk of developing esophageal cancer among non-alcohol drinkers (OR =2.46, 95% CI= 0.98-6.14), and a significantly elevated risk of developing esophageal cancer among alcohol drinkers among alcohol drinkers (OR = 9.86, 95% CI=3.10-31.38).CONCLUSION: ADH2 and ALDH2 genotypes are associated with esophageal cancer risk. ADH2*1 allele and ALDH2*2 allele carriers have a much higher risk of developing esophageal cancer, especially among alcohol drinkers.

  13. Associations between a common variant near the MC4R gene and serum triglyceride levels in an obese pediatric cohort.

    Science.gov (United States)

    Fernandes, Ariana Ester; de Melo, Maria Edna; Fujiwara, Clarissa Tamie Hiwatashi; Pioltine, Marina Brosso; Matioli, Sergio Russo; Santos, Aritânia; Cercato, Cintia; Halpern, Alfredo; Mancini, Marcio C

    2015-08-01

    Polymorphisms near the MC4R gene may be related to an increased risk for obesity, but studies of variations in this gene and its relation to cardiometabolic profiles and food intake are scarce and controversial. The aim of this study is to evaluate the influence of the variants rs12970134 and rs17782313 near the MC4R gene in food intake, binge eating (BE) behavior, anthropometric parameters, body composition, metabolic profile, and cardiometabolic risk factors in obese children and adolescents. This is a cross-sectional study that included obese children and adolescents. We evaluated anthropometric, metabolic parameters and cardiometabolic risk factors, including hypertension, impaired fasting glucose, hypertriglyceridemia, and low HDL-cholesterol. BE was assessed through the BE scale, and a 24-h recall was used to evaluate total caloric intake and percentage of macronutrients and types of dietary fat. The MC4R variants rs12970134 and rs17782313 were genotyped using TaqMan assay. To assess the magnitude of risk, a logistic regression adjusted for Z-BMI, age, and gender was performed, adopting the significance level of 0.05. The study included 518 subjects (52.1 % girls, 12.7 ± 2.7 years old, Z-BMI = 3.24 ± 0.57). Carriers of the variant rs17782313 exhibit increased triglyceride levels (108 ± 48 vs. 119 ± 54, p = 0.034) and an increased risk of hypertriglyceridemia (OR 1.985, 95 % CI 1.288-3.057, p = 0.002). There was no association of the SNP rs12970134 with clinical, metabolic, or nutritional parameters. The variant rs12970134 and rs17782313 did not influence food intake or the presence of BE. The variant rs17782313 is associated with an increased risk of hypertriglyceridemia in obese children and adolescents. PMID:25948074

  14. Mannose-binding lectin promoter polymorphisms and gene variants in pulmonary tuberculosis patients from cantabria (northern Spain).

    Science.gov (United States)

    Ocejo-Vinyals, J-Gonzalo; Lavín-Alconero, Lucía; Sánchez-Velasco, Pablo; Guerrero-Alonso, M-Ángeles; Ausín, Fernando; Fariñas, M-Carmen; Leyva-Cobián, Francisco

    2012-01-01

    Mannose-binding lectin is a central molecule of the innate immune system. Mannose-binding lectin 2 promoter polymorphisms and structural variants have been associated with susceptibility to tuberculosis. However, contradictory results among different populations have been reported, resulting in no convincing evidence of association between mannose-binding lectin 2 and susceptibility to tuberculosis. For this reason, we conducted a study in a well genetically conserved Spanish population in order to shed light on this controversial association. We analysed the six promoter and structural mannose-binding lectin 2 gene variants in 107 patients with pulmonary tuberculosis and 441 healthy controls. Only D variant and HYPD haplotype were significantly more frequents in controls which would indicate that this allele could confer protection against pulmonary tuberculosis, but this difference disappeared after statistical correction. Neither the rest of alleles nor the haplotypes were significantly associated with the disease. These results would indicate that mannose-binding lectin promoter polymorphisms and gene variants would not be associated with an increased risk to pulmonary tuberculosis. Despite the slight trend of the D allele and HYPD haplotype in conferring protection against pulmonary tuberculosis, susceptibility to this disease would probably be due to other genetic factors, at least in our population. PMID:23304495

  15. Mannose-Binding Lectin Promoter Polymorphisms and Gene Variants in Pulmonary Tuberculosis Patients from Cantabria (Northern Spain

    Directory of Open Access Journals (Sweden)

    J.-Gonzalo Ocejo-Vinyals

    2012-01-01

    Full Text Available Mannose-binding lectin is a central molecule of the innate immune system. Mannose-binding lectin 2 promoter polymorphisms and structural variants have been associated with susceptibility to tuberculosis. However, contradictory results among different populations have been reported, resulting in no convincing evidence of association between mannose-binding lectin 2 and susceptibility to tuberculosis. For this reason, we conducted a study in a well genetically conserved Spanish population in order to shed light on this controversial association. We analysed the six promoter and structural mannose-binding lectin 2 gene variants in 107 patients with pulmonary tuberculosis and 441 healthy controls. Only D variant and HYPD haplotype were significantly more frequents in controls which would indicate that this allele could confer protection against pulmonary tuberculosis, but this difference disappeared after statistical correction. Neither the rest of alleles nor the haplotypes were significantly associated with the disease. These results would indicate that mannose-binding lectin promoter polymorphisms and gene variants would not be associated with an increased risk to pulmonary tuberculosis. Despite the slight trend of the D allele and HYPD haplotype in conferring protection against pulmonary tuberculosis, susceptibility to this disease would probably be due to other genetic factors, at least in our population.

  16. Identification of variants in primary and recurrent glioblastoma using a cancer-specific gene panel and whole exome sequencing.

    Directory of Open Access Journals (Sweden)

    Selene M Virk

    Full Text Available Glioblastoma (GBM is an aggressive, malignant brain tumor typically resulting in death of the patient within one year following diagnosis; and those who survive beyond this point usually present with tumor recurrence within two years (5-year survival is 5%. The genetic heterogeneity of GBM has made the molecular characterization of these tumors an area of great interest and has led to identification of molecular subtypes in GBM. The availability of sequencing platforms that are both fast and economical can further the adoption of tumor sequencing in the clinical environment, potentially leading to identification of clinically actionable genetic targets. In this pilot study, comprised of triplet samples of normal blood, primary tumor, and recurrent tumor samples from three patients; we compared the ability of Illumina whole exome sequencing (ExomeSeq and the Ion AmpliSeq Comprehensive Cancer Panel (CCP to identify somatic variants in patient-paired primary and recurrent tumor samples. Thirteen genes were found to harbor variants, the majority of which were exclusive to the ExomeSeq data. Surprisingly, only two variants were identified by both platforms and they were located within the PTCH1 and NF1 genes. Although preliminary in nature, this work highlights major differences in variant identification in data generated from the two platforms. Additional studies with larger samples sizes are needed to further explore the differences between these technologies and to enhance our understanding of the clinical utility of panel based platforms in genomic profiling of brain tumors.

  17. De novo assembly and next-generation sequencing to analyse full-length gene variants from codon-barcoded libraries

    Science.gov (United States)

    Cho, Namjin; Hwang, Byungjin; Yoon, Jung-ki; Park, Sangun; Lee, Joongoo; Seo, Han Na; Lee, Jeewon; Huh, Sunghoon; Chung, Jinsoo; Bang, Duhee

    2015-01-01

    Interpreting epistatic interactions is crucial for understanding evolutionary dynamics of complex genetic systems and unveiling structure and function of genetic pathways. Although high resolution mapping of en masse variant libraries renders molecular biologists to address genotype-phenotype relationships, long-read sequencing technology remains indispensable to assess functional relationship between mutations that lie far apart. Here, we introduce JigsawSeq for multiplexed sequence identification of pooled gene variant libraries by combining a codon-based molecular barcoding strategy and de novo assembly of short-read data. We first validate JigsawSeq on small sub-pools and observed high precision and recall at various experimental settings. With extensive simulations, we then apply JigsawSeq to large-scale gene variant libraries to show that our method can be reliably scaled using next-generation sequencing. JigsawSeq may serve as a rapid screening tool for functional genomics and offer the opportunity to explore evolutionary trajectories of protein variants. PMID:26387459

  18. De novo assembly and next-generation sequencing to analyse full-length gene variants from codon-barcoded libraries.

    Science.gov (United States)

    Cho, Namjin; Hwang, Byungjin; Yoon, Jung-ki; Park, Sangun; Lee, Joongoo; Seo, Han Na; Lee, Jeewon; Huh, Sunghoon; Chung, Jinsoo; Bang, Duhee

    2015-01-01

    Interpreting epistatic interactions is crucial for understanding evolutionary dynamics of complex genetic systems and unveiling structure and function of genetic pathways. Although high resolution mapping of en masse variant libraries renders molecular biologists to address genotype-phenotype relationships, long-read sequencing technology remains indispensable to assess functional relationship between mutations that lie far apart. Here, we introduce JigsawSeq for multiplexed sequence identification of pooled gene variant libraries by combining a codon-based molecular barcoding strategy and de novo assembly of short-read data. We first validate JigsawSeq on small sub-pools and observed high precision and recall at various experimental settings. With extensive simulations, we then apply JigsawSeq to large-scale gene variant libraries to show that our method can be reliably scaled using next-generation sequencing. JigsawSeq may serve as a rapid screening tool for functional genomics and offer the opportunity to explore evolutionary trajectories of protein variants. PMID:26387459

  19. PPARα gene variants as predicted performance-enhancing polymorphisms in professional Italian soccer players

    Directory of Open Access Journals (Sweden)

    Proia P

    2014-12-01

    demonstrated an association of intron 7 G allele as well as the GG genotype in endurance athletes. Our result suggests that this is the case also in professional soccer players. Keywords: PCR-RFLP, gene variants, endurance athlete, G allele

  20. Collagen Gene Variants Previously Associated With Anterior Cruciate Ligament Injury Risk Are Also Associated With Joint Laxity

    OpenAIRE

    Bell, Richard D.; Shultz, Sandra J.; Wideman, Laurie; Vincent C. Henrich

    2012-01-01

    Background: Genetic association studies demonstrate a relationship between several collagen gene variants and anterior cruciate ligament (ACL) injury, yet the mechanism of these relationships is still unclear. Joint laxity is a heritable trait; increased magnitudes of anterior knee laxity (AKL), genu recurvatum (GR), and general joint laxity (GJL) have been consistently associated with a greater risk of ACL injury. Joint laxity may constitute an important intermediate phenotype for the geneti...

  1. Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders

    OpenAIRE

    McCracken, J. T.; Badashova, K K; Posey, D J; Aman, M G; Scahill, L.; Tierney, E.; Arnold, L E; Vitiello, B; Whelan, F.; Chuang, S Z; M. Davies; Shah, B.; McDougle, C J; Nurmi, E L

    2013-01-01

    Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to ...

  2. Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT.

    Science.gov (United States)

    Nicolaou, Nayia; Pulit, Sara L; Nijman, Isaac J; Monroe, Glen R; Feitz, Wout F J; Schreuder, Michiel F; van Eerde, Albertien M; de Jong, Tom P V M; Giltay, Jacques C; van der Zwaag, Bert; Havenith, Marlies R; Zwakenberg, Susan; van der Zanden, Loes F M; Poelmans, Geert; Cornelissen, Elisabeth A M; Lilien, Marc R; Franke, Barbara; Roeleveld, Nel; van Rooij, Iris A L M; Cuppen, Edwin; Bongers, Ernie M H F; Giles, Rachel H; Knoers, Nine V A M; Renkema, Kirsten Y

    2016-02-01

    The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5–15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed. PMID:26489027

  3. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

    DEFF Research Database (Denmark)

    Thompson, Bryony A; Spurdle, Amanda B; Plazzer, John-Paul;

    2014-01-01

    and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary...

  4. The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

    Directory of Open Access Journals (Sweden)

    Vanelli Maurizio

    2011-03-01

    Full Text Available Abstract Background The protein tyrosine phosphatase nonreceptor type 2 (PTPN22 has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c, glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab in children during the first year after diagnosis of type 1 diabetes. Methods The C1858T variant was genotyped in an international cohort of children (n = 257 patients with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset. Results A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03 for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002, which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03. Conclusions The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

  5. Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.

    Science.gov (United States)

    Hunter, Jesse M; Ahearn, Mary Ellen; Balak, Christopher D; Liang, Winnie S; Kurdoglu, Ahmet; Corneveaux, Jason J; Russell, Megan; Huentelman, Matthew J; Craig, David W; Carpten, John; Coons, Stephen W; DeMello, Daphne E; Hall, Judith G; Bernes, Saunder M; Baumbach-Reardon, Lisa

    2015-07-01

    Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes. PMID:26247046

  6. Cloning and identification of NS5ATP2 gene and its spliced variant transactivated by hepatitis C virus non-structural protein 5A

    Institute of Scientific and Technical Information of China (English)

    Qian Yang; Jun Cheng; Yan Liu; Yuan Hong; Jian-Jun Wang; Shu-Lin Zhang

    2004-01-01

    AIM: To clone, identify and study new NS5ATP2 gene and its spliced variant transactivated by hepatitis C virus nonstructural protein 5A.METHODS: On the basis of subtractive cDNA library of genes transactivated by NS5A protein of hepatitis C virus, the coding sequence of new gene and its spliced variant were obtained by bioinformatics method. Polymerase chain reaction (PCR)was conducted to amplify NS5ATP2 gene.RESUJLTS: The coding sequence of a new gene and its spliced variant were cloned and identified successfully.CONCLUSION: A new gene has been recognized as the new target transactivated by HCV NS5A protein. These results brought some new clues for studying the biological functions of new genes and pathogenesis of the viral proteins.

  7. Folate-related gene variants in Irish families affected by neural tube defects

    Directory of Open Access Journals (Sweden)

    Ridgely eFisk Green

    2013-11-01

    Full Text Available Periconceptional folic acid use can often prevent neural tube defects (NTDs. Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (risk genotypes and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p=0.017. We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential

  8. Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans

    OpenAIRE

    Leak, T. S.; Perlegas, P.S.; Smith, S. G.; Keene, K.L.; Hicks, P. J.; Langefeld, C. D.; Mychaleckyj, J. C.; Rich, S S; Kirk, J.K.; Freedman, B.I.; Bowden, D. W.; Sale, M.M.

    2009-01-01

    Variants in the engulfment and cell motility 1 (ELMO1) gene are associated with nephropathy due to type 2 diabetes mellitus (T2DM) in a Japanese cohort. We comprehensively evaluated this gene in African American (AA) T2DM patients with end-stage renal disease (ESRD). Three hundred nine HapMap tagging SNPs and 9 reportedly associated SNPs were genotyped in 577 AA T2DM-ESRD patients and 596 AA non-diabetic controls, plus 43 non-diabetic European American controls and 45 Yoruba Nigerian samples ...

  9. Associations between variants of FADS genes and omega-3 and omega-6 milk fatty acids of Canadian Holstein cows

    OpenAIRE

    Ibeagha-Awemu, Eveline M; Akwanji, Kingsley A; Beaudoin, Frédéric; Zhao, Xin

    2014-01-01

    Background Fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes code respectively for the enzymes delta-5 and delta-6 desaturases which are rate limiting enzymes in the synthesis of polyunsaturated omega-3 and omega-6 fatty acids (FAs). Omega-3 and-6 FAs as well as conjugated linoleic acid (CLA) are present in bovine milk and have demonstrated positive health effects in humans. Studies in humans have shown significant relationships between genetic variants in FADS1 and 2 genes with plasma and ...

  10. Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

    Directory of Open Access Journals (Sweden)

    Pina Julieta

    2009-09-01

    Full Text Available Abstract Background MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. Methods We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH. Results Using unconditional logistic regression we found that MLH3 (L844P, G>A polymorphism GA (Leu/Pro and AA (Pro/Pro genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95 (p = 0.03 and OR = 0.62 (0.41-0.94 (p = 0.03, respectively. Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83, p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49, p = 0.01], GG/AA [OR = 2.11 (1.12-3,98, p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15, p = 0.02] all associated with an increased risk for breast cancer. Conclusion It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results.

  11. Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression.

    Science.gov (United States)

    Cavalli, Marco; Pan, Gang; Nord, Helena; Wallerman, Ola; Wallén Arzt, Emelie; Berggren, Olof; Elvers, Ingegerd; Eloranta, Maija-Leena; Rönnblom, Lars; Lindblad Toh, Kerstin; Wadelius, Claes

    2016-05-01

    Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome. PMID:26993500

  12. Association of usf1s2 variant in the upstream stimulatory factor 1 gene with premature coronary artery disease in southern population of Iran

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    Najmeh Jouyan

    2015-03-01

    Conclusion: It appears that the usf1s2 variant in upstream transcription factor 1 gene is an independent predictor of premature coronary artery disease in our population and applies its effects without affecting blood sugar and lipid levels.

  13. Genetic variants in hypothalamic-pituitary-adrenal axis genes and breast cancer risk in Caucasians and African Americans.

    Science.gov (United States)

    Nan, Hongmei; Dorgan, Joanne F; Rebbeck, Timothy R

    2015-01-01

    Elevated circulating levels of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are associated with increased breast cancer risk in prospective studies. Genetic variants in hypothalamic-pituitary-adrenal (HPA) axis genes may contribute to these circulating hormone levels, and consequently to breast cancer risk. No previous studies have examined the effects of genetic variants in HPA axis genes on breast cancer risk. We evaluated the associations of 49 single nucleotide polymorphisms (SNPs) in five HPA axis genes (NR3C1, NR3C2, CRH, CRHR1, and CRHBP) with the risk of breast cancer in the Women's Insights and Shared Experiences (WISE) Study of Caucasians (346 cases and 442 controls), as well as African Americans (149 cases and 246 controls). Of the 49 SNPs evaluated, one showed a nominal significant association (P for trend < 0.05) with breast cancer risk among Caucasians, and another two among African Americans. The age-adjusted additive odds ratio (OR) (95% confidence interval (95% CI)) of the SNP rs11747190[A] in the CRHBP gene for the risk of breast cancer among Caucasian women was 1.45 (1.09-1.94). The age-adjusted additive ORs (95% CIs) of two SNPs (CRHBP rs1700688[T] and CRHR1 rs17689471[C]) for the risk of breast cancer among African American women were 1.84 (1.13-2.98) and 2.48 (1.20-5.13), respectively. However, these SNPs did not show significant associations after correction for multiple testing. Our findings do not provide strong supportive evidence for the contribution of genetic variants in these HPA axis genes to the risk of developing breast cancer in either Caucasians or African Americans. PMID:26417403

  14. Evaluating the Calibration and Power of Three Gene-Based Association Tests of Rare Variants for the X Chromosome.

    Science.gov (United States)

    Ma, Clement; Boehnke, Michael; Lee, Seunggeun

    2015-11-01

    Although genome-wide association studies (GWAS) have identified thousands of trait-associated genetic variants, there are relatively few findings on the X chromosome. For analysis of low-frequency variants (minor allele frequency kernel association test (SKAT), and optimal unified SKAT (SKAT-O). Using simulated case-control and quantitative trait (QT) data, we evaluate the calibration and power of these tests as a function of (1) male:female sample size ratio; and (2) coding of haploid male genotypes for variants under X-inactivation. For case-control studies, all three tests are reasonably well-calibrated for all scenarios we evaluated. As expected, power for gene-based tests depends on the underlying genetic architecture of the genomic region analyzed. Studies with more (haploid) males are generally less powerful due to decreased number of chromosomes. Power generally is slightly greater when the coding scheme for male genotypes matches the true underlying model, but the power loss for misspecifying the (generally unknown) model is small. For QT studies, type I error and power results largely mirror those for binary traits. We demonstrate the use of these three gene-based tests for X-chromosome association analysis in simulated data and sequencing data from the Genetics of Type 2 Diabetes (GoT2D) study. PMID:26454253

  15. Mutation screen in the GWAS derived obesity gene SH2B1 including functional analyses of detected variants

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    Volckmar Anna-Lena

    2012-12-01

    Full Text Available Abstract Background The SH2B1 gene (Src-homology 2B adaptor protein 1 gene is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation. Methods We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls. Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro. Results We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369 in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile and gamma (γPro674Ser splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23 and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23. The obesity risk-alleles at Thr484Ala and βThr656Ile/γPro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants β and γ. Conclusion The rare coding mutation βThr656Ile/γPro674Ser (g.9483C/T in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.

  16. A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging.

    Science.gov (United States)

    Payton, A; Sindrewicz, P; Pessoa, V; Platt, H; Horan, M; Ollier, W; Bubb, V J; Pendleton, N; Quinn, J P

    2016-03-01

    The Translocase of Outer Mitochondrial Membrane 40 Homolog and Apolipoprotein E (TOMM40-APOE) locus has been associated with a number of age-related phenotypes in humans including nonpathologic cognitive aging, late-onset Alzheimer's disease, and longevity. Here, we investigate the influence of the TOMM40 intron 6 poly-T variant (rs10524523) on TOMM40 gene expression and cognitive abilities and decline in a cohort of 1613 community-dwelling elderly volunteers who had been followed for changes in cognitive functioning over a period of 14 years (range = 12-18 years). We showed that the shorter length poly-T variants were found to act as a repressor of luciferase gene expression in reporter gene constructs. Expression was reduced to approximately half of that observed for the very long variant. We further observed that the shorter poly-T variant was significantly associated with reduced vocabulary ability and a slower rate of vocabulary decline with age compared to the very long poly-T variants. No significant associations were observed for memory, fluid intelligence or processing speed, although the direction of effect, where the short variant was correlated with reduced ability and slower rate of decline was observed for all tests. Our results indicate that the poly-T variant has the ability to interact with transcription machinery and differentially modulate reporter gene expression and influence vocabulary ability and decline with age. PMID:26742953

  17. Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy.

    Science.gov (United States)

    Nemethova, Martina; Radvanszky, Jan; Kadasi, Ludevit; Ascher, David B; Pires, Douglas E V; Blundell, Tom L; Porfirio, Berardino; Mannoni, Alessandro; Santucci, Annalisa; Milucci, Lia; Sestini, Silvia; Biolcati, Gianfranco; Sorge, Fiammetta; Aurizi, Caterina; Aquaron, Robert; Alsbou, Mohammed; Lourenço, Charles Marques; Ramadevi, Kanakasabapathi; Ranganath, Lakshminarayan R; Gallagher, James A; van Kan, Christa; Hall, Anthony K; Olsson, Birgitta; Sireau, Nicolas; Ayoob, Hana; Timmis, Oliver G; Sang, Kim-Hanh Le Quan; Genovese, Federica; Imrich, Richard; Rovensky, Jozef; Srinivasaraghavan, Rangan; Bharadwaj, Shruthi K; Spiegel, Ronen; Zatkova, Andrea

    2016-01-01

    Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy. PMID:25804398

  18. A splice site variant in the bovine RNF11 gene compromises growth and regulation of the inflammatory response.

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    Arnaud Sartelet

    Full Text Available We report association mapping of a locus on bovine chromosome 3 that underlies a Mendelian form of stunted growth in Belgian Blue Cattle (BBC. By resequencing positional candidates, we identify the causative c124-2A>G splice variant in intron 1 of the RNF11 gene, for which all affected animals are homozygous. We make the remarkable observation that 26% of healthy Belgian Blue animals carry the corresponding variant. We demonstrate in a prospective study design that approximately one third of homozygous mutants die prematurely with major inflammatory lesions, hence explaining the rarity of growth-stunted animals despite the high frequency of carriers. We provide preliminary evidence that heterozygous advantage for an as of yet unidentified phenotype may have caused a selective sweep accounting for the high frequency of the RNF11 c124-2A>G mutation in Belgian Blue Cattle.

  19. Testing the thrifty gene hypothesis: the Gly482Ser variant in PPARGC1A is associated with BMI in Tongans

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    Macartney-Coxson Donia P

    2011-01-01

    Full Text Available Abstract Background The thrifty gene hypothesis posits that, in populations that experienced periods of feast and famine, natural selection favoured individuals carrying thrifty alleles that promote the storage of fat and energy. Polynesians likely experienced long periods of cold stress and starvation during their settlement of the Pacific and today have high rates of obesity and type 2 diabetes (T2DM, possibly due to past positive selection for thrifty alleles. Alternatively, T2DM risk alleles may simply have drifted to high frequency in Polynesians. To identify thrifty alleles in Polynesians, we previously examined evidence of positive selection on T2DM-associated SNPs and identified a T2DM risk allele at unusually high frequency in Polynesians. We suggested that the risk allele of the Gly482Ser variant in the PPARGC1A gene was driven to high frequency in Polynesians by positive selection and therefore possibly represented a thrifty allele in the Pacific. Methods Here we examine whether PPARGC1A is a thrifty gene in Pacific populations by testing for an association between Gly482Ser genotypes and BMI in two Pacific populations (Maori and Tongans and by evaluating the frequency of the risk allele of the Gly482Ser variant in a sample of worldwide populations. Results We find that the Gly482Ser variant is associated with BMI in Tongans but not in Maori. In a sample of 58 populations worldwide, we also show that the 482Ser risk allele reaches its highest frequency in the Pacific. Conclusion The association between Gly482Ser genotypes and BMI in Tongans together with the worldwide frequency distribution of the Gly482Ser risk allele suggests that PPARGC1A remains a candidate thrifty gene in Pacific populations.

  20. An extended nomenclature for mammalian V-ATPase subunit genes and splice variants.

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    Kevin C Miranda

    Full Text Available The vacuolar-type H(+-ATPase (V-ATPase is a multisubunit proton pump that is involved in both intra- and extracellular acidification processes throughout the body. Multiple homologs and splice variants of V-ATPase subunits are thought to explain its varied spatial and temporal expression pattern in different cell types. Recently subunit nomenclature was standardized with a total of 22 subunit variants identified. However this standardization did not accommodate the existence of splice variants and is therefore incomplete. Thus, we propose here an extension of subunit nomenclature along with a literature and sequence database scan for additional V-ATPase subunits. An additional 17 variants were pulled from a literature search while 4 uncharacterized potential subunit variants were found in sequence databases. These findings have been integrated with the current V-ATPase knowledge base to create a new V-ATPase subunit catalogue. It is envisioned this catalogue will form a new platform on which future studies into tissue- and organelle-specific V-ATPase expression, localization and function can be based.

  1. Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

    Science.gov (United States)

    McCracken, J T; Badashova, K K; Posey, D J; Aman, M G; Scahill, L; Tierney, E; Arnold, L E; Vitiello, B; Whelan, F; Chuang, S Z; Davies, M; Shah, B; McDougle, C J; Nurmi, E L

    2014-06-01

    Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability. PMID:23856854

  2. Genome-Wide Association Study with Sequence Variants Identifies Candidate Genes for Mastitis Resistance in Dairy Cattle

    DEFF Research Database (Denmark)

    Sahana, Goutam; Guldbrandtsen, Bernt; Bendixen, Christian;

    Six genomic regions affecting clinical mastitis were identified through a GWAS study with imputed BovineHD chip genotype data in the Nordic Holstein cattle population. The association analyses were carried out using a SNP-by-SNP analysis by fitting the regression of allele dosage and a polygenic...... Variant Effect Predictor (VEP) vers. 2.6 using ENSEMBL vers. 67 databases. Candidate polymorphisms affecting clinical mastitis were selected based on their association with the traits and functional annotations. A strong positional candidate gene for mastitis resistance on chromosome-6 is the NPFFR2 which...... Factor Receptor Alpha (LIFR) emerged as a strong candidate gene for mastitis resistance. The LIFR gene is involved in acute phase response and is expressed in saliva and mammary gland....

  3. Aldh2 knockout mice were more sensitive to DNA damage in leukocytes due to ethyl tertiary butyl ether exposure.

    Science.gov (United States)

    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2011-01-01

    To clarify the genotoxicity of ethyl tertiary butyl ether (ETBE), a gasoline additive, male and female C57BL/6 mice of Aldh2+/+ and Aldh2-/- genotypes, aged 8 wk, were exposed to 0, 500, 1,750, or 5,000 ppm ETBE for 6 h/day, 5 d per week for 13 wk. DNA damage in leukocytes was measured by the alkaline comet assay and expressed quantitatively as Tail Intensity (TI). For male mice, TI was significantly higher in all three groups exposed to ETBE than in those without exposure within Aldh2-/- mice, whereas within Aldh2+/+ mice, TI increased only in those exposed to 5,000 ppm of ETBE as compared with mice without exposure. For female mice, a significant increase in TI values was observed in the group exposed to 5,000 ppm of ETBE as compared with those without exposure within Aldh2-/- mice; TI in Aldh2-/- mice exposed to 1,750 and 5,000 ppm was significantly higher than in Aldh2+/+ mice without exposure. TI did not significantly increase in any of the groups exposed to ETBE within female Aldh2+/+ mice. Based on the results we suggest that Aldh2-/- mice are more sensitive to DNA damage caused by ETBE than Aldh2+/+ mice and that males seem more susceptible to this effect than females. PMID:21372431

  4. ALDH expression characterizes G1-phase proliferating beta cells during pregnancy.

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    Lijuan Zhang

    Full Text Available High levels of aldehyde dehydrogenase (ALDH activity have been detected in various progenitor and stem cells. Thus, Aldefluor fluorescence, which represents precisely the ALDH activity, has been widely used for the identification, evaluation, and isolation of stem and progenitor cells. Recently, ALDH activity was detected in embryonic and adult mouse pancreas, specifically in adult centroacinar and terminal duct cells supposed to harbor endocrine and exocrine progenitor cells in the adult pancreas. Nevertheless, ALDH activity and aldeflour fluorescence have not been examined in beta cells. Here, we report a dynamic increase in the number of aldeflour+ beta cells during pregnancy. Interestingly, nearly all these aldeflour+ beta cells are positive for Ki-67, suggesting that they are in an active cell cycle (G1, S and M phases. To determine precisely at which phase beta cells activate ALDH activity and thus become aldeflour+, we co-stained insulin with additional proliferation markers, phosphohistone3 (PHH3, a marker for M-phase proliferating cells and Bromodeoxyuridine (BrdU, a marker for S-phase proliferating cells. Our data show little aldeflour+ beta cells that were positive for either PHH3, or BrdU, suggesting that beta cells activate ALDH and become Aldefluor+ when they enter G1-phase of active cell cycle, but may downregulate ALDH when they leave G1-phase and enter S phase. Our data thus reveal a potential change in ALDH activity of proliferating beta cells during pregnancy, which provides a novel method for isolation and analysis of proliferating beta cells. Moreover, our data also suggest that caution needs to be taken on interpretation of Aldefluor lineage-tracing data in pancreas.

  5. ALDH Expression Characterizes G1-Phase Proliferating Beta Cells during Pregnancy

    Science.gov (United States)

    Zhang, Lijuan; Wang, Lin; Liu, Xiaoliang; Zheng, Dongming; Liu, Sishi; Liu, Caixia

    2014-01-01

    High levels of aldehyde dehydrogenase (ALDH) activity have been detected in various progenitor and stem cells. Thus, Aldefluor fluorescence, which represents precisely the ALDH activity, has been widely used for the identification, evaluation, and isolation of stem and progenitor cells. Recently, ALDH activity was detected in embryonic and adult mouse pancreas, specifically in adult centroacinar and terminal duct cells supposed to harbor endocrine and exocrine progenitor cells in the adult pancreas. Nevertheless, ALDH activity and aldeflour fluorescence have not been examined in beta cells. Here, we report a dynamic increase in the number of aldeflour+ beta cells during pregnancy. Interestingly, nearly all these aldeflour+ beta cells are positive for Ki-67, suggesting that they are in an active cell cycle (G1, S and M phases). To determine precisely at which phase beta cells activate ALDH activity and thus become aldeflour+, we co-stained insulin with additional proliferation markers, phosphohistone3 (PHH3, a marker for M-phase proliferating cells) and Bromodeoxyuridine (BrdU, a marker for S-phase proliferating cells). Our data show little aldeflour+ beta cells that were positive for either PHH3, or BrdU, suggesting that beta cells activate ALDH and become Aldefluor+ when they enter G1-phase of active cell cycle, but may downregulate ALDH when they leave G1-phase and enter S phase. Our data thus reveal a potential change in ALDH activity of proliferating beta cells during pregnancy, which provides a novel method for isolation and analysis of proliferating beta cells. Moreover, our data also suggest that caution needs to be taken on interpretation of Aldefluor lineage-tracing data in pancreas. PMID:24787690

  6. New unstable variants of green fluorescent protein for studies of transient gene expression in bacteria

    DEFF Research Database (Denmark)

    Andersen, Jens Bo; Sternberg, Claus; Poulsen, Lars K.;

    1998-01-01

    Use of the green fluorescent protein (Gfp) from the jellyfish Aequorea victoria ia is a powerful method for nondestructive in situ monitoring, since expression of green fluorescence does not require any substrate addition. To expand the use of Gfp as a reporter protein, new variants have been...... constructed by the addition of short peptide sequences to the C-terminal end of intact Gfp. This rendered the Gfp susceptible to the action of indigenous housekeeping proteases, resulting in protein variants with half-lives ranging from 40 min to a few hours when synthesized in Escherichia coli...

  7. Local overexpression of Su(H)-MAPK variants affects Notch target gene expression and adult phenotypes in Drosophila.

    Science.gov (United States)

    Auer, Jasmin S; Nagel, Anja C; Schulz, Adriana; Wahl, Vanessa; Preiss, Anette

    2015-12-01

    In Drosophila, Notch and EGFR signalling pathways are closely intertwined. Their relationship is mostly antagonistic, and may in part be based on the phosphorylation of the Notch signal transducer Suppressor of Hairless [Su(H)] by MAPK. Su(H) is a transcription factor that together with several cofactors regulates the expression of Notch target genes. Here we address the consequences of a local induction of three Su(H) variants on Notch target gene expression. To this end, wild-type Su(H), a phospho-deficient Su(H) (MAPK-) (ko) and a phospho-mimetic Su(H) (MAPK-ac) isoform were overexpressed in the central domain of the wing anlagen. The expression of the Notch target genes cut, wingless, E(spl)m8-HLH and vestigial, was monitored. For the latter two, reporter genes were used (E(spl)m8-lacZ, vg (BE) -lacZ). In general, Su(H) (MAPK-) (ko) induced a stronger response than wild-type Su(H), whereas the response to Su(H) (MAPK-ac) was very weak. Notch target genes cut, wingless and vg (BE) -lacZ were ectopically activated, whereas E(spl)m8-lacZ was repressed by overexpression of Su(H) proteins. In addition, in epistasis experiments an activated form of the EGF-receptor (DER (act) ) or the MAPK (rl (SEM) ) and individual Su(H) variants were co-overexpressed locally, to compare the resultant phenotypes in adult flies (thorax, wings and eyes) as well as to assay the response of the Notch target gene cut in cell clones. PMID:26702412

  8. Local overexpression of Su(H)-MAPK variants affects Notch target gene expression and adult phenotypes in Drosophila

    Science.gov (United States)

    Auer, Jasmin S.; Nagel, Anja C.; Schulz, Adriana; Wahl, Vanessa; Preiss, Anette

    2015-01-01

    In Drosophila, Notch and EGFR signalling pathways are closely intertwined. Their relationship is mostly antagonistic, and may in part be based on the phosphorylation of the Notch signal transducer Suppressor of Hairless [Su(H)] by MAPK. Su(H) is a transcription factor that together with several cofactors regulates the expression of Notch target genes. Here we address the consequences of a local induction of three Su(H) variants on Notch target gene expression. To this end, wild-type Su(H), a phospho-deficient Su(H)MAPK-ko and a phospho-mimetic Su(H)MAPK-ac isoform were overexpressed in the central domain of the wing anlagen. The expression of the Notch target genes cut, wingless, E(spl)m8-HLH and vestigial, was monitored. For the latter two, reporter genes were used (E(spl)m8-lacZ, vgBE-lacZ). In general, Su(H)MAPK-ko induced a stronger response than wild-type Su(H), whereas the response to Su(H)MAPK-ac was very weak. Notch target genes cut, wingless and vgBE-lacZ were ectopically activated, whereas E(spl)m8-lacZ was repressed by overexpression of Su(H) proteins. In addition, in epistasis experiments an activated form of the EGF-receptor (DERact) or the MAPK (rlSEM) and individual Su(H) variants were co-overexpressed locally, to compare the resultant phenotypes in adult flies (thorax, wings and eyes) as well as to assay the response of the Notch target gene cut in cell clones. PMID:26702412

  9. New Tools for Mendelian Disease Gene Identification: PhenoDB Variant Analysis Module; and GeneMatcher, a Web-Based Tool for Linking Investigators with an Interest in the Same Gene

    Science.gov (United States)

    Sobreira, Nara; Schiettecatte, François; Boehm, Corinne; Valle, David; Hamosh, Ada

    2016-01-01

    Identifying the causative variant from among the thousands identified by whole-exome sequencing or whole-genome sequencing is a formidable challenge. To make this process as efficient and flexible as possible, we have developed a Variant Analysis Module coupled to our previously described Web-based phenotype intake tool, PhenoDB (http://researchphenodb.net and http://phenodb.org). When a small number of candidate-causative variants have been identified in a study of a particular patient or family, a second, more difficult challenge becomes proof of causality for any given variant. One approach to this problem is to find other cases with a similar phenotype and mutations in the same candidate gene. Alternatively, it may be possible to develop biological evidence for causality, an approach that is assisted by making connections to basic scientists studying the gene of interest, often in the setting of a model organism. Both of these strategies benefit from an open access, online site where individual clinicians and investigators could post genes of interest. To this end, we developed GeneMatcher (http://genematcher.org), a freely accessible Website that enables connections between clinicians and researchers across the world who share an interest in the same gene(s). PMID:25684268

  10. KCNQ1 gene variants in the risk for type 2 diabetes and impaired renal function in the Spanish Renastur cohort.

    Science.gov (United States)

    Riobello, Cristina; Gómez, Juan; Gil-Peña, Helena; Tranche, Salvador; Reguero, Julián R; de la Hera, Jesús M; Delgado, Elías; Calvo, David; Morís, César; Santos, Fernando; Coto-Segura, Pablo; Iglesias, Sara; Alonso, Belén; Alvarez, Victoria; Coto, Eliecer

    2016-05-15

    Several common KCNQ1 gene polymorphisms have been associated with the risk of type 2 diabetes (T2DM) and diabetic nephropathy. This effect is explained by the role of the kcnq1 protein as a potassium channel that in the pancreatic beta-cells drives an electrical signal that facilitates glucose-stimulated insulin secretion. The KCNQ1 gene is also expressed in the kidney, and could thus be implicated in the risk of developing impaired renal function. To test this hypothesis, we genotyped six common KCNQ1 gene variants (three single nucleotide polymorphisms, rs2237892, rs2237895, and rs231362, and three intronic indels) in 681 healthy elderly individuals (>65 years old) from the Spanish Renastur cohort. None of the six variants was associated with T2DM (180 diabetics vs. 581 non-diabetics). The intron 12 insertion allele was associated with a reduced estimated glomerular filtration rate (eGFRdiabetics (n = 4; p = 0.05). The two rare alleles were present in the two eGFR groups. Our results suggest that a common KCNQ1 intron 12 indel polymorphism is a risk factor for impaired renal function independent of T2DM. If this association is confirmed by others, further research to determine the mechanism that drives this association would be warranted. PMID:26970180

  11. Variants of the Matrix Metalloproteinase-2 but not the Matrix Metalloproteinase-9 genes significantly influence functional outcome after stroke

    Directory of Open Access Journals (Sweden)

    Sobral João

    2010-03-01

    Full Text Available Abstract Background Multiple lines of evidence suggest that genetic factors contribute to stroke recovery. The matrix metalloproteinases -2 (MMP-2 and -9 (MMP-9 are modulators of extracellular matrix components, with important regulatory functions in the Central Nervous System (CNS. Shortly after stroke, MMP-2 and MMP-9 have mainly damaging effects for brain tissue. However, MMPs also have a beneficial activity in angiogenesis and neurovascular remodelling during the delayed neuroinflammatory response phase, thus possibly contributing to stroke functional recovery. Methods In the present study, the role of MMP-2 and MMP-9 genetic variants in stroke recovery was investigated in 546 stroke patients. Functional outcome was assessed three months after a stroke episode using the modified Rankin Scale (mRS, and patients were classified in two groups: good recovery (mRS ≤ 1 or poor recovery (mRS>1. Haplotype tagging single nucleotide polymorphisms (SNPs in the MMP-2 (N = 21 and MMP-9 (N = 4 genes were genotyped and tested for association with stroke outcome, adjusting for significant non-genetic clinical variables. Results Six SNPs in the MMP-2 gene were significantly associated with stroke outcome (0.0018P P MMP-9 gene. Conclusions The results presented strongly indicate that MMP-2 genetic variants are an important mediator of functional outcome after stroke.

  12. Fatty-acid binding protein 4 gene variants and childhood obesity: potential implications for insulin sensitivity and CRP levels

    Directory of Open Access Journals (Sweden)

    Bhattacharjee Rakesh

    2010-02-01

    Full Text Available Abstract Introduction Obesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. FABP4 is a member of the intracellular lipid-binding protein family that is predominantly expressed in adipose tissue, and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to measure FABP4 plasma levels, assess FABP4 allelic variants, and explore potential associations with fasting glucose and insulin levels in young school-age children with and without obesity. Methods A total of 309 consecutive children ages 5-7 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score >1.65 and non-obese (NOB. Fasting plasma glucose, lipids, insulin, hsCRP, and FABP4 levels were measured. HOMA was used as correlate of insulin sensitivity. Four SNPs of the human FABP4 gene (rs1051231, rs2303519, rs16909233 and rs1054135, corresponding to several critical regions of the encoding FABP4 gene sequence were genotyped. Results Compared to NOB, circulating FABP4 levels were increased in OB, as were LDL, hsCRP and HOMA. FABP4 levels correlated with BMI, and also contributed to the variance of HOMA and hsCRP, but not serum lipids. The frequency of rs1054135 allelic variant was increased in OB, and was associated with increased FABP4 levels, while the presence of rs16909233 variant allele, although similar in OB and NOB, was associated with increased HOMA values. Conclusions Childhood obesity is associated with higher FABP4 levels that may promote cardiometabolic risk. The presence of selective SNPs in the FABP4 gene may account for increased risk for insulin resistance or systemic inflammation in the context of obesity.

  13. Determination of Stearoyl-Coenzyme A Desaturase 1 Gene Variants in South Anatolian Red and East Anatolian Red Cattle

    Directory of Open Access Journals (Sweden)

    İjlal İpek PAYA

    2015-07-01

    Full Text Available Fat composition in ruminant’s milk is one of the factors that can affect human health in positive or adverse ways. Optimizing ruminant feed to achieve ideal fatty acid composition in milk has been an ongoing area of research in recent years, without satisfactory results to date. It has been argued that in addition to changes in feed, genetic information can also be utilized to improve milk fatty acid composition. The aim of the study is to investigate the incidence of stearoyl-CoA-desaturase 1 (SCD gene variants, which are claimed to affect fat content and quality of milk in Turkish native cattle breeds. Fifty South Anatolian Red (SAR and 50 East Anatolian Red (EAR cattle were used in the study. The 5th exon of SCD gene was amplified using polymerase chain reaction (PCR and the PCR products were subjected to sequencing analysis. Among the samples sequenced polymorphism at three nucleotide positions have been observed on the 5th exon of the SCD gene, namely A702G, T762C and C878T. Of these three, the polymorphic position C878T was utilized to determine peptide variants of A (293Ala or the V (293 Val of individual samples. Frequency of A variant and AA genotype in SAR and EAR cattle breeds was 0.91 and 0.77 as well as 0.43 and 0.29, respectively. In particular the SAR exhibits a very low frequency of the V allele, believed to have been an ancestral allele. In both samples, 2 individuals were identified to have the VV genotype. The results suggested that high frequency of A allele and AA genotype which confers great advantage on milk composition and meat fatty acid composition was present in SAR and EAR cattle breeds

  14. Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes.

    Science.gov (United States)

    Hirschfield, G M; Xie, G; Lu, E; Sun, Y; Juran, B D; Chellappa, V; Coltescu, C; Mason, A L; Milkiewicz, P; Myers, R P; Odin, J A; Luketic, V A; Bacon, B; Bodenheimer, H; Liakina, V; Vincent, C; Levy, C; Pillai, S; Lazaridis, K N; Amos, C I; Siminovitch, K A

    2012-06-01

    We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (SOCS1) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A-SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 × 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 × 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 × 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC. PMID:22257840

  15. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

    Science.gov (United States)

    Fan, Qiao; Guo, Xiaobo; Tideman, J Willem L; Williams, Katie M; Yazar, Seyhan; Hosseini, S Mohsen; Howe, Laura D; Pourcain, Beaté St; Evans, David M; Timpson, Nicholas J; McMahon, George; Hysi, Pirro G; Krapohl, Eva; Wang, Ya Xing; Jonas, Jost B; Baird, Paul Nigel; Wang, Jie Jin; Cheng, Ching-Yu; Teo, Yik-Ying; Wong, Tien-Yin; Ding, Xiaohu; Wojciechowski, Robert; Young, Terri L; Pärssinen, Olavi; Oexle, Konrad; Pfeiffer, Norbert; Bailey-Wilson, Joan E; Paterson, Andrew D; Klaver, Caroline C W; Plomin, Robert; Hammond, Christopher J; Mackey, David A; He, Mingguang; Saw, Seang-Mei; Williams, Cathy; Guggenheim, Jeremy A

    2016-01-01

    Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04). PMID:27174397

  16. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

    Science.gov (United States)

    Fan, Qiao; Guo, Xiaobo; Tideman, J. Willem L.; Williams, Katie M.; Yazar, Seyhan; Hosseini, S. Mohsen; Howe, Laura D.; Pourcain, Beaté St; Evans, David M.; Timpson, Nicholas J.; McMahon, George; Hysi, Pirro G.; Krapohl, Eva; Wang, Ya Xing; Jonas, Jost B.; Baird, Paul Nigel; Wang, Jie Jin; Cheng, Ching-Yu; Teo, Yik-Ying; Wong, Tien-Yin; Ding, Xiaohu; Wojciechowski, Robert; Young, Terri L.; Pärssinen, Olavi; Oexle, Konrad; Pfeiffer, Norbert; Bailey-Wilson, Joan E.; Paterson, Andrew D.; Klaver, Caroline C. W.; Plomin, Robert; Hammond, Christopher J.; Mackey, David A.; He, Mingguang; Saw, Seang-Mei; Williams, Cathy; Guggenheim, Jeremy A.; Meguro, Akira; Wright, Alan F.; Hewitt, Alex W.; Young, Alvin L.; Veluchamy, Amutha Barathi; Metspalu, Andres; Paterson, Andrew D.; Döring, Angela; Khawaja, Anthony P.; Klein, Barbara E.; Pourcain, Beate St; Fleck, Brian; Klaver, Caroline C. W.; Hayward, Caroline; Williams, Cathy; Delcourt, Cécile; Pang, Chi Pui; Khor, Chiea-Chuen; Cheng, Ching-Yu; Gieger, Christian; Hammond, Christopher J.; Simpson, Claire L.; van Duijn, Cornelia M.; Mackey, David A.; Evans, David M.; Stambolian, Dwight; Chew, Emily; Tai, E-Shyong; Krapohl, Eva; Mihailov, Evelin; Smith, George Davey; McMahon, George; Biino, Ginevra; Campbell, Harry; Rudan, Igor; Seppälä, Ilkka; Kaprio, Jaakko; Wilson, James F.; Craig, Jamie E.; Tideman, J. Willem L.; Ried, Janina S.; Korobelnik, Jean-François; Guggenheim, Jeremy A.; Fondran, Jeremy R.; Wang, Jie Jin; Liao, Jiemin; Zhao, Jing Hua; Xie, Jing; Bailey-Wilson, Joan E.; Kemp, John P.; Lass, Jonathan H.; Jonas, Jost B.; Rahi, Jugnoo S.; Wedenoja, Juho; Mäkelä, Kari-Matti; Burdon, Kathryn P.; Williams, Katie M; Khaw, Kay-Tee; Yamashiro, Kenji; Oexle, Konrad; Howe, Laura D.; Chen, Li Jia; Xu, Liang; Farrer, Lindsay; Ikram, M. Kamran; Deangelis, Margaret M.; Morrison, Margaux; Schache, Maria; Pirastu, Mario; Miyake, Masahiro; Yap, Maurice K. H.; Fossarello, Maurizio; Kähönen, Mika; Tedja, Milly S.; He, Mingguang; Yoshimura, Nagahisa; Martin, Nicholas G.; Timpson, Nicholas J.; Wareham, Nick J.; Mizuki, Nobuhisa; Pfeiffer, Norbert; Pärssinen, Olavi; Raitakari, Olli; Polasek, Ozren; Tam, Pancy O.; Foster, Paul J.; Mitchell, Paul; Baird, Paul Nigel; Chen, Peng; Hysi, Pirro G.; Cumberland, Phillippa; Gharahkhani, Puya; Fan, Qiao; Höhn, René; Fogarty, Rhys D.; Luben, Robert N.; Igo Jr, Robert P.; Plomin, Robert; Wojciechowski, Robert; Klein, Ronald; Mohsen Hosseini, S.; Janmahasatian, Sarayut; Saw, Seang-Mei; Yazar, Seyhan; Ping Yip, Shea; Feng, Sheng; Vaccargiu, Simona; Panda-Jonas, Songhomitra; MacGregor, Stuart; Iyengar, Sudha K.; Rantanen, Taina; Lehtimäki, Terho; Young, Terri L.; Meitinger, Thomas; Wong, Tien-Yin; Aung, Tin; Haller, Toomas; Vitart, Veronique; Nangia, Vinay; Verhoeven, Virginie J. M.; Jhanji, Vishal; Zhao, Wanting; Chen, Wei; Zhou, Xiangtian; Guo, Xiaobo; Ding, Xiaohu; Wang, Ya Xing; Lu, Yi; Teo, Yik-Ying; Vatavuk, Zoran

    2016-01-01

    Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E–04). PMID:27174397

  17. Loss-of-function variants of the filaggrin gene are associated with clinical reactivity to foods

    NARCIS (Netherlands)

    van Ginkel, C. D.; Flokstra-de Blok, B. M. J.; Kollen, B. J.; Kukler, J.; Koppelman, G. H.; Dubois, A. E. J.

    2015-01-01

    The aim of this study was to assess the genetic association of Filaggrin loss-of-function (FLG LOF) genetic variants with food allergy, and to investigate the added value of this test in diagnosing food allergy. Clinical reactivity to foods was diagnosed by the gold standard, the double-blind, place

  18. List of gene variants developed for cancer cells from nine tissue types

    Science.gov (United States)

    NCI scientists have developed a comprehensive list of genetic variants for each of the types of cells that comprise what is known as the NCI-60 cell line collection. This new list adds depth to the most frequently studied human tumor cell lines in cancer

  19. Molecular Cloning and Expression of Sequence Variants of Manganese Superoxide Dismutase Genes from Wheat

    Science.gov (United States)

    Reactive oxygen species (ROS) are very harmful to living organisms due to the potential oxidation of membrane lipids, DNA, proteins, and carbohydrates. Transformed E.coli strain QC 871, superoxide dismutase (SOD) double-mutant, with three sequence variant MnSOD1, MnSOD2, and MnSOD3 manganese supero...

  20. Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia

    NARCIS (Netherlands)

    Nibbeling, Esther; Schaake, Susen; Tijssen, Marina A.; Weissbach, Anne; Groen, Justus L.; Altenmueller, Eckart; Verbeek, Dineke S.; Lohmann, Katja

    2015-01-01

    Musician's dystonia and writer's cramp are examples of task-specific dystonia. Recently, the arylsulfatase G (ARSG) locus was suggested to be associated with musician's dystonia and writer's cramp by a genome-wide association study. To test for the presence of causal variants, the entire coding regi

  1. Escherichia coli harboring Shiga toxin 2 gene variants : frequency and association with clinical symptoms

    NARCIS (Netherlands)

    Friedrich, Alexander W; Bielaszewska, Martina; Zhang, Wen-Lan; Pulz, Matthias; Kuczius, Thorsten; Ammon, Andrea; Karch, Helge

    2002-01-01

    Shiga toxin (Stx)-producing Escherichia coli (STEC) from patients with hemolytic-uremic syndrome (HUS), patients with diarrhea without HUS, or asymptomatic subjects were genotyped to assess associations between stx2 variants and clinical manifestations of infection. Neither stx2d nor stx2e was found

  2. New unstable variants of green fluorescent protein for studies of transient gene expression in bacteria

    DEFF Research Database (Denmark)

    Andersen, Jens Bo; Sternberg, Claus; Poulsen, Lars K.; Bjørn, Sara P.; Givskov, Michael Christian; Molin, Søren

    1998-01-01

    constructed by the addition of short peptide sequences to the C-terminal end of intact Gfp. This rendered the Gfp susceptible to the action of indigenous housekeeping proteases, resulting in protein variants with half-lives ranging from 40 min to a few hours when synthesized in Escherichia coli and...

  3. Genetic Variants Of Cytochrome b-245, Alpha Polypeptide Gene And Premature Acute Myocardial Infarction Risk In An Iranian Population

    Directory of Open Access Journals (Sweden)

    Amin Fatemeh

    2015-10-01

    Full Text Available Background: Oxidative stress induced by superoxide anion plays critical roles in the pathogenesis of coronary artery disease (CAD and hence acute myocardial infarction (AMI. The major source of superoxide production in vascular smooth muscle and endothelial cells is the NADPH oxidase complex. An essential component of this complex is p22phox, that is encoded by the cytochrome b-245, alpha polypeptide (CYBA gene. The aim of this study was to investigate the association of CYBA variants (rs1049255 and rs4673 and premature acute myocardial infarction risk in an Iranian population.

  4. Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

    OpenAIRE

    Théry, Jean Christophe; Krieger, Sophie,; Gaildrat, Pascaline; Révillion, Françoise; Buisine, Marie-Pierre; Killian, Audrey; Duponchel, Christiane; Rousselin, Antoine; Vaur, Dominique; Peyrat, Jean-Philippe; Berthet, Pascaline; Frébourg, Thierry; Martins, Alexandra; Hardouin, Agnès; Tosi, Mario

    2011-01-01

    A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more pr...

  5. Association of Polymorphic Variants of miRNA Processing Genes with Larynx Cancer Risk in a Polish Population

    Directory of Open Access Journals (Sweden)

    Ewa Osuch-Wojcikiewicz

    2015-01-01

    Full Text Available Laryngeal cancer (LC is one of the most prevalent types of head and neck cancer. An increasing interest has been focused on the role of microRNA (miRNAs in LC development. The study group consisted of 135 larynx cancer patients and 170 cancer-free individuals. Nine polymorphisms of pre-miRNA processing genes, DROSHA (rs6877842, DGCR8 (rs3757, rs417309, and rs1640299, RAN (rs14035, XPO5 (rs11077, DICER1 (rs13078 and rs3742330 and TARBP2 (rs784567, were performed by TaqMan SNP Genotyping Assay. It was found that the frequency of the GT and the TT polymorphic variants of XPO5 gene were higher in LC patients than in controls (p<0.0001 and p=0.000183, resp.. In turn, the frequency of the CT genotype of RAN gene was higher in controls than in LC patients (p<0.0001. The TT and the AG of DICER1 gene (p=0.034697 for rs13078 and p=0.0004 for rs3742330 as well as the AG and the GG genotypes of TARBP2 gene (p=0.008335 and p<0.0001, resp. were associated with higher risk of LC occurrence. Our data suggested that polymorphisms of miRNA processing genes might be useful as predictive factors for the LC development.

  6. Genetic variants in matrix metalloproteinase genes as disposition factors for ovarian cancer risk, survival, and clinical outcome.

    Science.gov (United States)

    Wang, Yan; Ye, Yuanqing; Lin, Jie; Meyer, Larissa; Wu, Xifeng; Lu, Karen; Liang, Dong

    2015-06-01

    Ovarian cancer is one of the leading female cancers in the United States. Challenges remain in early diagnosis of this deadly disease. Matrix metalloproteinases (MMPs) family genes are paradoxically involved in cancer promotion and suppression. We hypothesize that genetic variants in MMP genes are associated with ovarian cancer development, so they could be potential markers for ovarian cancer diagnosis and prognosis. In this study of 417 ovarian cancer cases and 417 healthy controls, we genotyped a comprehensive panel of 266 single nucleotide polymorphisms (SNPs) in 23 MMP genes and analysed their associations with ovarian cancer risk, overall survival and treatment response in ovarian cancer cases who received platinum-based chemotherapy with surgery. In the analysis on 339 Caucasian cases and 349 Caucasian controls, 4 SNPs were significantly associated with cancer risk. The most significant association was observed for rs2292730 (OR = 2.03, 95% CI = 1.39-2.96, P = 0.0002). Classification and regression tree analysis identified four terminal nodes with differential risk of ovarian cancer. Thirty-four SNPs were significantly associated with overall survival and four of which showed significant association with response to chemotherapy. Unfavourable genotype analysis of top SNPs on overall risk of death showed significant gene-dosage effect, survival tree analysis differentiated patients into distinct risk groups based on their genetic profiles with median survival times (MSTs) ranging from 17.7 to 151.7 months. In conclusion, our results suggest that genetic variants in MMP pathway genes may modulate the risk and clinical outcomes of ovarian cancer, both individually and jointly. PMID:25867973

  7. Talc use, variants of the GSTM1, GSTT1, and NAT2 genes, and risk of epithelial ovarian cancer.

    Science.gov (United States)

    Gates, Margaret A; Tworoger, Shelley S; Terry, Kathryn L; Titus-Ernstoff, Linda; Rosner, Bernard; De Vivo, Immaculata; Cramer, Daniel W; Hankinson, Susan E

    2008-09-01

    Epidemiologic evidence suggests a possible association between genital use of talcum powder and risk of epithelial ovarian cancer; however, the biological basis for this association is not clear. We analyzed interactions between talc use and genes in detoxification pathways [glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and N-acetyltransferase 2 (NAT2)] to assess whether the talc/ovarian cancer association is modified by variants of genes potentially involved in the response to talc. Our analysis included 1,175 cases and 1,202 controls from a New England-based case-control study and 210 cases and 600 controls from the prospective Nurses' Health Study. We genotyped participants for the GSTM1 and GSTT1 gene deletions and three NAT2 polymorphisms. We used logistic regression to analyze the main effect of talc use, genotype, and gene-talc interactions in each population and pooled the estimates using a random-effects model. Regular talc use was associated with increased ovarian cancer risk in the combined study population (RR, 1.36; 95% CI, 1.14-1.63; P(trend) talc, the genes examined were not clearly associated with risk. However, the talc/ovarian cancer association varied by GSTT1 genotype and combined GSTM1/GSTT1 genotype. In the pooled analysis, the association with talc was stronger among women with the GSTT1-null genotype (P(interaction) = 0.03), particularly in combination with the GSTM1-present genotype (P(interaction) = 0.03). There was no clear evidence of an interaction with GSTM1 alone or NAT2. These results suggest that women with certain genetic variants may have a higher risk of ovarian cancer associated with genital talc use. Additional research is needed on these interactions and the underlying biological mechanisms. PMID:18768514

  8. Allele-specific PCR genotyping of the HSP70 gene polymorphism discriminating the green and red color variants sea cucumber (Apostichopus japonicus)

    Institute of Scientific and Technical Information of China (English)

    Jung-Ha Kang; Ki Hwan Yu; Jung-Youn Park; Chul-Min An; Je-Cheon Jun; Sang-Jun Lee

    2011-01-01

    Color variation is a well-known feature of sea cucumbers (Apostichopus japonicus),which are classified into three groups based on their colors of red,green and black.It is also one of the most important traits related to how they taste,and it thereby affects their market price.Attempts were made to identify single-nucleotide polymorphisms (SNPs) and to analyze differences associated with SNP genotypes between green and red color variants using HSP70 as the target gene.The HSP70 gene,which is found universally in organisms from bacteria to humans,is one of the most evolutionarily conserved genes and the most widely studied biomarker of stress response.DNA fragments of 1074 bp covering a partial sequence of the sea cucumber HSP70 gene,were amplified from both red and green variants,and subsequently analyzed for the presence of SNPs.Twenty-seven polymorphic sites in total,including heterozygous sites,were observed.Of these,six sites were found to be significantly different SNP genotypes between green and red variants.Furthermore,PCR with an internal primer designed to include an allelespecific SNP at the 3' end (site 443) showed differentiation between the two variants,100% and 4.2% amplification in green and red variants,respectively.The validated SNPs may serve as informative genetic markers that can be used to distinguish variants at the early developmental stage,prior to color differentiation.

  9. Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

    Science.gov (United States)

    Théry, Jean Christophe; Krieger, Sophie; Gaildrat, Pascaline; Révillion, Françoise; Buisine, Marie-Pierre; Killian, Audrey; Duponchel, Christiane; Rousselin, Antoine; Vaur, Dominique; Peyrat, Jean-Philippe; Berthet, Pascaline; Frébourg, Thierry; Martins, Alexandra; Hardouin, Agnès; Tosi, Mario

    2011-01-01

    A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more programs to induce a significant reduction of splice site strength or activation of cryptic splice sites or generation of new splice sites. Minigene-based splicing assays confirmed four of these predictions. Five additional VUSs, all at internal exon positions, were not predicted to induce alterations of splice sites, but revealed variable levels of exon skipping, most likely induced by the modification of exonic splicing regulatory elements. We provide new data in favor of the pathogenic nature of the variants BRCA1 c.212+3A>G and BRCA1 c.5194−12G>A, which induced aberrant out-of-frame mRNA forms. Moreover, the novel variant BRCA2 c.7977−7C>G induced in frame inclusion of 6 nt from the 3′ end of intron 17. The novel variants BRCA2 c.520C>T and BRCA2 c.7992T>A induced incomplete skipping of exons 7 and 18, respectively. This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions. PMID:21673748

  10. Characterization of influenza virus variants with different sizes of the non-structural (NS) genes and their potential as live influenza vaccine in poultry

    Science.gov (United States)

    The influenza virus isolate A/turkey/Oregon/71-delNS1 (H7N3) has a 10 nucleotide deletion in the coding region of the NS1 gene and as a result produces a truncated NS1 protein. From a stock of this virus, we found that several variants with different sizes of the NS genes exist. The number of varian...

  11. Zygote arrest 1 gene in pig, cattle and human: evidence of different transcript variants in male and female germ cells

    Directory of Open Access Journals (Sweden)

    Royere Dominique

    2006-03-01

    Full Text Available Abstract Background Zygote arrest 1 (ZAR1 is one of the few known oocyte-specific maternal-effect genes essential for the beginning of embryo development discovered in mice. This gene is evolutionary conserved in vertebrates and ZAR1 protein is characterized by the presence of atypical plant homeobox zing finger domain, suggesting its role in transcription regulation. This work was aimed at the study of this gene, which could be one of the key regulators of successful preimplantation development of domestic animals, in pig and cattle, as compared with human. Methods Screenings of somatic cell hybrid panels and in silico research were performed to characterize ZAR1 chromosome localization and sequences. Rapid amplification of cDNA ends was used to obtain full-length cDNAs. Spatio-temporal mRNA expression patterns were studied using Northern blot, reverse transcription coupled to polymerase chain reaction and in situ hybridization. Results We demonstrated that ZAR1 is a single copy gene, positioned on chromosome 8 in pig and 6 in cattle, and several variants of correspondent cDNA were cloned from oocytes. Sequence analysis of ZAR1 cDNAs evidenced numerous short inverted repeats within the coding sequences and putative Pumilio-binding and embryo-deadenylation elements within the 3'-untranslated regions, indicating the potential regulation ways. We showed that ZAR1 expressed exclusively in oocytes in pig ovary, persisted during first cleavages in embryos developed in vivo and declined sharply in morulae and blastocysts. ZAR1 mRNA was also detected in testis, and, at lower level, in hypothalamus and pituitary in both species. For the first time, ZAR1 was localized in testicular germ cells, notably in round spermatids. In addition, in pig, cattle and human only shorter ZAR1 transcript variants resulting from alternative splicing were found in testis as compared to oocyte. Conclusion Our data suggest that in addition to its role in early embryo

  12. Common type 2 diabetes risk gene variants associate with gestational diabetes

    DEFF Research Database (Denmark)

    Lauenborg, Jeannet; Grarup, Niels; Damm, Peter;

    2009-01-01

    Objective: We aimed to examine the association between gestational diabetes (GDM) and eleven recently identified type 2 diabetes susceptibility loci. Research Design and Methods: Type 2 diabetes risk variants in TCF7L2, CDKAL1, SLC30A8, HHEX/IDE, CDKN2A/2B, IGF2BP2, FTO, TCF2, PPARG, KCNJ11 and WFS......1 loci were genotyped in a cohort of women with a history of GDM (n=283) and in glucose tolerant women of the population-based Inter99 cohort (n=2,446). Results: All the risk alleles in the 11 examined type 2 diabetes risk variants showed an odds ratio greater than 1 for the GDM group compared to...... previously proven type 2 diabetes risk alleles equals the findings from association studies on type 2 diabetes. This supports the hypothesis that GDM and type 2 diabetes are two of the same entity....

  13. Concordant association of insulin degrading enzyme gene (IDE variants with IDE mRNA, Abeta, and Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Minerva M Carrasquillo

    Full Text Available BACKGROUND: The insulin-degrading enzyme gene (IDE is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD. METHODOLOGY/PRINCIPAL FINDINGS: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8, fold-increase = 2.12,; the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003. Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2-C (p = 0.006 and HepG2 (p = 0.02 cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879, we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011 and total measured plasma Abeta levels (b = -0.130, p = 0.009. Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03, and the eleven IDE haplotypes (global p = 0.02 also showed significant association. CONCLUSIONS: Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.

  14. ALDH1A1-overexpressing cells are differentiated cells but not cancer stem or progenitor cells in human hepatocellular carcinoma.

    Science.gov (United States)

    Tanaka, Kaori; Tomita, Hiroyuki; Hisamatsu, Kenji; Nakashima, Takayuki; Hatano, Yuichiro; Sasaki, Yoshiyuki; Osada, Shinji; Tanaka, Takuji; Miyazaki, Tatsuhiko; Yoshida, Kazuhiro; Hara, Akira

    2015-09-22

    Aldehyde dehydrogenase 1A1 (ALDH1A1) is considered to be a cancer stem cell marker in several human malignancies. However, the role of ALDH1A1 in hepatocellular carcinoma (HCC) has not been well elucidated. In this study, we investigated the relationship between ALDH1A1 and clinicopathological findings and examined whether ALDH1A1 deserves to be a cancer stem cell marker in HCC. Sixty HCC samples obtained from surgical resection were collected for immunohistochemical (IHC) staining. Of these 60 samples, 47 samples of HCC tumorous and non-tumorous tissues were evaluated with qRT-PCR. There was no significant difference in the ALDH1A1-mRNA level between tumorous and non-tumorous tissues. Tumorous ALDH1A1-mRNA level had no relationship with the clinicopathological features. Immunoreactivity of ALDH1A1 was classified into two groups based on the percentage of ALDH1A1-overexpressing cells. The ALDH1A1-high group was significantly associated with low serum levels of α-fetoprotein, small tumor diameter, very little lymphovascular invasion, more differentiated pathology and good stage. The ALDH1A1-high group showed more favorable prognosis for recurrence-free survival. In double-staining IHC, ALDH1A1 was not co-expressed with BMI1, EpCAM, CD13, CD24, CD90 and CD133, which reported as cancer stem cell markers in HCC. In conclusion, ALDH1A1-overexpressing cells could appear to be differentiated cells rather than cancer stem cells in HCC. PMID:26160842

  15. The Immunohistochemical Assessment of ALDH1 Activity in Breast Cancer and it’s Correlation With Pathologic Features

    Directory of Open Access Journals (Sweden)

    Molanae S

    2011-12-01

    Full Text Available Background: Aldehyde dehydrogenase 1 (ALDH1 is a marker of normal and malignant human mammary stem cells that has been reported to be associated with poor prognosis. Studies on the detection of ALDH1+ cells can help the treatment of patients with breast cancer. The aim of this study was to determine the activity of ALDH1 in breast cancer and its relationship with the pathological features of the tumors.Methods: ALDH1 activity was studied by immunohistochemistry in 121 paraffin-embedded histological samples of breast cancer patients from Department of Pathology of Milad Hospital, Tehran, Iran during 2006-2007. The relationship of ALDH1 with the pathological features of the tumors (size, grade, lymph node metastasis and vascular invasion was also investigated.Results: Eighty-five percent of breast cancer samples expressed ALDH1 in their cytoplasm with a wide range of intensity (weak, moderate and strong, while 18 samples (14.9% were completely negative. The majority of cases (97.1% showed ALDH1 positivity in the stroma of tumors which varied from weak (2.9% to strong (73.5%. ALDH1 H-score (ALDH1% × intensity of tumor cells varied from 0 to 240 (mean= 80. ALDH1 H-score was ≤80 in 62 (51.2% and >80 in 59 (48.8% samples. There was no statistically significant relationship between ALDH1 H-score and age (P=0.358, tumor size (P=0.375, tumor grade (P=0.207, lymph node metastasis (P=0.125 or vascular invasion (P=0.190.Conclusion: ALDH1 activity was demonstrated in 85.1% of breast cancer samples although its level of expression was not correlated with the pathologic features of breast tumors.

  16. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

    DEFF Research Database (Denmark)

    Neve, Bernadette; Fernandez-Zapico, Martin E; Ashkenazi-Katalan, Vered; Dina, Christian; Hamid, Yasmin H; Joly, Erik; Vaillant, Emmanuel; Benmezroua, Yamina; Durand, Emmanuelle; Bakaher, Nicolas; Delannoy, Valerie; Vaxillaire, Martine; Cook, Tiffany; Dallinga-Thie, Geesje M; Jansen, Hans; Charles, Marie-Aline; Clément, Karine; Galan, Pilar; Hercberg, Serge; Helbecque, Nicole; Charpentier, Guillaume; Prentki, Marc; Hansen, Torben; Pedersen, Oluf; Urrutia, Raul; Melloul, Danielle; Froguel, Philippe

    2005-01-01

    KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first...... time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in...... beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1...

  17. Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking.

    Directory of Open Access Journals (Sweden)

    Nicola Pirastu

    Full Text Available Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.

  18. Expression Variants of the Lipogenic AGPAT6 Gene Affect Diverse Milk Composition Phenotypes in Bos taurus

    OpenAIRE

    Littlejohn, Mathew D; Kathryn Tiplady; Thomas Lopdell; Law, Tania A.; Andrew Scott; Chad Harland; Ric Sherlock; Kristen Henty; Vlad Obolonkin; Klaus Lehnert; Alistair Macgibbon; Spelman, Richard J; Stephen R. Davis; Snell, Russell G.

    2014-01-01

    Milk is composed of a complex mixture of lipids, proteins, carbohydrates and various vitamins and minerals as a source of nutrition for young mammals. The composition of milk varies between individuals, with lipid composition in particular being highly heritable. Recent reports have highlighted a region of bovine chromosome 27 harbouring variants affecting milk fat percentage and fatty acid content. We aimed to further investigate this locus in two independent cattle populations, consisting o...

  19. Genetic Variants in the FADS Gene: Implications for Dietary Recommendations for Fatty Acid Intake

    OpenAIRE

    Mathias, Rasika A; Pani, Vrindarani; Chilton, Floyd H.

    2014-01-01

    Unequivocally, genetic variants within the fatty acid desaturase (FADS) cluster are determinants of long chain polyunsaturated fatty acid (LC-PUFA) levels in circulation, cells and tissues. A recent series of papers have addressed these associations in the context of ancestry; evidence clearly supports that the associations are robust to ethnicity. However ∼80% of African Americans carry two copies of the alleles associated with increased levels of arachidonic acid, compared to only ∼45% of E...

  20. Coexistencia de variantes HIV-1 com insercao dipeptidica no gene da transcriptase reversa

    Directory of Open Access Journals (Sweden)

    Aline Aki Tanikawa

    2013-08-01

    Full Text Available O objetivo desta comunicação foi descrever a detecção de coexistência de variantes HIV-1 com inserções de dois aminoácidos entre os códons 69 e 70 da transcriptase reversa. Tais variantes foram isoladas de paciente do sexo masculino, 16 anos de idade, em tratamento no interior do estado de São Paulo. Após confirmação de falha terapêutica, foi realizado teste de resistência a antirretrovirais, a partir do qual foram detectadas duas variantes contendo inserções dos aminoácidos Ser-Gly/Ser-Ala no códon 69 da transcriptase reversa, além da mutação T69S. Tais inserções possuem baixa prevalência, não foram relatadas em caráter de coexistência no Brasil e estão relacionadas com a resistência a múltiplas drogas, tornando o achado relevante do ponto de vista epidemiológico.

  1. Cloning and Sequencing of S Gene of Novel Variant of Infectious Bronchitis Virus ZJ971 Isolates in China

    Institute of Scientific and Technical Information of China (English)

    ZHOU Ji-yong; CHENG Li-qin; SHEN Xing-yan; DING Hong-mei; WU Jian-xiang

    2002-01-01

    A novel proventriculopathogic variant (isolate ZJ971) of infectious bronchitis virus (IBV) was identified from enlarged proeventriculus of the sick chickens in the study. The S gene cDNA segment with 3.6 kb in length was amplified by RT-PCR with special primers from the ZJ971 viral isolate of (IBV) and cloned into plasmid pBluescript SK( + ). The recombinants containing S gene of IBV-ZJ971 isotate were identified by digestion of restriction enzyme EcoRI, BamHI and PCR amplification. The cloned S gene from isolate IBVZJ971 was composed of 3492 bp in length encoding for a polypeptide of 1080 amino acids. Comparing the nucleotide of S gene of IBV isolate ZJ971 with that of reported IBV strains Beaudette, M41, Ark99 and CuT2,the homology was 97.3%, 97.5%, 88.6% and 85.6%, respectively; and the homology of the deduced amino acids of S protein of IBV isolate ZJ971 was 96%, 96.3%, 86.1% and 83.1% respectively; especially, the mutation of 3241st nucleotide of S gene of IBV isolate ZJ971 from G to T resulted in the translating termination of S protein at 3240th nucleotide site.

  2. Transcription variants of the prostate-specific PrLZ gene and their interaction with 14-3-3 proteins

    International Nuclear Information System (INIS)

    We have reported isolation and characterization of the prostate-specific and androgen-regulated PrLZ gene abnormally expressed in prostate cancer. PrLZ is a potential biomarker for prostate cancer and a candidate oncogene promoting cell proliferation and survival in prostate cancer cells. A full delineation of the PrLZ gene and its gene products may provide clues to the mechanisms regulating its expression and function. In this report, we identified three additional exons in the PrLZ gene and recognized five transcript variants from alternative splicing that could be detected by RT-PCR and Western blotting. Structural comparison demonstrated that the PrLZ proteins are highly conserved among species. PrLZ contains multiple potential sites for interaction with other proteins. We used mammalian two-hybrid assays to demonstrate that PrLZ isoforms interact with 14-3-3 proteins, and multiple sites in the PrLZ may be involved in the interaction. Alternative splicing may contribute to abnormally enhanced PrLZ levels in prostate cancer, and interaction with 14-3-3 proteins may be a mechanism by which PrLZ promotes cell proliferation and survival during prostate cancer development and progression. This information is a valuable addition to the investigation of the oncogenic properties of the PrLZ gene.

  3. The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia

    Science.gov (United States)

    Yokoyama, Jennifer S.; Bonham, Luke W.; Sturm, Virginia E.; Adhimoolam, Babu; Karydas, Anna; Coppola, Giovanni; Miller, Bruce L.; Rankin, Katherine P.

    2015-01-01

    The serotonin transporter length polymorphism (5-HTTLPR) short allele (5-HTTLPR-s) has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD), a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2) of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03) and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01). These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity. PMID:26509115

  4. The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Jennifer S. Yokoyama

    2015-01-01

    Full Text Available The serotonin transporter length polymorphism (5-HTTLPR short allele (5-HTTLPR-s has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD, a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2 of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03 and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01. These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity.

  5. Imaging oxytocin × dopamine interactions: an epistasis effect of CD38 and COMT gene variants influences the impact of oxytocin on amygdala activation to social stimuli

    OpenAIRE

    PeterKirsch; ChristianMontag

    2013-01-01

    Although oxytocin (OT) has become a major target for the investigation of positive social processes, it can be assumed that it exerts its effects in concert with other neurotransmitters. One candidate for such an interaction is dopamine (DA). For both systems, genetic variants have been identified that influence the availability of the particular substance. A variant of the gene coding for the transmembrane protein CD38 (rs3796863), which is engaged in OT secretion, has been associated with O...

  6. A sex-specific association of common variants of neuroligin genes (NLGN3 and NLGN4X with autism spectrum disorders in a Chinese Han cohort

    Directory of Open Access Journals (Sweden)

    Li Hui

    2011-05-01

    Full Text Available Abstract Background Synaptic genes, NLGN3 and NLGN4X, two homologous members of the neuroligin family, have been supposed as predisposition loci for autism spectrum disorders (ASDs, and defects of these two genes have been identified in a small fraction of individuals with ASDs. But no such rare variant in these two genes has as yet been adequately replicated in Chinese population and no common variant has been further investigated to be associated with ASDs. Methods 7 known ASDs-related rare variants in NLGN3 and NLGN4X genes were screened for replication of the initial findings and 12 intronic tagging single nucleotide polymorphisms (SNPs were genotyped for case-control association analysis in a total of 229 ASDs cases and 184 control individuals in a Chinese Han cohort, using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF mass spectrometry. Results We found that a common intronic variant, SNP rs4844285 in NLGN3 gene, and a specific 3-marker haplotype XA-XG-XT (rs11795613-rs4844285-rs4844286 containing this individual SNP were associated with ASDs and showed a male bias, even after correction for multiple testing (SNP allele: P = 0.048, haplotype:P = 0.032. Simultaneously, none of these 7 known rare mutation of NLGN3 and NLGN4X genes was identified, neither in our patients with ASDs nor controls, giving further evidence that these known rare variants might be not enriched in Chinese Han cohort. Conclusion The present study provides initial evidence that a common variant in NLGN3 gene may play a role in the etiology of ASDs among affected males in Chinese Han population, and further supports the hypothesis that defect of synapse might involvement in the pathophysiology of ASDs.

  7. Negative Regulation-Resistant p53 Variant Enhances Oncolytic Adenoviral Gene Therapy

    OpenAIRE

    Koo, Taeyoung; Choi, Il-Kyu; Kim, Minjung; Lee, Jung-Sun; Oh, Eonju; Kim, Jungho; Yun, Chae-Ok

    2012-01-01

    Intact p53 function is essential for responsiveness to cancer therapy. However, p53 activity is attenuated by the proto-oncoprotein Mdm2, the adenovirus protein E1B 55kD, and the p53 C-terminal domain. To confer resistance to Mdm2, E1B 55kD, and C-terminal negative regulation, we generated a p53 variant (p53VPΔ30) by deleting the N-terminal and C-terminal regions of wild-type p53 and inserting the transcriptional activation domain of herpes simplex virus VP16 protein. The oncolytic adenovirus...

  8. Association between variants in inflammation and cancer-associated genes and risk and survival of cholangiocarcinoma

    OpenAIRE

    Chaiteerakij, Roongruedee; Juran, Brian D; Aboelsoud, Mohammed M.; Harmsen, William S.; Moser, Catherine D.; Giama, Nasra H; Allotey, Loretta K; Mettler, Teresa A.; Baichoo, Esha; Zhang, Xiaodan; Therneau, Terry M.; Lazaridis, Konstantinos N; Roberts, Lewis R.

    2015-01-01

    Genetic risk factors for cholangiocarcinoma (CCA) remain poorly understood. We assessed the effect of single-nucleotide polymorphisms (SNPs) of genes modulating inflammation or carcinogenesis on CCA risk and survival. We conducted a case-control, candidate gene association study of 370 CCA patients and 740 age-, sex-, and residential area-matched healthy controls. Eighteen functional or putatively functional SNPs in nine genes were genotyped. The log-additive genotype effects of SNPs on CCA r...

  9. The association of ACE, ACTN3 and PPARA gene variants with strength phenotypes in middle school-age children.

    Science.gov (United States)

    Ahmetov, Ildus I; Gavrilov, Dmitry N; Astratenkova, Irina V; Druzhevskaya, Anastasiya M; Malinin, Alexandr V; Romanova, Elena E; Rogozkin, Victor A

    2013-01-01

    The aim of the study was to determine the association between ACE I/D, ACTN3 R577X and PPARA intron 7 G/C gene polymorphisms and strength-related traits in 457 middle school-age children (219 boys and 238 girls; aged 11 ± 0.4 years). The assessment of different phenotypes was conducted with a number of performance tests. Gene polymorphisms were determined by PCR. The ACE D allele was associated with high results of standing long-jump test in boys [II 148.3 (16.3) cm, ID 152.6 (19.6) cm, DD 158.2 (19.1) cm; P = 0.037]. The ACTN3 R allele was associated with high results of performance tests in males only in combination with other genes (standing long-jump test: P = 0.021; handgrip strength test: P ACTN3 and PPARA gene variants are associated with strength-related traits in physically active middle school-age boys. PMID:22983821

  10. The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host-parasite interaction

    KAUST Repository

    Jackson, Andrew P.

    2014-05-05

    Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5? ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct. 2014 The Author(s) 2014.

  11. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

    Science.gov (United States)

    Arcos-Burgos, M; Jain, M; Acosta, M T; Shively, S; Stanescu, H; Wallis, D; Domené, S; Vélez, J I; Karkera, J D; Balog, J; Berg, K; Kleta, R; Gahl, W A; Roessler, E; Long, R; Lie, J; Pineda, D; Londoño, A C; Palacio, J D; Arbelaez, A; Lopera, F; Elia, J; Hakonarson, H; Johansson, S; Knappskog, P M; Haavik, J; Ribases, M; Cormand, B; Bayes, M; Casas, M; Ramos-Quiroga, J A; Hervas, A; Maher, B S; Faraone, S V; Seitz, C; Freitag, C M; Palmason, H; Meyer, J; Romanos, M; Walitza, S; Hemminger, U; Warnke, A; Romanos, J; Renner, T; Jacob, C; Lesch, K-P; Swanson, J; Vortmeyer, A; Bailey-Wilson, J E; Castellanos, F X; Muenke, M

    2010-11-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD. PMID:20157310

  12. Variants of tumor necrosis factor-induced protein 3 gene are associated with left ventricular hypertrophy in hypertensive patients

    Institute of Scientific and Technical Information of China (English)

    XUE Hao; WANG Shu-xia; WANG Xiao-jian; XIN Ying; WANG Hu; SONG Xiao-dong; SUN Kai; WANG Yi-bo; HUI Ru-tai

    2011-01-01

    Background Tumor necrosis factor-induced protein 3 (TNFAIP3) gene has been shown important in cardiac remodeling. The aim of the present study was to investigate whether the variants of TNFAIP3 gene are associated with left ventricular hypertrophy (LVH) in hypertensive patients.Methods Four representatives of all the other single nucleotide polymorphisms (SNPs) in TNFAIP3 gene were tested for association with hypertrophy in two independent hypertensive populations (n=2120 and n=324).Results We found that only the tag SNP (rs5029939) was consistently lower in the hypertensives with cardiac hypertrophy than in those without cardiac hypertrophy in the two study populations, indicating a protective effect on LVH (odds ratio (OR) (95% confidence interval (CI))0.58 (0.358-0.863), P=0.035; OR (95% CI)=0.477 (0.225-0.815), P<0.05,respectively). Multiple regression analyses confirmed that the patients with G allele of rs5029939 had less thickness in inter-ventricular septum, left ventricular posterior wall, relative wall thickness and left ventricular mass index than did those with CC allele in the hypertensive patients in both study populations (all P<0.01).Conclusion These findings indicate that the SNP (rs5029939) in the TNFAIP3 gene may serve as a novel protective genetic marker for the development of LVH in patients with hypertension.

  13. Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans.

    Science.gov (United States)

    Leak, T S; Perlegas, P S; Smith, S G; Keene, K L; Hicks, P J; Langefeld, C D; Mychaleckyj, J C; Rich, S S; Kirk, J K; Freedman, B I; Bowden, D W; Sale, M M

    2009-03-01

    Variants in the engulfment and cell motility 1 (ELMO1) gene are associated with nephropathy due to type 2 diabetes mellitus (T2DM) in a Japanese cohort. We comprehensively evaluated this gene in African American (AA) T2DM patients with end-stage renal disease (ESRD). Three hundred and nine HapMap tagging SNPs and 9 reportedly associated SNPs were genotyped in 577 AA T2DM-ESRD patients and 596 AA non-diabetic controls, plus 43 non-diabetic European American controls and 45 Yoruba Nigerian samples for admixture adjustment. Replication analyses were conducted in 558 AA with T2DM-ESRD and 564 controls without diabetes. Extension analyses included 328 AA with T2DM lacking nephropathy and 326 with non-diabetic ESRD. The original and replication analyses confirmed association with four SNPs in intron 13 (permutation p-values for combined analyses = 0.001-0.003), one in intron 1 (P = 0.004) and one in intron 5 (P = 0.002) with T2DM-associated ESRD. In a subsequent combined analysis of all 1,135 T2DM-ESRD cases and 1,160 controls, an additional 7 intron 13 SNPs produced evidence of association (P = 3.5 x 10(-5)- P = 0.05). No associations were seen with these SNPs in those with T2DM lacking nephropathy or with ESRD due to non-diabetic causes. Variants in intron 13 of the ELMO1 gene appear to confer risk for diabetic nephropathy in AA. PMID:19183347

  14. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.

    Directory of Open Access Journals (Sweden)

    Angelo Scuteri

    2007-07-01

    Full Text Available The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7, hip circumference (p = 3.4 x 10(-8, and weight (p = 9.1 x 10(-7. In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46 were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6. Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12 were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496 and in Hispanic Americans (N = 839, we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001, weight (p = 0.001, and hip circumference (p = 0.0005. We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for

  15. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects.

    Science.gov (United States)

    Erk, Susanne; Meyer-Lindenberg, Andreas; Linden, David E J; Lancaster, Thomas; Mohnke, Sebastian; Grimm, Oliver; Degenhardt, Franziska; Holmans, Peter; Pocklington, Andrew; Schmierer, Phöbe; Haddad, Leila; Mühleisen, Thomas W; Mattheisen, Manuel; Witt, Stephanie H; Romanczuk-Seiferth, Nina; Tost, Heike; Schott, Björn H; Cichon, Sven; Nöthen, Markus M; Rietschel, Marcella; Heinz, Andreas; Walter, Henrik

    2014-07-01

    Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analyzed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same system-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia

  16. Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

    OpenAIRE

    Hendrickson, Sher L.; Lautenberger, James A; Chinn, Leslie Wei; Malasky, Michael; Sezgin, Efe; Kingsley, Lawrence A.; Goedert, James J.; Kirk, Gregory D.; Gomperts, Edward D.; Buchbinder, Susan P.; Troyer, Jennifer L.; O'Brien, Stephen J.

    2010-01-01

    Background The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. Methodology/Principal Findings Here we explore whether single nucleotide polymorphisms (SNPs) within 9...

  17. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

    NARCIS (Netherlands)

    Simpson, Claire L.; Lemmens, Robin; Miskiewicz, Katarzyna; Broom, Wendy J.; Hansen, Valerie K.; van Vught, Paul W. J.; Landers, John E.; Sapp, Peter; Van Den Bosch, Ludo; Knight, Joanne; Neale, Benjamin M.; Turner, Martin R.; Veldink, Jan H.; Ophoff, Roel A.; Tripathi, Vineeta B.; Beleza, Ana; Shah, Meera N.; Proitsi, Petroula; Van Hoecke, Annelies; Carmeliet, Peter; Horvitz, H. Robert; Leigh, P. Nigel; Shaw, Christopher E.; van den Berg, Leonard H.; Sham, Pak C.; Powell, John F.; Verstreken, Patrik; Brown, Robert H.; Robberecht, Wim; Al-Chalabi, Ammar

    2009-01-01

    Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both can

  18. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D; Lundmark, F; Seddighzadeh, M; Oturai, A; Sørensen, P S; Lorentzen, Anne; Celius, E G; Leppä, V; Koivisto, K; Tienari, P J; Alfredsson, L; Padyukov, L; Hillert, J; Kockum, I; Jagodic, M; Olsson, T

    2010-01-01

    chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries. A...

  19. Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population

    Directory of Open Access Journals (Sweden)

    Marre Michel

    2006-05-01

    Full Text Available Abstract Background The protein tyrosine phosphatase-1B, a negative regulator for insulin and leptin signalling, potentially modulates glucose and energy homeostasis. PTP1B is encoded by the PTPN1 gene located on chromosome 20q13 showing linkage with type 2 diabetes (T2D in several populations. PTPN1 gene variants have been inconsistently associated with T2D, and the aim of our study was to investigate the effect of PTPN1 genetic variations on the risk of T2D, obesity and on the variability of metabolic phenotypes in the French population. Methods Fourteen single nucleotide polymorphisms (SNPs spanning the PTPN1 locus were selected from previous association reports and from HapMap linkage disequilibrium data. SNPs were evaluated for association with T2D in two case-control groups with 1227 cases and 1047 controls. Association with moderate and severe obesity was also tested in a case-control study design. Association with metabolic traits was evaluated in 736 normoglycaemic, non-obese subjects from a general population. Five SNPs showing a trend towards association with T2D, obesity or metabolic parameters were investigated for familial association. Results From 14 SNPs investigated, only SNP rs914458, located 10 kb downstream of the PTPN1 gene significantly associated with T2D (p = 0.02 under a dominant model; OR = 1.43 [1.06–1.94] in the combined sample set. SNP rs914458 also showed association with moderate obesity (allelic p = 0.04; OR = 1.2 [1.01–1.43]. When testing for association with metabolic traits, two strongly correlated SNPs, rs941798 and rs2426159, present multiple consistent associations. SNP rs2426159 exhibited evidence of association under a dominant model with glucose homeostasis related traits (p = 0.04 for fasting insulin and HOMA-B and with lipid markers (0.02 = p = 0.04. Moreover, risk allele homozygotes for this SNP had an increased systolic blood pressure (p = 0.03. No preferential transmission of alleles was observed

  20. Systematic examination of DNA variants in the parkin gene in patients with Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    王涛; 梁直厚; 孙圣刚; 曹学兵; 彭海; 刘红进; 童萼塘

    2004-01-01

    @@ Increasing evidence suggests that genetic factors play an important role in the pathogenesis of Parkinson ' s disease (PD). Three genes, namely α-synuclein, parkin, and UCH-L1, have been implicated in familial PD. An exon deletion in the parkin gene is the mutation most frequently mentioned in published data. The parkin gene was first identified by Japanese researchers, and, since fragment deletions in coding exons of this gene have been proven responsible for autosomal recessive juvenile parkinsonism (AR-JP),1 several follow-up reports from European groups have shown that point mutations in this gene also contribute to the pathogenesis of PD, especially early-onset PD.2 Further research has suggested that mutations in parkin may also be involved in sporadic PD (idiopathic PD).2-4 Japanese researchers have also identified 3 single nucleotide polymorphisms (SNPs) located in exon 4 (S/N 167) and exon 10 (R/W 366, V/L 380).

  1. Tumor necrosis factor alpha and alpha-1 antitrypsin gene variants in Serbian pediatric arterial ischemic stroke patients

    Directory of Open Access Journals (Sweden)

    Đorđević Valentina

    2013-01-01

    Full Text Available The etiology of arterial ischemic stroke (AIS in children is complex, and different from that in adults. Although rare, stroke in children is an important cause of mortality and morbidity. There is increasing evidence that genetic factors, including inflammation mediators, have a role in occurrence and outcome of stroke. We have chosen to assess the role of polymorphism -308G/A in the promoter of tumor necrosis factor α (TNFα gene and S and Z mutations in alpha 1-antitrypsin (AAT gene in the etiology of stroke in children. TNFα polymorphism affects plasma levels of this proinflamatory cytokine, and this could contribute to stroke pathology. It has been shown that increased AAT concentration may present a risk for AIS in children. Since S and Z mutations in AAT gene reduce its levels in plasma they could have a protective role in pediatric stroke. In this study twenty six children with AIS and 100 unrelated individuals from Serbian general population were investigated by PCR/RFLP for these gene variations. No statistically significant difference was observed between patients and general population in distribution of genotypes for -308G/A TNFα polymorphism, so its contributory role in the etiology of stroke was not evident in our group of patients. None of the tested AAT gene mutations were found in patients, which is in concordance with the proposed protective role of deficient AAT variants. AIS is a multifactorial disease, with many genes having a modest role in its pathophysiology, so further analyses of their combined effect are needed to elucidate genetic risk factors in the etiology and outcome of stroke in pediatric patients.

  2. The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

    OpenAIRE

    Vanelli Maurizio; Hougaard Philip; Svensson Jannet; Fredheim Siri; Andersen Marie Louise M; Pörksen Sven; Nielsen Lotte B; Åman Jan; Mortensen Henrik B; Hansen Lars

    2011-01-01

    Abstract Background The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycem...

  3. MDM2 285G>C and 344T>A gene variants and their association with hepatocellular carcinoma: a Moroccan case–control study

    OpenAIRE

    Rebbani, Khadija; Ezzikouri, Sayeh; Marchio, Agnès; Kandil, Mostafa; Pineau, Pascal; Benjelloun, Soumaya

    2014-01-01

    International audience Background MDM2 gene polymorphisms 285G/C and 344 T/A are two single nucleotide polymorphisms (SNPs) recently identified as important variants that could influence the expression of MDM2 gene through the modulation of transcription factors binding on the SNP309T/G. The 285C variant seems to present a geographically distinct distribution in humans and to be associated with a low cancer risk. In the present report, we studied the distribution of the three SNPs in a pop...

  4. Variants of the FADS1 FADS2 Gene Cluster, Blood Levels of Polyunsaturated Fatty Acids and Eczema in Children within the First 2 Years of Life

    OpenAIRE

    Rzehak, Peter; Thijs, Carel; Standl, Marie; Mommers, Monique; Glaser, Claudia; Jansen, Eugène; Klopp, Norman; Koppelman, Gerard H.; Singmann, Paula; Postma, Dirkje S.; Sausenthaler, Stefanie; Dagnelie, Pieter C; van den Brandt, Piet A.; Koletzko, Berthold; Heinrich, Joachim

    2010-01-01

    Background Association of genetic-variants in the FADS1-FADS2-gene-cluster with fatty-acid-composition in blood of adult-populations is well established. We analyze this genetic-association in two children-cohort-studies. In addition, the association between variants in the FADS-gene-cluster and blood-fatty-acid-composition with eczema was studied. Methods and Principal Findings Data of two population-based-birth-cohorts in the Netherlands and Germany (KOALA, LISA) were pooled (n = 879) and a...

  5. Analyzing Interaction of μ-, δ- and κ-opioid Receptor Gene Variants on Alcohol or Drug Dependence Using a Pattern Discovery-based Method

    OpenAIRE

    Li, Zhong; Zhang, Huiping

    2013-01-01

    Background Polymorphisms in the μ-, δ- and κ-opioid receptor genes (OPRM1, OPRD1 and OPRK1) have been reported to be associated with substance (alcohol or drug) dependence. The influence of an individual gene on a disease trait should be more evident when analyzed in the context of gene-gene interactions. Thus, we assessed the joint effect of variants in these three opioid receptor genes on alcohol, cocaine, or opioid dependence. Methods Genotype data for 13 OPRM1 Single Nucleotide Polymorphi...

  6. Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case-control samples

    DEFF Research Database (Denmark)

    Tesli, Martin; Koefoed, Pernille; Athanasiu, Lavinia;

    2011-01-01

    Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case–control sample (N¿=¿854/2,614). Due to evidence of gen...... associated with SZ in the combined Nordic SZ case–control sample (N¿=¿1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved. © 2011 Wiley Periodicals, Inc.......Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case–control sample (N¿=¿854/2,614). Due to evidence of...... genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case–control sample (N¿=¿1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N¿=¿435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to...

  7. C677T polymorphism of the MTHFR gene and variant hemoglobins: a study in newborns from Salvador, Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    Fábio David Couto

    2004-04-01

    Full Text Available The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR is associated with an increase in total homocysteine serum levels (tHcy, described as a risk factor for cardiovascular disease. Eight hundred forty-three neonates from two different maternity hospitals, one public and another private, in Salvador, Bahia, Brazil were screened for this polymorphism by PCR and RFLP. The T-allele frequency in the total sample was 0.23, and the prevalence rates of heterozygous and homozygous carriers were 36.2% and 5.3%, respectively. The T-allele frequency differed and the T/T genotype was more prevalent at the private maternity hospital. The hemoglobin (Hb profile was investigated by HPLC in 763 newborns. The frequency of variant Hb was higher at the public than at the private maternity hospital. The association of the C677T polymorphism and the Hb profile was investigated in 683 newborns, showing a relatively high frequency of variant Hbs and the T allele. These data could provide an important basis for further studies focusing on potential risks of vaso-occlusive events in these individuals.

  8. C677T polymorphism of the MTHFR gene and variant hemoglobins: a study in newborns from Salvador, Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    Couto Fábio David

    2004-01-01

    Full Text Available The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR is associated with an increase in total homocysteine serum levels (tHcy, described as a risk factor for cardiovascular disease. Eight hundred forty-three neonates from two different maternity hospitals, one public and another private, in Salvador, Bahia, Brazil were screened for this polymorphism by PCR and RFLP. The T-allele frequency in the total sample was 0.23, and the prevalence rates of heterozygous and homozygous carriers were 36.2% and 5.3%, respectively. The T-allele frequency differed and the T/T genotype was more prevalent at the private maternity hospital. The hemoglobin (Hb profile was investigated by HPLC in 763 newborns. The frequency of variant Hb was higher at the public than at the private maternity hospital. The association of the C677T polymorphism and the Hb profile was investigated in 683 newborns, showing a relatively high frequency of variant Hbs and the T allele. These data could provide an important basis for further studies focusing on potential risks of vaso-occlusive events in these individuals.

  9. Functional variants in CYP1B1, KRAS and MTHFR genes are associated with shorter telomere length in postmenopausal women.

    Science.gov (United States)

    Cerne, Jasmina Z; Pohar-Perme, Maja; Cerkovnik, Petra; Gersak, Ksenija; Novakovic, Srdjan

    2015-07-01

    Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length. PMID:25987236

  10. Functional promoter -31G/C variant of Survivin gene predict prostate cancer susceptibility among Chinese: a case control study

    International Nuclear Information System (INIS)

    Abnormal expression of Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin), a novel member of the inhibitor of apoptosis protein (IAP) family, has implications in many types of cancer and is considered as a new therapeutic target. We suppose that genetic variant rs9904341 in the 5′ UTR region of survivin gene may be associated with the development and progression of prostate cancer (PCa) in Chinese population. TaqMan assay method was used to genotype the polymorphism in the hospital-based case–control analysis of 665 patients with PCa and 710 age-matched cancer-free controls. The genetic associations with the occurrence and progression of PCa were calculated by logistic regression. Our results indicated that compared with GG genotypes, there was a statistically significant increased risk of PCa associated with those with CC genotypes [odds ratios (ORs) = 1.57, 95%confidence intervals (CIs) = 1.17-2.13, P = 0.004]. Moreover, stratification analysis revealed that the association was more pronounced in subgroups of nondrinkers, nonsmokers and those without a family history of cancer (all P < 0.05). In addition, we observed that PSA ≥ 20 was more frequent in patients carrying GC/CC genotypes than in those with a wild type genotype. The functional survivin rs9904341 genetic variant may have a substantial influence on the PCa susceptibility and evolution

  11. Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression.

    Directory of Open Access Journals (Sweden)

    Sher L Hendrickson

    Full Text Available BACKGROUND: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. METHODOLOGY/PRINCIPAL FINDINGS: Here we explore whether single nucleotide polymorphisms (SNPs within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4 on chromosome 12 and peroxisomal D3,D2-enoyl-CoA isomerase (PECI on chromosome 6. CONCLUSIONS: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis.

  12. Variants of the HNF1α gene: a molecular approach concerning diabetic patients from southern Brazil

    OpenAIRE

    Naieli Bonatto; Viviane Nogaroto; Svidnicki, Paulo V.; Milléo, Fábio Q.; Sabrina Grassiolli; Almeida, Mara C.; Marcelo R. Vicari; Artoni, Roberto F.

    2012-01-01

    Maturity Onset Diabetes of the Young (MODY) presents monogenic inheritance and mutation factors which have already been identified in six different genes. Given the wide molecular variation present in the hepatocyte nuclear factor-1α gene (HNF1α) MODY3, the aim of this study was to amplify and sequence the coding regions of this gene in seven patients from the Campos Gerais region, Paraná State, Brazil, presenting clinical MODY3 features. Besides the synonymous variations, A15A, L17L, Q141Q, ...

  13. Chiari malformation type I: a case-control association study of 58 developmental genes.

    Directory of Open Access Journals (Sweden)

    Aintzane Urbizu

    Full Text Available Chiari malformation type I (CMI is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF, often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186, underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI.

  14. Hypoxia inducible factor 1α gene (HIF-1α splice variants: potential prognostic biomarkers in breast cancer

    Directory of Open Access Journals (Sweden)

    Bonnier Pascal

    2010-07-01

    Full Text Available Abstract Background Hypoxia-inducible factor 1 (HIF-1 is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear translocator (ARNT subunits. The prognostic relevance of HIF-1α protein overexpression has been shown in breast cancer. The impact of HIF-1α alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known. Methods Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1α and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign and 53 primary carcinomas. In breast cancers HIF-1α splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival. Results HIF-1α isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1αTAG and HIF-1α736 mRNAs were found expressed at higher levels in oestrogen receptor (OR-negative carcinomas compared to normal/benign tissues (P = 0.009 and P = 0.004 respectively. In breast carcinoma specimens, lymph node status was significantly associated with HIF-1αTAG mRNA levels (P = 0.037. Significant statistical association was found between tumour grade and HIF-1αTAG (P = 0.048, and total HIF-1α (P = 0.048 mRNA levels. HIF-1αTAG mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively. Univariate analysis showed that high HIF-1αTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01. Conclusions Our results show for the first time that mRNA expression of a HIF-1αTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis. See commentary: http://www.biomedcentral.com/1741-7015/8/45

  15. Evaluation of point mutations in dystrophin gene in Iranian Duchenne and Becker muscular dystrophy patients: introducing three novel variants

    Indian Academy of Sciences (India)

    MARYAM HAGHSHENAS; MOHAMMAD TAGHI AKBARI; SHOHREH ZARE KARIZI; FARAVAREH KHORDADPOOR DEILAMANI; SHAHRIAR NAFISSI; ZIVAR SALEHI

    2016-06-01

    Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked neuromuscular diseases characterized by progres-sive muscular weakness and degeneration of skeletal muscles. Approximately two-thirds of the patients have large deletionsor duplications in the dystrophin gene and the remaining one-third have point mutations. This study was performed to eval-uate point mutations in Iranian DMD/BMD male patients. A total of 29 DNA samples from patients who did not show anylarge deletion/duplication mutations following multiplex polymerase chain reaction (PCR) and multiplex ligation-dependentprobe amplification (MLPA) screening were sequenced for detection of point mutations in exons 50–79. Also exon 44 wassequenced in one sample in which a false positive deletion was detected by MLPA method. Cycle sequencing revealed fournonsense, one frameshift and two splice site mutations as well as two missense variants

  16. Variant evidence of three genes of Potato vein yellow virus infecting Solanum tubersosum sp. using single strand conformational polymorphism.

    Directory of Open Access Journals (Sweden)

    Karen Andrea CUBILLOS ABELLO

    2014-10-01

    Full Text Available 1024x768 Potato yellow vein virus (PYVV with tripartite RNA (ss+ genome is classified as Crinivirus within the family Closteoviridae. PYVV is the causal agent of potato yellow vein disease (PYVD with yield effect. Single strand conformational polymorphism (SSCP was reported to estimate variability in eukaryotes and different viruses’ species. In this study, the molecular variability of PYVV was analyzed by SSCP patterns regarding three genes: major capsid protein (CP, minor capsid protein (CPm, and heat shock protein (Hsp70 obtained from isolates of 60 potato plants leaves expressing PYVD. Leaves were collected in Nariño, Colombia from 30 Solanum tuberosum, Phureja Group (PhG and 30 Andigena Group (AG. Genes were amplified by RT-PCR and the purified direct PCR products were used for SSCP. Three SSCP patterns were detected for CP gen, 12 for CPm and 12 for Hsp70 genes. The AG host, most frequent pattern was C (66.6% for the Hsp70 gene and IV (33.3% for CPm gene. Complex SSCP patters with inter and intra variation were detected. CP gene pattern 1 was present in 93.3% of the isolates of both host groups, indicating low number of variants compared to CPm and Hsp70 genes. This is the first attempt to estimate intra e inter PYVV variability by the use of a simple molecular method considering three genes in a large group of potato samples affected by PYVD. SSCP technique was useful to discriminate the migration patterns generated for each gene Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabla normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso

  17. Distribution of transferrin binding protein B gene (tbpB variants among Neisseria species

    Directory of Open Access Journals (Sweden)

    Maiden Martin CJ

    2008-04-01

    Full Text Available Abstract Background Transferrin binding protein B (tbpB, an outer membrane lipoprotein, is required for the acquisition of iron from human transferrin. Two tbpB families have been documented in Neisseria meningitidis: an isotype I tbpB gene of 1.8 kb and an isotype II tbpB gene of 2.1 kb, the former expressed by meningococci in the disease-associated ST-11 clonal complex and the latter found among meningococci belonging to the hyper-invasive clonal complexes including ST-8, ST-18, ST-32, ST-41/44 as well as N. gonorrhoeae isolates. The origin of the isotype I tbpB gene is unknown, however several features in common with non-pathogenic Neisseria and the ST-11 clonal complex N. meningitidis isolate FAM18 have been documented leading to the hypothesis that the isotype I tbpB gene may also be shared between non-pathogenic Neisseria and ST-11 meningococci. As a result, the diversity of the tbpB gene was investigated in a defined collection of Neisseria species. Results Two families of isotype I tbpB were identified: family A containing conserved genes belonging to ST-11 meningococci, N. polysaccharea and N. lactamica isolates and family B including more diverse isotype I tbpB genes from N. sicca, N. mucosa, N. flava, N. subflava as well as N. cinerea, N. flavescens and N. polysaccharea isolates. Three isotype II tbpB families were identified with: family C containing diverse tbpB genes belonging to N. polysaccharea, N. lactamica, N. gonorrhoeae and N. meningitidis isolates, family D including another subset of isotype II tbpB genes from N. lactamica isolates and family E solely composed of N. gonorrhoeae tbpB genes. Conclusion This study reveals another instance of similarity between meningococci of the ST-11 clonal complex and non-pathogenic Neisseria with the origin of the isotype I tbpB gene resulting from a horizontal genetic transfer event occurring between these two populations.

  18. Common variant in myocilin gene is associated with high myopia in isolated population of Korcula Island, Croatia.

    LENUS (Irish Health Repository)

    Vatavuk, Zoran

    2012-01-31

    AIM: To study the association between genetic variants in myocilin and collagen type I alpha 1 genes and high myopia in an isolated island population. METHODS: A total of 944 examinees from the genetic epidemiology study conducted on the island of Korcula, Croatia, were included in the study. We selected 2 short nucleotide polymorphisms (SNP) available in our genome-wide scan set of SNPs that were previously associated with high myopia and used them to replicate previous claims of possible association. RESULTS: Nineteen cases of high myopia, defined as the refraction of <\\/=-6.00 diopters, were identified and included in the analysis. We showed that rs2075555 in the COL1A1 gene was not associated with high myopia. In contrast, rs2421853 in the myocilin gene was significantly associated in both bivariate (P=0.006) and age- and sex-adjusted analysis (P=0.049). CONCLUSION: Myocilin seems to be a very strong candidate for explaining some of the pathophysiological pathways leading to the development of both glaucoma and high myopia. As our finding was obtained in a relatively under-powered sample, further research and replication of these results is needed.

  19. MSX 1 gene variant and non-syndromic clefting: Association or rejection?

    OpenAIRE

    Naveen Admala Reddy; Adusumilli Gopinath; JayaprakashThirumala Reddy; Raghu Devanna; Pichai Saravanan; Rohra, Mayur G

    2014-01-01

    Context: Non-syndromic cleft lip/palate (NSCL/P) is a congenital anomaly with significant medical, psychological and social ramifications. There is sufficient evidence to hypothesize that locus for this condition can be identified by candidate genes. Aims: The aim of this study is to amplify the chosen region (799 G >T) of MSX 1 gene, investigate the degree of association and perform a mutation research from Raichur cleft lip and palate patient sample. Settings and Design: Case history...

  20. Genetic variants in the cocaine- and amphetamine-regulated transcript gene (CARTPT) and cocaine dependence

    OpenAIRE

    Lohoff, Falk W.; Bloch, Paul J.; Weller, Andrew E.; Nall, Aleksandra H.; Doyle, Glenn A.; Buono, Russell J.; Ferraro, Thomas N.; Kampman, Kyle M.; Pettinati, Helen M.; Dackis, Charles A.; Oslin, David W.; O'Brien, Charles P.; BERRETTINI, WADE H.

    2008-01-01

    Dopaminergic brain systems have been implicated to play a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The cocaine- and amphetamine-regulated transcript peptide (CARTPT) is involved in reward and feeding behavior and has functional characteristics of an endogenous psychostimulant. In this study we tested the hypothesis that variation in the CARTPT gene increases susceptibility to cocaine dependence ...

  1. Non-Hodgkin Lymphoma Risk and Variants in Genes Controlling Lymphocyte Development

    OpenAIRE

    Johanna M. Schuetz; Denise Daley; Stephen Leach; Lucia Conde; Berry, Brian R.; Gallagher, Richard P.; Connors, Joseph M; Gascoyne, Randy D.; Bracci, Paige M.; Skibola, Christine F.; Spinelli, John J.; Angela R Brooks-Wilson

    2013-01-01

    Non-Hodgkin lymphomas (NHL) are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs), wh...

  2. eNOS Gene Variant in Patients with Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Milad Abolhalaj

    2013-01-01

    Full Text Available Subject & Aim. Endothelial nitric oxide synthase (eNOS is one of the most important candidate genes in CAD. A functional polymorphism within eNOS gene is a 27 bp VNTR on its intron 4 which has been shown to be associated with various diseases. In this study we investigated eNOS VNTR polymorphism in addition to eNOS gene expression profile in patients with CAD. Material and Methods. The study comprised patients with angiographically confirmed CAD (CAD+ and individuals with normal coronary as CAD−. eNOS VNTR polymorphism frequencies were determined in both groups. In addition eNOS gene expression profile was examined using a quantitative real-time PCR. Results. We have found that aa genotype was significantly increasing the risk of CAD in our patients (aa versus ab + bb, , ; 95% CI: = 0.98 to 16.2. The differences in eNOS expression were not significant between patients and normal group; however in CAD+ patients eNOS expression was higher than the expression level of patients carrying other genotypes (. Conclusion. We have observed that eNOS gene polymorphism was associated with CAD in angiography-confirmed patients. However, the difference in eNOS gene expression was not statistically significant between patients and control which might be due to the contribution of other confounding factors which require further investigations.

  3. A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients

    International Nuclear Information System (INIS)

    The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients. The study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays. Over a mean follow up period of 5.3 (± 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05-1.82]; p = 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; p = 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05). For the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings

  4. Association between variants in the genes for leptin, leptin receptor, and proopiomelanocortin with chronic heart failure in the Czech population.

    Science.gov (United States)

    Bienertová-Vasků, Julie Anna; Spinarová, Lenka; Bienert, Petr; Vasků, Anna

    2009-03-01

    Patients with chronic heart failure (CHF) express enhanced catabolic metabolism finally resulting in overall weight loss, whereas adipokines might play a crucial role in signaling among tissues. The aim of this study was to investigate the possible associations of defined variability in leptin (dbSNP ID rs7799039), proopiomelanocortin (dbSNP ID rs3754860 and dbSNP ID rs1009388), and leptin receptor gene (dbSNP rs1137101) with CHF and evaluate their potential as the CHF susceptibility genes. The case-control study comprised a total of 372 patients of Caucasian origin with chronic heart failure (New York Heart Association [NYHA] functional classes II-IV, ejection fraction (EF) <40%) and 407 healthy controls. They were genotyped for the leptin (LEP) -2548 G/A, leptin receptor (LEPR) Gln223Arg, and proopiomelanocortin (POMC) RsaI (5'-untranslated region) and C1032G variants (intron 1) using PCR-based methodology. No case-control differences in genotype as well as allele frequencies were observed between CHF patients and controls. We constructed POMC RsaI/C1032G haplotypes, having found no significant association with body mass index (BMI), left ventricle ejection fraction (LVEF), left ventricle hypertrophy (LVH) and diabetes mellitus (DM). Multivariate regression analyses revealed an approximately 2-fold risk for NYHA class IV associated with the LEPR Gln223Arg (P = 0.0000001, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.56-2.84); it also displayed an independent prediction role for LVEF in heart failure cases of all etiologies (P = 0.002, OR = 4.05, 95% CI = 1.36-10.06). In subanalyses according to CHF etiology the LEPR Gln223Arg showed an independent prediction role for NYHA IV in IHD patients (P = 0.0001, OR = 2.50, 95% CI = 1.69-3.82) and both for NYHA IV(P = 0.007, OR = 2.04, 95% CI = 1.20-3.84) and LVEF (P = 0.004, OR = 11.87, 95% CI = 2.08-55.6) in DCMP patients. The role of the polymorphic variants in the genes encoding for adipokines as potential

  5. An unusual case of an ACTH-secreting macroadenoma with a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene

    DEFF Research Database (Denmark)

    Dinesen, Pia T; Dal, Jakob; Gabrovska, Plamena; Gaustadnes, Mette; Gravholt, Claus H; Stals, Karen; Denes, Judit; Asa, Sylvia L; Korbonits, Márta; Jørgensen, Jens O L

    2015-01-01

    diagnosed with a large pituitary tumor by magnetic resonance imaging (MRI). His visual fields were intact and he exhibited no features of CD. Owing to an exuberant response to synacthen, an overnight dexamethasone suppression test was performed revealing inadequate suppression of plasma cortisol (419 nmol...... adrenocortical failure. Genetic testing revealed an AIP variant of unknown significance (p.R16H) without loss of the normal AIP allele in the tumor. A literature review showed ten CD patients with AIP gene variants, of whom five (including our case) were p.R16H. CD is occasionally dominated by pituitary tumor...... pituitary tumor growth rather than symptoms of hypersecretion.Resolution of both tumor remnant and hormonal hypersecretion may occur within 2 months after postoperative radiotherapy.The particular AIP gene variant identified in our patient is shared by four other reported cases of CD....

  6. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin-responsive GLUT4 genes in NIDDM

    DEFF Research Database (Denmark)

    Bjørbaek, C; Echwald, Søren Morgenthaler; Hubricht, P; Vestergaard, H; Hansen, Torben; Zierath, J; Pedersen, O

    1994-01-01

    '-untranslated region, and the coding region of the GLUT4 gene showed four polymorphisms, all single nucleotide substitutions, positioned at -581, 1, 30, and 582. None of the three changes in the regulatory region of the gene had any major influence on expression of the GLUT4 gene in muscle. The variant at 582......, -16, -43, -143, and -250. The three most common variants could be excluded for having major impact on allele-specific GS mRNA expression in muscle. Scanning of GS cDNA revealed one frequent silent polymorphism at codon 342. Moreover, SSCP analysis of approximately 900 bp of the promoter, the 5...... in the GLUT4 cDNA was a silent polymorphism at codon 130. Southern blotting of both gene loci did not detect any major abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)...

  7. Investigation of genetic variants, birthweight and hypothalamic-pituitary-adrenal axis function suggests a genetic variant in the SERPINA6 gene is associated with corticosteroid binding globulin in the western Australia pregnancy cohort (Raine study.

    Directory of Open Access Journals (Sweden)

    Laura N Anderson

    Full Text Available The hypothalamic-pituitary-adrenal (HPA axis regulates stress responses and HPA dysfunction has been associated with several chronic diseases. Low birthweight may be associated with HPA dysfunction in later life, yet human studies are inconclusive. The primary study aim was to identify genetic variants associated with HPA axis function. A secondary aim was to evaluate if these variants modify the association between birthweight and HPA axis function in adolescents.Morning fasted blood samples were collected from children of the Western Australia Pregnancy Cohort (Raine at age 17 (n = 1077. Basal HPA axis function was assessed by total cortisol, corticosteroid binding globulin (CBG, and adrenocorticotropic hormone (ACTH. The associations between 124 tag single nucleotide polymorphisms (SNPs within 16 HPA pathway candidate genes and each hormone were evaluated using multivariate linear regression and penalized linear regression analysis using the HyperLasso method.The penalized regression analysis revealed one candidate gene SNP, rs11621961 in the CBG encoding gene (SERPINA6, significantly associated with total cortisol and CBG. No other candidate gene SNPs were significant after applying the penalty or adjusting for multiple comparisons; however, several SNPs approached significance. For example, rs907621 (p = 0.002 and rs3846326 (p = 0.003 in the mineralocorticoid receptor gene (NR3C2 were associated with ACTH and SERPINA6 SNPs rs941601 (p = 0.004 and rs11622665 (p = 0.008, were associated with CBG. To further investigate our findings for SERPINA6, rare and common SNPs in the gene were imputed from the 1,000 genomes data and 8 SNPs across the gene were significantly associated with CBG levels after adjustment for multiple comparisons. Birthweight was not associated with any HPA outcome, and none of the gene-birthweight interactions were significant after adjustment for multiple comparisons.Our study suggests that genetic variation in the SERPINA

  8. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5

    DEFF Research Database (Denmark)

    Baker, Peter R; Friederich, Marisa W; Swanson, Michael A;

    2014-01-01

    Patients with nonketotic hyperglycinemia and deficient glycine cleavage enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent proteins, constitute a clinical group which we call 'variant nonketotic hyperglycinemia'. We hypothesize that in some patients th...

  9. MC1R gene variants and non-melanoma skin cancer: A pooled-analysis from the M-SKIP project

    NARCIS (Netherlands)

    E. Tagliabue; M.C. Fargnoli (Maria Concetta); S. Gandini (Sara); P. Maisonneuve (Patrick); F. Liu; M. Kayser; T.E.C. Nijsten (Tamar); J. Han; R. Kumar; N.A. Gruis (Nelleke); L. Ferrucci; W. Branicki (Wojciech); T. Dwyer; L. Blizzard; P. Helsing; P.J.M. Autier (Philippe); J.C. García-Borrón (José C); P.A. Kanetsky; M.T. Landi; J. Little; J. Newton-Bishop; J.P. de Sera; S. Raimondi (Susana); S. Raimondi (Sara); P. Autier (Philippe); M.C. Fargnoli (Maria Concetta); J. Han (Jiali); P.A. Kanetsky (Peter A.); M.T. Landi (Maria Teresa); J. Little (Julian); J. Little (Julian); J.A. Newton Bishop (Julia); S. Caini (Saverio); S. Gandini (Sara); P. Maisonneuve (Patrick); A. Hofman (Albert); M.H. Kayser (Manfred); F. Liu (Fan); T.E.C. Nijsten (Tamar); A.G. Uitterlinden (André); R. Kumar (Rajiv); R. Kumar (Rajiv); E. Nagore (Eduardo); J. Hansson (Johan); V. Höiom (Veronica); P. Ghiorzo (Paola); L. Pastorino (Lorenza); N.A. Gruis (Nelleke A.); J.N.B. Bavinck (Jan Nico Bouwes); P. Aguilera (Paula); C. Badenas (Celia); C. Carrera (Cristina); J. Malvehy (Josep); M.P. Mateu (Miriam Potrony); S. Puig (Susana); J.A. Puig-Butille (Joan Anton); G. Tell (Gemma); T. Dwyer (Terence); T. Dwyer (Terry); J. Cochrane (Jennifer); R. Fernandez-De-Misa (Ricardo); W. Branicki (Wojciech); T. Debniak (Tadeusz); N. Morling (Niels); P. Johansen (Peter); S. Mayne (Susan); A. Bale (Allen); B. Cartmel (Brenda); L. Ferrucci (Leah); R. Pfeiffer (Ruth); G. Palmieri (Giuseppe); G. Ribas (Gloria); A. Stratigos (Alexander); K. Kypreou (Katerina); A. Bowcock (Anne); L. Cornelius (Lynn); M.L. Council (M. Laurin); T. Motokawa (Tomonori); S. Anno (Sumiko); H. Anno (Hirofumi); P.A. Andresen (Per Arne); T.H. Wong (Terence H.); M. Berwick (Marianne); M. Berwick (Marianne); I. Orlow (Irene); U. Mujumdar (Urvi); A. Hummer (Amanda); K. Busam (Klaus); P. Roy (Pampa); R. Canchola (Rebecca); B. Clas (Brian); J. Cotignola (Javiar); Y. Monroe (Yvette); B. Armstrong (Bruce); A. Kricker (Anne); M. Litchfield (Melisa); T. Dwye (Terence); P. Tucker (Paul); N. Stephens (Nicola); R. Gallagher (Richard); T. Switzer (Teresa); L. Marrett (Loraine); B. Theis (Beth); L. From (Lynn); N. Chowdhury (Noori); L. Vanasse (Louise); M. Purdue (Mark); D. Northrup (David); R. Zanetti (Roberto); S.M. Rosso (Sonia); C. Sacerdote (Carlotta); H. Anton-Culver (Hoda); N. Leighton (Nancy); M. Gildea (Maureen); S.B. Gruber (Stephen); J. Bonner (Joe); J. Jeter (Joanne); J. Klotz (Judith); H. Wilcox (Homer); H. Weiss (Helen); R.M. Millikan (Robert); N. Thomas (Nancy); D. Mattingly (Dianne); J. Player (Jon); C.-K. Tse (Chiu-Kit); R. Rebbeck (Timothy); P.P. Kanetsky (Peter P.); A. Walker (Amy); S. Panossian (Saarene); H.W. Mohrenweiser (Harvey); R. Setlow (Richard)

    2015-01-01

    textabstractBackground:The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate

  10. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

    NARCIS (Netherlands)

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D; Granados-Silvestre, Ma de Angeles; Montufar-Robles, Isela; Tito-Alvarez, Ana M; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Lisker, Ruben; Moises, Regina S; Menjivar, Marta; Salzano, Francisco M; Knowler, William C; Bortolini, M Cátira; Hayden, Michael R; Baier, Leslie J; Canizales-Quinteros, Samuel

    2010-01-01

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was

  11. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

    NARCIS (Netherlands)

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D; Granados-Silvestre, Ma de Angeles; Montufar-Robles, Isela; Tito-Alvarez, Ana M; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Lisker, Ruben; Moises, Regina S; Menjivar, Marta; Salzano, Francisco M; Knowler, William C; Bortolini, M Cátira; Hayden, Michael R; Baier, Leslie J; Canizales-Quinteros, Samuel

    2010-01-01

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was

  12. A Common Missense Variant in the Glucokinase Regulatory Protein Gene (GCKR) Is Associated with Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

    Science.gov (United States)

    OBJECTIVE-Using the genome-wide-association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metaboli...

  13. Novel pathogenic variant (c.3178G>A) in the SMC1A gene in a family with Cornelia de Lange syndrome identified by exome sequencing.

    Science.gov (United States)

    Jang, Mi Ae; Lee, Chang Woo; Kim, Jin Kyung; Ki, Chang Seok

    2015-11-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, mother, and maternal grandmother presented with mild mental retardation. By exome sequencing of the proband, a novel SMC1A variant, c.3178G>A, was identified, which was expected to cause an amino acid substitution (p.Glu1060Lys) in the highly conserved coiled-coil domain of the SMC1A protein. Sanger sequencing confirmed that the three female relatives with mental retardation also carry this variant. Our results reveal that SMC1A gene defects are associated with milder phenotypes of CdLS. Furthermore, we showed that exome sequencing could be a useful tool to identify pathogenic variants in patients with CdLS. PMID:26354354

  14. A rapid method for the discrimination of genes encoding classical Shiga toxin (Stx) 1 and its variants, Stx1c and Stx1d, in Escherichia coli

    NARCIS (Netherlands)

    Kuczius, Thorsten; Bielaszewska, Martina; Friedrich, Alexander W; Zhang, Wenlan

    2004-01-01

    Subtyping of Shiga toxin (Stx)-encoding genes by conventional polymerase chain reaction (PCR) is time-consuming. We developed a single step real-time fluorescence PCR with melting curve analysis to distinguish rapidly stx1 from its variants, stx1c and stx1d. Melting temperatures (Tm) of 206 Stx-prod

  15. Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke.

    Science.gov (United States)

    Seppälä, Ilkka; Kleber, Marcus E; Bevan, Steve; Lyytikäinen, Leo-Pekka; Oksala, Niku; Hernesniemi, Jussi A; Mäkelä, Kari-Matti; Rothwell, Peter M; Sudlow, Cathie; Dichgans, Martin; Mononen, Nina; Vlachopoulou, Efthymia; Sinisalo, Juha; Delgado, Graciela E; Laaksonen, Reijo; Koskinen, Tuomas; Scharnagl, Hubert; Kähönen, Mika; Markus, Hugh S; März, Winfried; Lehtimäki, Terho

    2016-01-01

    Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44-2.74) and chronic AF (OR = 2.03, 95% CI 1.35-3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications. PMID:26984639

  16. Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study

    International Nuclear Information System (INIS)

    We have previously shown that a functional polymorphism of the UGT2B15 gene (rs1902023) was associated with increased risk of prostate cancer (PC). Novel functional polymorphisms of the UGT2B17 and UGT2B15 genes have been recently characterized by in vitro assays but have not been evaluated in epidemiologic studies. Fifteen functional SNPs of the UGT2B17 and UGT2B15 genes, including cis-acting UGT2B gene SNPs, were genotyped in African American and Caucasian men (233 PC cases and 342 controls). Regression models were used to analyze the association between SNPs and PC risk. After adjusting for race, age and BMI, we found that six UGT2B15 SNPs (rs4148269, rs3100, rs9994887, rs13112099, rs7686914 and rs7696472) were associated with an increased risk of PC in log-additive models (p < 0.05). A SNP cis-acting on UGT2B17 and UGT2B15 expression (rs17147338) was also associated with increased risk of prostate cancer (OR = 1.65, 95% CI = 1.00-2.70); while a stronger association among men with high Gleason sum was observed for SNPs rs4148269 and rs3100. Although small sample size limits inference, we report novel associations between UGT2B15 and UGT2B17 variants and PC risk. These associations with PC risk in men with high Gleason sum, more frequently found in African American men, support the relevance of genetic differences in the androgen metabolism pathway, which could explain, in part, the high incidence of PC among African American men. Larger studies are required

  17. Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer

    Science.gov (United States)

    Endesfelder, David; McGranahan, Nicholas; Howell, Mike; Parker, Peter J.; Downward, Julian; Swanton, Charles; Kschischo, Maik

    2014-01-01

    Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context-dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesised that CIN permits accelerated genomic evolution through the generation of diverse DNA copy number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy number alterations which drive cancer proliferation. PMID:24970479

  18. Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases

    NARCIS (Netherlands)

    Zhang, J.X.; Fu, L.; Voer, R.M. de; Hahn, M.M.; Jin, P.; Lv, C.X.; Verwiel, E.T.; Ligtenberg, M.J.L.; Hoogerbrugge, N.; Kuiper, R.P.; Sheng, J.Q.; Geurts van Kessel, A.H.M.

    2015-01-01

    AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases. METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC

  19. Role of a molecular variant of rat atrial natriuretic Peptide gene in vascular remodeling.

    Science.gov (United States)

    De Paolis, Paola; Nobili, Valerio; Lombardi, Alessia; Tarasi, David; Barbato, Daniela; Marchitti, Simona; Ganten, Ursula; Brunetti, Ercole; Volpe, Massimo; Rubattu, Speranza

    2007-01-01

    Previous studies in a hypertensive animal model of stroke and in humans showed that mutations of the atrial natriuretic peptide (ANP) gene are associated with increased risk of stroke. To elucidate the vascular disease mechanisms that result from structural modifications of the ANP gene, we investigated a coding mutation of the ANP gene in stroke-prone spontaneously hypertensive rats (SHRsp). This mutation leads to a Gly/Ser transposition in the prosegment of ANP. We found that presence of this mutation is associated with increased immunostaining of ANP in the wall of SHRsp cerebral vessels. The mutation causes a major inhibitory effect on endothelial cell proliferation, as assessed by thymidine incorporation, and on angiogenesis, as determined by an endothelial cell tube formation assay, in human umbilical vein endothelial cells (HUVEC) exposed to ANP/SHRsp. These in vitro findings show that the SHRsp-derived form of ANP has an inhibitory effect on vascular remodeling and they provide further support for a role of the ANP gene in the pathogenesis of cerebrovascular disease in the animal model. PMID:17522368

  20. Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia.

    Science.gov (United States)

    Malik, S; Greenwood, C M T; Eguale, T; Kifle, A; Beyene, J; Habte, A; Tadesse, A; Gebrexabher, H; Britton, S; Schurr, E

    2006-02-01

    Lungs are the central organ affected and targeted by Mycobacterium tuberculosis and immune processes in the lung are of critical importance in the pathogenesis of tuberculosis. A major lung defense against invading pathogens is provided by surfactant protein A, a multi-chain protein encoded by the SFTPA1 and SFTPA2 genes. Here, we investigated polymorphisms in the SFTPA1 and SFTPA2 genes for association with tuberculosis in 181 Ethiopian families comprising 226 tuberculosis cases. Four polymorphisms, SFTPA1 307A, SFTPA1 776T, SFTPA2 355C, and SFTPA2 751C, were associated with tuberculosis (P=0.00008; P=0.019, P=0.029 and P=0.042, respectively). Additional subgroup analysis in male, female and more severely affected patients provided evidence for SFTPA1/2-covariate interaction. Finally, out of five intragenic haplotypes identified in the SFTPA1 gene and nine identified in the SFTPA2 gene, 1A(3) was most significantly associated with tuberculosis susceptibility (P=0.026). These findings suggest that SFTPA1 and SFTPA2 modify the risk of tuberculosis susceptibility and that this risk is influenced by additional covariates. PMID:16292672

  1. CLOCK Gene Variants Associate with Sleep Duration in Two Independent Populations

    NARCIS (Netherlands)

    Allebrandt, Karla V.; Teder-Laving, Maris; Akyol, Mahmut; Pichler, Irene; Mueller-Myhsok, Bertram; Pramstaller, Peter; Merrow, Martha; Meitinger, Thomas; Metspalu, Andreas; Roenneberg, Till; Müller-Myhsok, Bertram

    2010-01-01

    Background: Sleep is an active and complex behavior, yet it has two straightforward properties-timing and duration. Clock genes are associated with dysfunctional timing of sleep, mood, and obesity disorders, which are commonly associated with sleep duration. Methods: Sleep duration was assessed in C

  2. Surfactant Protein-D-Encoding Gene Variant Polymorphisms Are Linked to Respiratory Outcome in Premature Infants

    DEFF Research Database (Denmark)

    Sorensen, Grith Lykke; Dahl, Marianne; Tan, Qihua;

    2014-01-01

    OBJECTIVE: Associations between the genetic variation within or downstream of the surfactant protein-D-encoding gene (SFTPD), which encodes the collectin surfactant protein-D (SP-D) and may lead to respiratory distress syndrome or bronchopulmonary dysplasia, recently were reported. Our aim was to...

  3. Pelizaeus-Merzbacher disease: Tight linkage to proteolipid protein gene exon variant

    Energy Technology Data Exchange (ETDEWEB)

    Trofatter, J.A.; Dlouhy, S.R.; DeMyer, W.; Conneally, P.M.; Hodes, M.E. (Indiana Univ. Medical Center, Indianapolis (USA))

    1989-12-01

    Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which if found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C {yields} T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. The results show tight linkage of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred.

  4. Characterization and differential gene expression between two phenotypic phase variants in Salmonella enterica serovar Typhimurium.

    Science.gov (United States)

    Patterson, Sheila K; Borewicz, Klaudyna; Johnson, Timothy; Xu, Wayne; Isaacson, Richard E

    2012-01-01

    Salmonella enterica serovar Typhimurium strain 798 has previously been shown to undergo phenotypic phase variation. One of the phenotypes expresses virulence traits such as adhesion, while the other phenotype does not. Phenotypic phase variation appears to correlate with the ability of this strain to cause persistent, asymptomatic infections of swine. A new method to detect cells in either phenotypic phase was developed using Evans Blue-Uranine agar plates. Using this new assay, rates of phenotypic phase variation were obtained. The rate of phase variation from non-adhesive to adhesive phenotype was approximately 10(-4) per cell per generation while phase variation from the adhesive to the non-adhesive phenotype was approximately 10(-6) per cell per generation. Two highly virulent S. Typhimurium strains, SL1344 and ATCC 14028, were also shown to undergo phase variation. However, while the rate from adhesive to non-adhesive phenotype was approximately the same as for strain 798, the non-adhesive to adhesive phenotype shift was 37-fold higher. Differential gene expression was measured using RNA-Seq. Eighty-three genes were more highly expressed by 798 cells in the adhesive phenotype compared to the non-adhesive cells. Most of the up-regulated genes were in virulence genes and in particular all genes in the Salmonella pathogenicity island 1 were up-regulated. When compared to the virulent strain SL1344, expression of the virulence genes was approximately equal to those up-regulated in the adhesive phenotype of strain 798. A comparison of invasive ability demonstrated that strain SL1344 was the most invasive followed by the adhesive phenotype of strain 798, then the non-adhesive phenotype of strain 798. The least invasive strain was ATCC 14028. The genome of strain 798 was sequenced and compared to SL1344. Both strains had very similar genome sequences and gene deletions could not readily explain differences in the rates of phase variation from non-adhesive to the

  5. Characterization and differential gene expression between two phenotypic phase variants in Salmonella enterica serovar Typhimurium.

    Directory of Open Access Journals (Sweden)

    Sheila K Patterson

    Full Text Available Salmonella enterica serovar Typhimurium strain 798 has previously been shown to undergo phenotypic phase variation. One of the phenotypes expresses virulence traits such as adhesion, while the other phenotype does not. Phenotypic phase variation appears to correlate with the ability of this strain to cause persistent, asymptomatic infections of swine. A new method to detect cells in either phenotypic phase was developed using Evans Blue-Uranine agar plates. Using this new assay, rates of phenotypic phase variation were obtained. The rate of phase variation from non-adhesive to adhesive phenotype was approximately 10(-4 per cell per generation while phase variation from the adhesive to the non-adhesive phenotype was approximately 10(-6 per cell per generation. Two highly virulent S. Typhimurium strains, SL1344 and ATCC 14028, were also shown to undergo phase variation. However, while the rate from adhesive to non-adhesive phenotype was approximately the same as for strain 798, the non-adhesive to adhesive phenotype shift was 37-fold higher. Differential gene expression was measured using RNA-Seq. Eighty-three genes were more highly expressed by 798 cells in the adhesive phenotype compared to the non-adhesive cells. Most of the up-regulated genes were in virulence genes and in particular all genes in the Salmonella pathogenicity island 1 were up-regulated. When compared to the virulent strain SL1344, expression of the virulence genes was approximately equal to those up-regulated in the adhesive phenotype of strain 798. A comparison of invasive ability demonstrated that strain SL1344 was the most invasive followed by the adhesive phenotype of strain 798, then the non-adhesive phenotype of strain 798. The least invasive strain was ATCC 14028. The genome of strain 798 was sequenced and compared to SL1344. Both strains had very similar genome sequences and gene deletions could not readily explain differences in the rates of phase variation from non

  6. AB103. Excess of rare variants in genes that are key epigenetic regulators of spermatogenesis in the patients with non-obstructive azoospermia

    OpenAIRE

    Li, Zesong; Huang, Yi; Cai, Zhiming

    2015-01-01

    Objective Non-obstructive azoospermia (NOA), a severe form of male infertility, is often suspected to be linked to currently undefined genetic abnormalities. The objective of the study is to explore the genetic basis of this condition. Methods We successfully sequenced ~650 infertility-related genes in 757 NOA patients and 709 fertile males. We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genet...

  7. Preterm birth in Caucasians is associated with coagulation and inflammation pathway gene variants.

    Directory of Open Access Journals (Sweden)

    Digna R Velez

    Full Text Available Spontaneous preterm birth (<37 weeks gestation-PTB occurs in approximately 12% of pregnancies in the United States, and is the largest contributor to neonatal morbidity and mortality. PTB is a complex disease, potentially induced by several etiologic factors from multiple pathophysiologic pathways. To dissect the genetic risk factors of PTB a large-scale high-throughput candidate gene association study was performed examining 1536 SNP in 130 candidate genes from hypothesized PTB pathways. Maternal and fetal DNA from 370 US Caucasian birth-events (172 cases and 198 controls was examined. Single locus, haplotype, and multi-locus association analyses were performed separately on maternal and fetal data. For maternal data the strongest associations were found in genes in the complement-coagulation pathway related to decidual hemorrhage in PTB. In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB. These include factor V (FV that was previously associated with PTB, factor VII (FVII, and tissue plasminogen activator (tPA. The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30x10(-3 and genotypic association (p = 2.0x10(-6 with PTB. The odds ratio (OR for this SNP was 2.80 [CI 1.77-4.44] for a recessive model. Given that 6 of 8 markers in tPA were statistically significant, sliding window haplotype analyses were performed and revealed an associating 4 marker haplotype in tPA (p = 6.00x10(-3. The single strongest effect in fetal DNA was observed in the inflammatory pathway at rs17121510 in the interleukin-10 receptor antagonist (IL-10RA gene for allele (p = 0.01 and genotype (p = 3.34x10(-4. The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15-3.19] (p = 2.00x10(-3. Finally, exploratory multi-locus analyses in the complement and coagulation pathway were performed and revealed a potentially significant interaction between a marker in FV (rs2187952 and FVII (rs3211719 (p

  8. The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment

    DEFF Research Database (Denmark)

    Skov, Jane; Bladbjerg, Else-Marie; Leppin, Anja; Jespersen, Jørgen

    2013-01-01

    INTRODUCTION: A substantial part of the inter-individual variation in vitamin K-antagonist dose can be explained by certain sequence variants in the genes CYP2C9 (NG_008385.1:g.8633C>T or *1/*2, NG_008385.1:g.47639A>C or *1/*3) and VKORC1 (NG_011564.1:g.6399C>T). Patients possessing these variant...... alleles require lower doses and have increased risk of overanticoagulation. METHODS: We investigated the influence of the above sequence variants on stability of maintenance phase warfarin therapy in a prospective study of 300 consecutive patients followed for one year at an anticoagulant clinic. RESULTS...... effects of common gene sequence variants in CYP2C9 and VKORC1 on stability of maintenance phase warfarin therapy. Patients attending an anticoagulant clinic using computer-assisted dosage were safely monitored regardless of these sequence variants, but for the small subgroup of patients with the CYP2C9...

  9. Enhanced Acid Tolerance in Bifidobacterium longum by Adaptive Evolution: Comparison of the Genes between the Acid-Resistant Variant and Wild-Type Strain.

    Science.gov (United States)

    Jiang, Yunyun; Ren, Fazheng; Liu, Songling; Zhao, Liang; Guo, Huiyuan; Hou, Caiyun

    2016-03-28

    Acid stress can affect the viability of probiotics, especially Bifidobacterium. This study aimed to improve the acid tolerance of Bifidobacterium longum BBMN68 using adaptive evolution. The stress response, and genomic differences of the parental strain and the variant strain were compared by acid stress. The highest acid-resistant mutant strain (BBMN68m) was isolated from more than 100 asexual lines, which were adaptive to the acid stress for 10(th), 20(th), 30(th), 40(th), and 50(th) repeats, respectively. The variant strain showed a significant increase in acid tolerance under conditions of pH 2.5 for 2 h (from 7.92 to 4.44 log CFU/ml) compared with the wildtype strain (WT, from 7.87 to 0 log CFU/ml). The surface of the variant strain was also smoother. Comparative whole-genome analysis showed that the galactosyl transferase D gene (cpsD, bbmn68_1012), a key gene involved in exopolysaccharide (EPS) synthesis, was altered by two nucleotides in the mutant, causing alteration in amino acids, pI (from 8.94 to 9.19), and predicted protein structure. Meanwhile, cpsD expression and EPS production were also reduced in the variant strain (p < 0.05) compared with WT, and the exogenous WT-EPS in the variant strain reduced its acid-resistant ability. These results suggested EPS was related to acid responses of BBMN68. PMID:26608165

  10. Variants in maternal COMT and MTHFR genes and risk of neural tube defects in offspring.

    Science.gov (United States)

    Liu, Jufen; Zhang, Yali; Jin, Lei; Li, Guoxing; Wang, Linlin; Bao, Yanping; Fu, Yunting; Li, Zhiwen; Zhang, Le; Ye, Rongwei; Ren, Aiguo

    2015-04-01

    Methylenetetrahydrofolate reductase (MTHFR) C677T and catechol-O-Methyltransferase (COMT) G158A are associated with a risk of neural tube defects (NTDs) in offspring. This study examined the effect of a MTHFR × COMT interaction on the risk of NTDs in a Chinese population with a high prevalence of NTDs. A total of 576 fetuses or newborns with NTDs and 594 controls were genotyped for MTHFRrs1801133, MTHFRrs1801131, and COMTrs4680 and COMTrs737865. Information on maternal sociodemographic characteristics, reproductive history, and related behavior was collected through face-to-face interviews. Possible interactions between genetic variants of MTHFR and COMT were examined. MTHFR C677T homozygous TT was associated with an elevated risk of total NTDs (odds ratio [OR] = 1.37, 95 % confidence interval [CI] = 0.93-2.03) and of anencephaly (OR = 1.67, 95 % CI = 0.98-2.84) compared with the CC genotype. There was a COMT rs737865 CC × MTHFR rs1801133 TT interaction for total NTDs (OR = 3.02, 95 % CI = 1.00-9.14) and for anencephaly (OR = 3.39, 95 % CI = 0.94-12.18). No interaction was found between COMT rs4680 AA/AG and MTHFR CT/TT genotypes for total NTDs or any subtype of NTD. The interaction of COMT rs737865 and MTHFR C677T was associated with an increased risk of NTDs, especially anencephaly, in a Chinese population with a high prevalence of NTDs. PMID:24990354

  11. Gene expression profiling in chemoresistant variants of three cell lines of different origin

    DEFF Research Database (Denmark)

    Johnsson, Anders; Vallon-Christensson, Johan; Strand, Carina;

    2005-01-01

    BACKGROUND: Drug resistance is a major problem in clinical cancer chemotherapy. Several mechanisms of resistance have been identified, but the underlying genomic changes are still poorly understood. MATERIALS AND METHODS: Gene expression profiling, using cDNA microarray, was performed in eight cell...... lines (K562 leukemia, MCF-7 breast cancer and S1 colon cancer) with acquired resistance against five cytostatic drugs; daunorubicin (DNR), doxorubicin (DOX), vincristine (VCR), etoposide (VP) and mitoxantrone (MX). RESULTS: The resistant cell lines clustered together based on their type of origin....... Several genes encoding ABC transporters were highly up-regulated, most notably ABCB1 (MDR1) and ABCB4 in several cell lines and ABCG2 (MXR) specifically in MX-resistant cell lines. A pronounced down-regulation of several histones was noted in the MCF-7-derived resistant sublines. Altered expression was...

  12. Common variants in QPCT gene confer risk of schizophrenia in the Han Chinese population.

    Science.gov (United States)

    Khan, Raja Amjad Waheed; Chen, Jianhua; Shen, Jiawei; Li, Zhiqiang; Wang, Meng; Wen, Zujia; Song, Zhijian; Li, Wenjin; Xu, Yifeng; Shi, Yongyong; Yi, Qizhong; Ji, Weidong

    2016-03-01

    Schizophrenia (SCZ) is a common and severe mental disorder, its etiology has not been elucidated completely. In one previous genome-wide association study (GWAS) of SCZ in the Caucasian population, the QPCT has been reported as susceptible gene for SCZ. The QPCT gene encodes Glutaminyl cyclase (QC), an enzyme which is involved in the post translational modification by converting N-terminal glutamate of protein to pyroglutamate, which is resistant to protease degradation, more hydrophobic, and prone to aggregation and neurotoxic. To further investigate the role of this gene in the pathogenesis of schizophrenia in the Han Chinese population, we conducted this study in 1,248 (Mean age ± S.D, 36.44 years ± 9.0) SCZ cases, 1,248 (Mean age ± S.D, 30.62 years ± 11.35) healthy control samples for a case control study. We genotyped six SNPs in this study, including one positive SNP of the previous study, using the Sequenom MassARRAY platform. We found that rs2373000 was significantly associated with SCZ before correction [rs2373000: P allele = 0.016, χ(2)  = 5.784, OR [95%CI] = 0.861 [0.762-0.972], P genotype = 0.018, χ(2)  = 0.069]. After permutation correction for multiple testing, rs2373000 [rs2373000: P Allele corrected = 0.063, P genotype corrected = 0.069] showed marginal association with SCZ. Additionally, one pathogenic haplotype (TGT) containing rs2373000 was also significantly associated with SCZ. Our results are consistent with the findings of previous study and the genetic risk of QPCT gene for SCZ also exists in the Han Chinese population. © 2015 Wiley Periodicals, Inc. PMID:26492838

  13. Parkinson's Disease in Relation to Pesticide Exposure and Nuclear Encoded Mitochondrial Complex I Gene Variants

    OpenAIRE

    Corder, Elizabeth H.; Mellick, George D.

    2006-01-01

    Parkinson's disease (PD) is a common age-related neurodegenerative disorder thought to result from the integrated effects of genetic background and exposure to neuronal toxins. Certain individual nuclear-encoded mitochondrial complex I gene polymorphisms were found to be associated with ∼ 2-fold risk variation in an Australian case-control sample. We further characterized this sample of 306 cases and 321 controls to determine the mutual information contained in the 22 SNPs and, additionally, ...

  14. Two common genetic variants near nuclear encoded OXPHOS genes are associated with insulin secretion in vivo.

    OpenAIRE

    Olsson, Anders H.; Rönn, Tina; Ladenvall, Claes; Parikh, Hemang; Isomaa, Bo; Groop, Leif; Ling, Charlotte

    2011-01-01

    Context Mitochondrial ATP production is important in the regulation of glucose-stimulated insulin secretion. Genetic factors may modulate the capacity of the β-cells to secrete insulin and thereby contribute to the risk of type 2 diabetes. OBJECTIVE: The aim of this study was to identify genetic loci in or adjacent to nuclear encoded genes of the oxidative phosphorylation (OXPHOS) pathway that are associated with insulin secretion in vivo. DESIGN AND METHODS: To find polymorphisms associated ...

  15. Rare Variants in the TREX1 Gene and Susceptibility to Autoimmune Diseases

    OpenAIRE

    Nadia Barizzone; Sara Monti; Simona Mellone; Michela Godi; Maurizio Marchini; Raffaella Scorza; Danieli, Maria G.; Sandra D’Alfonso

    2013-01-01

    TREX1 (DNase III) is an exonuclease involved in response to oxidative stress and apoptosis. Heterozygous mutations in TREX1 were previously observed in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). We performed a mutational analysis of the TREX1 gene on three autoimmune diseases: SLE (210 patients) and SS (58 patients), to confirm a TREX1 involvement in the Italian population, and systemic sclerosis (SSc, 150 patients) because it shares similarities with SLE (p...

  16. Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosa

    OpenAIRE

    Herpertz-Dahlmann Beate; Herzog Wolfgang; Scherag André; Nguyen Thuy; Kirschner Jeanette; Brönner Günter; Reichwald Kathrin; Müller Timo; Lichtner Peter; Meitinger Thomas; Platzer Matthias; Schäfer Helmut; Hebebrand Johannes; Hinney Anke

    2008-01-01

    Abstract Background Several lines of evidence indicate that the central cannabinoid receptor 1 (CNR1) as well as the major endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH), N-acylethanolamine-hydrolyzing acid amidase (NAAA) and monoglyceride lipase (MGLL) are implicated in mediating the orexigenic effects of cannabinoids. The aim of this study was to analyse whether nucleotide sequence variations in the CNR1, FAAH, NAAA and MGLL genes are associated with anorexia nervosa (A...

  17. Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, Lydia; Dafou, Dimitra; Ramus, Susan J;

    2009-01-01

    ) [hazard ratio (HR) = 1.13 (95% CI: 1.00-1.27), P = 0.042] and two tSNPs in the retinoblastoma binding protein (RBBP8) gene [HR = 0.85 (95% CI: 0.75-0.95), P = 0.007 and HR = 0.83 (95% CI: 0.71-0.95), P = 0.009]. After adjusting for multiple prognostic factors in a multivariate Cox regression analysis...

  18. Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder

    OpenAIRE

    Campbell, Daniel B.; Datta, Dibyadeep; Jones, Shaine T.; Batey Lee, Evon; Sutcliffe, James S.; Hammock, Elizabeth A.D.; Levitt, Pat

    2011-01-01

    Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each invo...

  19. Transthyretin: No association between serum levels or gene variants and schizophrenia

    OpenAIRE

    Ruano, Dina; Macedo, António; Soares, Maria J.; Valente, José; Azevedo, Maria H; Hutz, Mara H.; Clarissa S. Gama; Lobato, Maria I.; Belmonte-de-Abreu, Paulo; Goodman, Ann B.; Pato, Carlos; Saraiva, Maria J.; Heutink, Peter; Joana A Palha

    2007-01-01

    It has been proposed that schizophrenia results from an environmental insult in genetically predisposed individuals. Environmental factors capable of modulating transcriptional activity and their carriers could link the genetic and environmental components of schizophrenia. Among these is transthyretin (TTR), a major carrier of thyroid hormones and retinol-binding protein (RBP). Retinoids and thyroid hormones regulate the expression of several genes, both during development and in the adult b...

  20. No Significant Effect of ASAP1 Gene Variants on the Susceptibility to Tuberculosis in Chinese Population

    Science.gov (United States)

    Hu, Xuejiao; Peng, Wu; Chen, Xuerong; Zhao, Zhenzhen; Zhang, Jingya; Zhou, Juan; Cai, Bei; Chen, Jie; Zhou, Yanhong; Lu, Xiaojun; Ying, Binwu

    2016-01-01

    Abstract Recent studies have proposed that the ASAP1 gene participates in regulating the adaptive immune response to Mycobacterium tuberculosis infection. A GWAS study has reported that ASAP1 polymorphisms (rs4733781 and rs10956514) were associated with the risk of tuberculosis (TB) in Russians. But due to population heterogeneity, different races would have different causative polymorphisms, and the aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of the ASAP1 gene and TB risk in Chinese population. A total of 7 SNPs in the ASAP1 gene were genotyped in 1115 Western Chinese Han and 914 Tibetan population using an improved multiplex ligation detection reaction (iMLDR) method. The associations of SNPs with TB risk and clinical phenotypes were determined based on the distributions of allelic frequencies and different genetic models. A meta-analysis was carried out to further assess the relationship between ASAP1 polymorphism and TB risk. Statistical comparisons of cases and controls after correction for multiple testing did not yield any significant associations with the risk of TB via analyses of a single locus, haplotype, and subgroup differences. Meta-analysis showed no evidence supporting association between rs10956514 and overall risk for TB. Subsequent analysis referring to the genotypes of SNPs in relationship to clinical phenotypes identified that rs4236749 was associated with different serum C-reactive protein levels, suggesting a role of this locus in influencing the inflammatory state of Western Chinese Han patients with TB. Our present data revealed that ASAP1 polymorphisms are unlikely to confer susceptibility to TB in the Western Chinese Han and Tibetan populations, which challenges the promising roles of the ASAP1 gene in the development of TB and highlights the importance of validating the association findings across ethnicities. PMID:27227929

  1. Common Variants in the Trichohyalin Gene Are Associated with Straight Hair in Europeans

    OpenAIRE

    Medland, Sarah E.; Nyholt, Dale R.; Painter, Jodie N.; McEvoy, Brian P; McRae, Allan F; Zhu, Gu; Gordon, Scott D.; Ferreira, Manuel A. R.; Wright, Margaret J.; Henders, Anjali K.; Campbell, Megan J.; Duffy, David L; Hansell, Narelle K.; MacGregor, Stuart; Slutske, Wendy S.

    2009-01-01

    Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expres...

  2. Identification and characterisation of coding tandem repeat variants in incA gene of Chlamydophila pecorum

    OpenAIRE

    Yousef Mohamad, Khalil; Rekiki, Abdessalem; Myers, Garry; Bavoil, Patrick M; Rodolakis, Annie

    2008-01-01

    Bacteria of the family Chlamydiaceae are obligate intracellular pathogens of human and animals. Chlamydophila pecorum is associated with different pathological conditions in ruminants, swine and koala. To characterize a coding tandem repeat (CTR) identified at the 3' end of incA gene of C. pecorum, 51 strains of different chlamydial species were examined. The CTR were observed in 18 of 18 tested C. pecorum isolates including symptomatic and asymptomatic animals from diverse geographical origi...

  3. mutation3D: Cancer Gene Prediction Through Atomic Clustering of Coding Variants in the Structural Proteome.

    Science.gov (United States)

    Meyer, Michael J; Lapcevic, Ryan; Romero, Alfonso E; Yoon, Mark; Das, Jishnu; Beltrán, Juan Felipe; Mort, Matthew; Stenson, Peter D; Cooper, David N; Paccanaro, Alberto; Yu, Haiyuan

    2016-05-01

    A new algorithm and Web server, mutation3D (http://mutation3d.org), proposes driver genes in cancer by identifying clusters of amino acid substitutions within tertiary protein structures. We demonstrate the feasibility of using a 3D clustering approach to implicate proteins in cancer based on explorations of single proteins using the mutation3D Web interface. On a large scale, we show that clustering with mutation3D is able to separate functional from nonfunctional mutations by analyzing a combination of 8,869 known inherited disease mutations and 2,004 SNPs overlaid together upon the same sets of crystal structures and homology models. Further, we present a systematic analysis of whole-genome and whole-exome cancer datasets to demonstrate that mutation3D identifies many known cancer genes as well as previously underexplored target genes. The mutation3D Web interface allows users to analyze their own mutation data in a variety of popular formats and provides seamless access to explore mutation clusters derived from over 975,000 somatic mutations reported by 6,811 cancer sequencing studies. The mutation3D Web interface is freely available with all major browsers supported. PMID:26841357

  4. Prevalence of Catalase (-21 A/T Gene Variant in South Indian (Tamil Population

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    A. Lourdhu Mary

    2014-01-01

    Full Text Available Catalase, an endogenous antioxidant enzyme, is responsible for regulating reactive species levels. Several epidemiologic studies have suggested that single nucleotide polymorphism in catalase gene may be associated with many diseases. The genotype of CAT (-21 A/T point mutation in promoter region of catalase gene was determined by polymerase chain based restriction fragment length polymorphism analysis in the DNA of 100 healthy volunteers. The frequency of CAT (-21 A/T gene polymorphism AA, AT, and TT genotypes was found to be 7, 23, and 70 percent, respectively. The mutant “T” allele frequency was found to be 0.82 among the south Indian (Tamil population. Chi square analysis showed that the study population lies within the Hardy-Weinberg equilibrium. The wild type genotype (AA was found to be very low (7% and the mutant genotype (AT/TT was found to be more prevalent (93% among the south Indian population. This suggests that the high prevalence of mutant genotype may increase the susceptibility to oxidative stress associated diseases.

  5. Non-Hodgkin lymphoma risk and variants in genes controlling lymphocyte development.

    Directory of Open Access Journals (Sweden)

    Johanna M Schuetz

    Full Text Available Non-Hodgkin lymphomas (NHL are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs, which were tested for association with NHL and its subtypes. The main analysis used logistic regression (additive model to estimate odds ratios in European-ancestry cases and controls. 599 SNPs and 1116 samples (569 cases and 547 controls passed quality control measures and were included in analyses. Following multiple-testing correction, one SNP in MSH3, a mismatch repair gene, showed an association with diffuse large B-cell lymphoma (OR: 1.91; 95% CI: 1.41-2.59; uncorrected p = 0.00003; corrected p = 0.010. This association was not replicated in an independent European-ancestry sample set of 251 diffuse large B-cell lymphoma cases and 737 controls, indicating this result was likely a false positive. It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings.

  6. Parental cigarette smoking, transforming growth factor-alpha gene variant and the risk of orofacial cleft in Iranian infants

    Science.gov (United States)

    Ebadifar, Asghar; Hamedi, Roya; KhorramKhorshid, Hamid Reza; Kamali, Koorosh; Moghadam, Fatemeh Aghakhani

    2016-01-01

    Objective(s): We investigated the influence of genetic variation of the transforming growth-factor alpha (TGFA) locus on the relationship between smoking and oral clefts. Materials and Methods: In this study 105 Iranian infants with non-syndromic cleft lip/palate and 218 controls with non-cleft birth defects were examined to test for associations among maternal exposures, genetic markers, and oral clefts. Maternal and parental smoking histories during pregnancy were obtained through questionnaire. DNA was extracted from newborn screening blood samples, and genotyping of the BamHI polymorphism in the TGFA gene was performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. A number of factors including gender of the newborns, type of oral cleft, consanguinity of the parents, as well as the mother’s age and education were evaluated as potential confounders and effect modifiers. Results: Maternal smoking, in the absence of paternal smoking, was associated with an increased risk for CL/P (OR = 19.2, 95% CI = [(6.2-59.5)]) and cleft palate only (OR =48.7, 95% CI = [(8-29.3)]). If both parents smoked, risks were generally greater (OR = 55.6, 95% CI = [12-20.25]). Analyses for the risk of clefting from maternal smoking, stratified by the presence or absence of the TGFA/BamH1variant, revealed that the risk of clefting among the infants with the TGFA/BamH1 variant when their mothers smoked cigarettes was much greater than the infants who had non-smoker mothers (P=0.001, OR=10.4,95% CI=[3.2,33.6]). Conclusion: The results of this study indicate that first-trimester maternal smoking and infant TGFA locus mutations are both associated with nonsyndromic cleft lip and/or palate (CL/P). PMID:27279979

  7. Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.

    Directory of Open Access Journals (Sweden)

    Jian Zhao

    2011-05-01

    Full Text Available Systemic lupus erythematosus (SLE, a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH and five CFH-related proteins (CFHR1-CFHR5 within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA and African Americans (AA, which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta = 6.6×10(-8, OR = 1.18 and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta = 2.9×10(-7, OR = 1.17 rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS. Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ, a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta = 3.2×10(-7, OR = 1.47 conferred a higher risk of SLE than heterozygous deletion (P(meta = 3.5×10(-4, OR = 1.14. These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of

  8. Variations in ADH and ALDH in Southwest California Indians

    OpenAIRE

    Ehlers, Cindy L.

    2007-01-01

    Native Americans as a group have the highest rates of alcohol-related deaths of all ethnicities in the United States; however, it remains unclear how and why a greater proportion of individuals in some Native American communities develop alcohol-related problems and alcohol use disorders (AUDs). One potential factor that can influence responses to alcohol are variations in alcohol-metabolizing enzymes. Researchers have analyzed the frequencies of variants in the alcohol-metabolizing enzymes a...

  9. Detection of S-gene 'a' determinant variants in hepatitis B patients with both positive HBsAg and HBsAb markers

    International Nuclear Information System (INIS)

    Objective: To explore the S-gene 'a' determinant variants in hepatitis B patients with both positive HBsAg and HBsAb markers and the effect on the antigenicity of HBsAg. Methods: Quantitative determination of HBV - DNA with competent PCR microfluidic chit method was performed in eight sera specimens from seven hepatitis B patients with both positive HBsAg and HBsAb markers. HBV S-gene was amplified with nested PCR, the PCR product was directly examined for any sequence variant of the amino acids. HBV markers were tested with the very sensitive ELISA/MEIA method in these seven patients. The above rests were also performed in 15 children after failed immunization with hepatitis B vaccine and 9 recipients of liver transplantation for terminal hepatitis B treated with HBIG and lamivudine, serving as controls. Results: The HBsAb contents in the seven patients were all below 80 mIu/ml. Two of the patients with positive HBV-DNA showed no 'a' determinant variant. Two of the four HBV-DNA negative patients demonstrated amino-acid variants (126, 131). One patients who was originally HBV-DNA positive but later turned negative after treatment with interferon and lamivudine demonstrated variant (126). In the 9 patients after successful liver transplantation, the HBsAb contents were all about 150mIu/ml with negative HBV-DNA and no variant. In the 15 immunization failures, HBV-DNA was positive in 14 of them, with 2 cases of variant at 145, 1 case at 126 and 1 case at 134. Conclusion: In some patients with chronic B hepatitis with both positive HBsAg and HBsAb markers, as well as in some vaccine immunization failures, there were 'a' determinant variants, which might alter the antigenicity of HBsAg with escape from the neutralization of low HBsAb. The 'a' determinant variant might also affect the replication of the virus. In this study, no variant was shown in patients after successful liver transplantation. However, the number of patients was too small and the result was of no

  10. NADH fluorescence lifetime analysis of the effect of magnesium ions on ALDH2

    Science.gov (United States)

    ALDH2 catalyzes oxidation of toxic aldehydes to their corresponding carboxylic acids. Magnesium ions influence enzyme activity in part by increasing NADH binding affinity. Traditional fluorescence measurements have monitored the blue shift of the NADH fluorescence spectrum to elucidate the extent of...

  11. Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1

    NARCIS (Netherlands)

    Fischer, B.; Callewaert, B.; Schroter, P.; Coucke, P.J.; Schlack, C.; Ott, C.E.; Morroni, M.; Homann, W.; Mundlos, S.; Morava, E.; Ficcadenti, A.; Kornak, U.

    2014-01-01

    Autosomal recessive cutis laxa (ARCL) type 2 constitutes a heterogeneous group of diseases mainly characterized by lax and wrinkled skin, skeletal anomalies, and a variable degree of intellectual disability. ALDH18A1-related ARCL is the most severe form within this disease spectrum. Here we report o

  12. Mutation analysis of methylmalonyl CoA mutase gene exon 2 in Egyptian families: Identification of 25 novel allelic variants

    Directory of Open Access Journals (Sweden)

    Dina A. Ghoraba

    2015-02-01

    Full Text Available Methylmalonic aciduria (MMA is an autosomal recessive disorder of methylmalonate and cobalamin (cbl; vitamin B12 metabolism. It is an inborn error of organic acid metabolism which commonly results from a defect in the gene encoding the methylmalonyl-CoA mutase (MCM apoenzyme. Here we report the results of mutation study of exon 2 of the methylmalonyl CoA mutase (MUT gene, coding MCM residues from 1 to 128, in ten unrelated Egyptian families affected with methylmalonic aciduria. Patients were presented with a wide-anion gap metabolic acidosis. The diagnosis has established by the measurement of C3 (propionylcarnitine and C3:C2 (propionylcarnitine/acetylcarnitine in blood by using liquid chromatography–tandem mass spectrometry (LC/MS–MS and was confirmed by the detection of an abnormally elevated level of methylmalonic acid in urine by using gas chromatography–mass spectrometry (GC/MS and isocratic cation exchange high-performance liquid-chromatography (HPLC. Direct sequencing of gDNA of the MUT gene exon 2 has revealed a total of 26 allelic variants: ten of which were intronic, eight were located upstream to the exon 2 coding region, four were novel modifications predicted to affect the splicing region, three were novel mutations within the coding region: c.15G>A (p.K5K, c.165C>A (p.N55K and c.7del (p.R3EfsX14, as well as the previously reported mutation c.323G>A (p.R108H.

  13. Stability of the aryl hydrocarbon receptor and its regulated genes in the low activity variant of Hepa-1 cell line.

    Science.gov (United States)

    Humphrey-Johnson, Andria; Abukalam, Rawia; Eltom, Sakina E

    2015-03-01

    We examined the expression kinetics of some of the aryl hydrocarbon receptor (AhR)-regulated genes in LA1 variant cells compared to wild type (WT) Hepa-1 mouse hepatoma cell lines, and we investigated the stability of AhR protein as a key step in the function of this receptor. Treatment of both cell types with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in increased CYP1A1 and CYP1B1 mRNA with a subsequent down regulation of AhR. We show here that co-treatment with transcription inhibitor actinomycin D (ActD) has reversed the TCDD-induced depletion of AhR protein in WT. However, the proteolytic degradation of AhR in absence of TCDD was significantly higher in LA1 cells than in WT, and ActD treatment reduced this loss. Induction of CYP1A1 and CYP1B1 mRNA by TCDD in WT cells each exhibited bursts of activity in the initial hour which were about 3-fold greater than in LAI cells. The induced mRNA levels in LA1 exhibited a slow and sustained increase approximating the WT levels by 20h. The induction of two other AhR-regulated genes also showed comparable turnover differences between the two types of cell. Thus, altered regulation of the AhR responsive genes in LA1 may result from a difference in AhR stability. PMID:25637755

  14. ACTN3 R577X and ACE I/D gene variants influence performance in elite sprinters: a multi-cohort study

    OpenAIRE

    Papadimitriou, Ioannis D.; Lucia, Alejandro; Pitsiladis, Yannis P; Pushkarev, Vladimir P; Dyatlov, Dmitry A.; Orekhov, Evgeniy F.; Artioli, Guilherme G.; Guilherme, João Paulo L. F.; Lancha, Antonio H; Ginevičienė, Valentina; Cieszczyk, Pawel; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Muniesa, Carlos A.; Kouvatsi, Anastasia

    2016-01-01

    Background To date, studies investigating the association between ACTN3 R577X and ACE I/D gene variants and elite sprint/power performance have been limited by small cohorts from mixed sport disciplines, without quantitative measures of performance. Aim: To examine the association between these variants and sprint time in elite athletes. Methods We collected a total of 555 best personal 100-, 200-, and 400-m times of 346 elite sprinters in a large cohort of elite Caucasian or African origin s...

  15. ACTN3 R577X and ACE I/D gene variants influence performance in elite sprinters: a multi-cohort study

    OpenAIRE

    Papadimitriou, Ioannis D.; Lucía Mulas, Alejandro; Pitsiladis, Yannis; Pushkarev, Vladimir P; Dyatlov, D. A.; Orekhov, Evgeniy F.; Artioli, Guilherme G.; Guilherme, João Paulo L. F.; Lancha, Antonio H; Ginevičienė, Valentina; Pawel, Cieszczyk; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Muniesa Ferrero, Carlos Alberto; Kouvatsi, Anastasia

    2016-01-01

    To date, studies investigating the association between ACTN3 R577X and ACE I/D gene variants and elite sprint/power performance have been limited by small cohorts from mixed sport disciplines, without quantitative measures of performance. The aim of this study was to examine the association between these variants and sprint time in elite athletes. We collected a total of 555 best personal 100-, 200-, and 400-m times of 346 elite sprinters in a large cohort of elite Caucasian or African origin...

  16. Novel variant (bla(VIM-4)) of the metallo-beta-lactamase gene bla(VIM-1) in a clinical strain of Pseudomonas aeruginosa.

    Science.gov (United States)

    Pournaras, Spyros; Tsakris, Athanassios; Maniati, Maria; Tzouvelekis, Leonidas S; Maniatis, Antonios N

    2002-12-01

    A Pseudomonas aeruginosa isolate highly resistant to carbapenems was collected from a patient with postsurgical cerebrospinal infection in Greece. The isolate carried a class 1 integron that contained as a sole cassette the gene bla(VIM-4), a novel variant of bla(VIM-1), with one nucleotide difference resulting in a Ser-to-Arg change at amino acid position 175 of the VIM-1 enzyme. This is the first detection of a VIM-1 variant after its appearance in Italy. PMID:12435718

  17. A novel β-globin gene mutation HBB.c.22 G>C produces a hemoglobin variant (Hb Vellore) mimicking HbS in HPLC.

    Science.gov (United States)

    Edison, E S; Sathya, M; Rajkumar, S V; Nair, S C; Srivastava, A; Shaji, R V

    2012-10-01

    Hemoglobinopathies are highly prevalent in Indian population. DNA analysis to detect causative mutations is required for identifying rare hemoglobin variants or when hematological results are discordant with the clinical phenotype. In this report, we describe a novel hemoglobin variant caused by a mutation in beta-globin gene, Codon 7 GAG→CAG (Glu→Gln) that elutes in the position of sickle haemoglobin (HbS) in cation exchange high performance liquid chromatography. This report highlights possible diagnostic pitfalls in interpreting data solely based on haemoglobin analysis and usefulness of mutation screening in definitive diagnosis of hemoglobinopathies. PMID:22471768

  18. Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome.

    Directory of Open Access Journals (Sweden)

    Hazuki Komuro

    Full Text Available Corticotropin-releasing hormone (CRH plays an important role in the pathophysiology of irritable bowel syndrome (IBS and regulates the stress response through two CRH receptors (R1 and R2. Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436 and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220 were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale.We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017 and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS, and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710 and two SNPs (rs2284217 and rs2284220 in strong linkage disequilibrium (D' > 0.90. We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion.Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH

  19. Human PTCHD3 nulls: rare copy number and sequence variants suggest a non-essential gene

    Directory of Open Access Journals (Sweden)

    Lionel Anath C

    2011-03-01

    Full Text Available Abstract Background Copy number variations (CNVs can contribute to variable degrees of fitness and/or disease predisposition. Recent studies show that at least 1% of any given genome is copy number variable when compared to the human reference sequence assembly. Homozygous deletions (or CNV nulls that are found in the normal population are of particular interest because they may serve to define non-essential genes in human biology. Results In a genomic screen investigating CNV in Autism Spectrum Disorders (ASDs we detected a heterozygous deletion on chromosome 10p12.1, spanning the Patched-domain containing 3 (PTCHD3 gene, at a frequency of ~1.4% (6/427. This finding seemed interesting, given recent discoveries on the role of another Patched-domain containing gene (PTCHD1 in ASD. Screening of another 177 ASD probands yielded two additional heterozygous deletions bringing the frequency to 1.3% (8/604. The deletion was found at a frequency of ~0.73% (27/3,695 in combined control population from North America and Northern Europe predominately of European ancestry. Screening of the human genome diversity panel (HGDP-CEPH covering worldwide populations yielded deletions in 7/1,043 unrelated individuals and those detected were confined to individuals of European/Mediterranean/Middle Eastern ancestry. Breakpoint mapping yielded an identical 102,624 bp deletion in all cases and controls tested, suggesting a common ancestral event. Interestingly, this CNV occurs at a break of synteny between humans and mouse. Considering all data, however, no significant association of these rare PTCHD3 deletions with ASD was observed. Notwithstanding, our RNA expression studies detected PTCHD3 in several tissues, and a novel shorter isoform for PTCHD3 was characterized. Expression in transfected COS-7 cells showed PTCHD3 isoforms colocalize with calnexin in the endoplasmic reticulum. The presence of a patched (Ptc domain suggested a role for PTCHD3 in various biological

  20. Association of IL17A gene variants with chronic Chagas cardiomyopathy

    OpenAIRE

    Daniel Arturo León; Luis Eduardo Echeverría; Clara Isabel González

    2015-01-01

    Human host genetic factors have been suggested to be determinants of the prevalence and clinical forms of Chagas disease. In this regard, IL-17A is believed to control parasitemia and protect against heart disease. In this work, we assessed whether IL17A gene polymorphisms are related to infection and/or development of the cardiac form of Chagas disease by genotyping for five IL17A SNPs (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) in 1171 individuals from a Colombian region ende...

  1. The effects of a DTNBP1 gene variant on attention networks: an fMRI study

    Directory of Open Access Journals (Sweden)

    Thimm Markus

    2010-09-01

    Full Text Available Abstract Background Attention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers. Methods The present event-related fMRI study investigated the effect of the single nucleotide polymorphism (SNP rs1018381 of the DTNBP1 (dystrobrevin-binding protein 1 gene on brain activity in 80 subjects while performing the attention network test (ANT. In this reaction time task three domains of attention are probed simultaneously: alerting, orienting and executive control of attention. Results Risk allele carriers showed impaired performance in the executive control condition associated with reduced neural activity in the left superior frontal gyrus [Brodmann area (BA 9]. Risk allele carriers did not show alterations in the alerting and orienting networks. Conclusions BA 9 is a key region of schizophrenia pathology and belongs to a network that has been shown previously to be involved in impaired executive control mechanisms in schizophrenia. Our results identified the impact of DTNBP1 on the development of a specific attention deficit via modulation of a left prefrontal network.

  2. Association of NOS3 gene variants and clinical contributors of hypoxic-ischemic encephalopathy

    Energy Technology Data Exchange (ETDEWEB)

    Kuzmanić Šamija, R. [Department of Pediatrics, University Hospital Split, Split (Croatia); Primorac, D. [School of Medicine Split, University of Split, Split (Croatia); Department of Pediatrics, School of Medicine, University of Osijek, Osijek (Croatia); Eberly College of Science, Penn State University, University Park, PA (United States); St. Catherine Speciality Hospital, Zabok (Croatia); Rešić, B. [School of Medicine Split, University of Split, Split (Croatia); Pavlov, V. [Department of Neonatology, University Hospital Split, Split (Croatia); Čapkun, V. [Department of Nuclear Medicine, University Hospital Split, Split (Croatia); Punda, H. [School of Medicine Split, University of Split, Split (Croatia); Lozić, B. [Department of Pediatrics, University Hospital Split, Split (Croatia); Zemunik, T. [Department of Medical Biology, School of Medicine Split, University of Split, Split (Croatia)

    2014-08-15

    The aim of this study was to analyze the association of different clinical contributors of hypoxic-ischemic encephalopathy with NOS3 gene polymorphisms. A total of 110 children with hypoxic-ischemic encephalopathy and 128 control children were selected for this study. Association of gender, gestational age, birth weight, Apgar score, cranial ultrasonography, and magnetic resonance imaging findings with genotypic data of six haplotype-tagging single nucleotide polymorphisms and the most commonly investigated rs1800779 and rs2070744 polymorphisms was analyzed. The TGT haplotype of rs1800783, rs1800779, and rs2070744 polymorphisms was associated with hypoxic-ischemic encephalopathy. Children with the TGT haplotype were infants below 32 weeks of gestation and they had the most severe brain damage. Increased incidence of the TT genotype of the NOS3 rs1808593 SNP was found in the group of hypoxic-ischemic encephalopathy patients with medium and severe brain damage. The probability of brain damage was twice as high in children with the TT genotype than in children with the TG genotype of the same polymorphism. Furthermore, the T allele of the same polymorphism was twice as frequent in children with lower Apgar scores. This study strongly suggests associations of NOS3 gene polymorphism with intensity of brain damage and severity of the clinical picture in affected children.

  3. Common genetic variants and gene expression associated with white matter microstructure in the human brain.

    Science.gov (United States)

    Sprooten, Emma; Knowles, Emma E; McKay, D Reese; Göring, Harald H; Curran, Joanne E; Kent, Jack W; Carless, Melanie A; Dyer, Thomas D; Drigalenko, Eugene I; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Kochunov, Peter; Blangero, John; Glahn, David C

    2014-08-15

    Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease. PMID:24736177

  4. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses.

    Science.gov (United States)

    Gilman SR; Iossifov I; Levy D; Ronemus M; Wigler M; Vitkup D

    2011-06-09

    Identification of complex molecular networks underlying common human phenotypes is a major challenge of modern genetics. In this study, we develop a method for network-based analysis of genetic associations (NETBAG). We use NETBAG to identify a large biological network of genes affected by rare de novo CNVs in autism. The genes forming the network are primarily related to synapse development, axon targeting, and neuron motility. The identified network is strongly related to genes previously implicated in autism and intellectual disability phenotypes. Our results are also consistent with the hypothesis that significantly stronger functional perturbations are required to trigger the autistic phenotype in females compared to males. Overall, the presented analysis of de novo variants supports the hypothesis that perturbed synaptogenesis is at the heart of autism. More generally, our study provides proof of the principle that networks underlying complex human phenotypes can be identified by a network-based functional analysis of rare genetic variants.

  5. Identification of a Novel De Novo Variant in the PAX3 Gene in Waardenburg Syndrome by Diagnostic Exome Sequencing: The First Molecular Diagnosis in Korea.

    Science.gov (United States)

    Jang, Mi-Ae; Lee, Taeheon; Lee, Junnam; Cho, Eun-Hae; Ki, Chang-Seok

    2015-05-01

    Waardenburg syndrome (WS) is a clinically and genetically heterogeneous hereditary auditory pigmentary disorder characterized by congenital sensorineural hearing loss and iris discoloration. Many genes have been linked to WS, including PAX3, MITF, SNAI2, EDNRB, EDN3, and SOX10, and many additional genes have been associated with disorders with phenotypic overlap with WS. To screen all possible genes associated with WS and congenital deafness simultaneously, we performed diagnostic exome sequencing (DES) in a male patient with clinical features consistent with WS. Using DES, we identified a novel missense variant (c.220C>G; p.Arg74Gly) in exon 2 of the PAX3 gene in the patient. Further analysis by Sanger sequencing of the patient and his parents revealed a de novo occurrence of the variant. Our findings show that DES can be a useful tool for the identification of pathogenic gene variants in WS patients and for differentiation between WS and similar disorders. To the best of our knowledge, this is the first report of genetically confirmed WS in Korea. PMID:25932447

  6. Identification of critical variants within SLC44A4, an ulcerative colitis susceptibility gene identified in a GWAS in north Indians.

    Science.gov (United States)

    Gupta, A; Thelma, B K

    2016-03-01

    SLC44A4 is one of the seven novel susceptibility genes that were discovered in the first ever genome-wide association study (GWAS) on ulcerative colitis (UC) in the genetically distinct north Indians. This gene seems to be functionally relevant to disease biology as it may contribute to the associated phenotype of Vitamin B1 deficiency among UC patients, hence playing a role in disease pathogenesis. A large number of single-nucleotide polymorphisms (SNPs) are known to be distributed throughout this gene, but the functional status of most are not known. Thus, an extensive investigation of structural and regulatory variants within this gene was undertaken in this study to identify the critical variants amongst them using a combination of fine mapping, in silico and in vitro approaches. A few intronic SNPs were predicted to have regulatory roles on the basis of in silico analysis, suggesting that they may be the critical variants within SLC44A4. This highlights the importance of this gene in UC biology, thus confirming the finding of the GWAS and also warranting additional studies. PMID:26741288

  7. Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence.

    Science.gov (United States)

    Xie, Pingxing; Kranzler, Henry R; Krystal, John H; Farrer, Lindsay A; Zhao, Hongyu; Gelernter, Joel

    2014-09-01

    The N-methyl-D-aspartate (NMDA) glutamate receptors play important roles in the pathophysiology of substance dependence (SD), but no strong genetic evidence has associated common variants in NMDAR-related genes to SD. We hypothesized that rare variants (RVs) with minor allele frequency genes might exert large effects on SD risk. We sequenced 34 544 bp of coding and flanking intronic regions of 17 genes involved in the NMDA system in 760 subjects, all with co-occurring alcohol dependence, cocaine dependence and opioid dependence (OD), and 760 healthy control subjects. One hundred percent of the target regions were sequenced at >1000× coverage. We identified 454 variants, including 380 RVs. Based on case-control allele count differences, we genotyped 11 exonic RVs in 6751 additional subjects, and the 1520 subjects from the sequencing stage for validation. All alleles of the 11 RVs called in the sequencing stage were confirmed. We found a statistically significant association of the 11 RVs with OD in African Americans (P = 0.00080). Results from gene-based association tests showed that the association signal derived mostly from DISC1 (P = 0.0010) and GRIN2B (P = 0.00085). DISC1 is a well-validated schizophrenia risk gene. This is the first demonstration that RVs affect the risk of OD and the first demonstration of biological convergence of schizophrenia and OD risk-via DISC1. PMID:23855403

  8. Variants in doublecortin- and calmodulin kinase like 1, a gene up-regulated by BDNF, are associated with memory and general cognitive abilities.

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    Stéphanie Le Hellard

    Full Text Available BACKGROUND: Human memory and general cognitive abilities are complex functions of high heritability and wide variability in the population. The brain-derived neurotrophic factor (BDNF plays an important role in mammalian memory formation. METHODOLOGY / PRINCIPAL FINDING: Based on the identification of genes markedly up-regulated during BDNF-induced synaptic consolidation in the hippocampus, we selected genetic variants that were tested in three independent samples, from Norway and Scotland, of adult individuals examined for cognitive abilities. In all samples, we show that markers in the doublecortin- and calmodulin kinase like 1 (DCLK1 gene, are significantly associated with general cognition (IQ scores and verbal memory function, resisting multiple testing. DCLK1 is a complex gene with multiple transcripts which vary in expression and function. We show that the short variants are all up-regulated after BDNF treatment in the rat hippocampus, and that they are expressed in the adult human brain (mostly in cortices and hippocampus. We demonstrate that several of the associated variants are located in potential alternative promoter- and cis-regulatory elements of the gene and that they affect BDNF-mediated expression of short DCLK1 transcripts in a reporter system. CONCLUSION: These data present DCLK1 as a functionally pertinent gene involved in human memory and cognitive functions.

  9. Novel variants in the PRDX6 Gene and the risk of Acute Lung Injury following major trauma

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    Localio A Russell

    2011-05-01

    Full Text Available Abstract Background Peroxiredoxin 6 (PRDX6 is involved in redox regulation of the cell and is thought to be protective against oxidant injury. Little is known about genetic variation within the PRDX6 gene and its association with acute lung injury (ALI. In this study we sequenced the PRDX6 gene to uncover common variants, and tested association with ALI following major trauma. Methods To examine the extent of variation in the PRDX6 gene, we performed direct sequencing of the 5' UTR, exons, introns and the 3' UTR in 25 African American cases and controls and 23 European American cases and controls (selected from a cohort study of major trauma, which uncovered 80 SNPs. In silico modeling was performed using Patrocles and Transcriptional Element Search System (TESS. Thirty seven novel and tagging SNPs were tested for association with ALI compared with ICU at-risk controls who did not develop ALI in a cohort study of 259 African American and 254 European American subjects that had been admitted to the ICU with major trauma. Results Resequencing of critically ill subjects demonstrated 43 novel SNPs not previously reported. Coding regions demonstrated no detectable variation, indicating conservation of the protein. Block haplotype analyses reveal that recombination rates within the gene seem low in both Caucasians and African Americans. Several novel SNPs appeared to have the potential for functional consequence using in silico modeling. Chi2 analysis of ALI incidence and genotype showed no significant association between the SNPs in this study and ALI. Haplotype analysis did not reveal any association beyond single SNP analyses. Conclusions This study revealed novel SNPs within the PRDX6 gene and its 5' and 3' flanking regions via direct sequencing. There was no association found between these SNPs and ALI, possibly due to a low sample size, which was limited to detection of relative risks of 1.93 and above. Future studies may focus on the role of

  10. Characterization of a variant vlhA gene of Mycoplasma synoviae, strain WVU 1853, with a highly divergent haemagglutinin region

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    Ben Abdelmoumen Mardassi Boutheina

    2010-01-01

    Full Text Available Abstract Background In Mycoplasma synoviae, type strain WVU 1853, a single member of the haemaglutinin vlhA gene family has been previously shown to be expressed. Variants of vlhA are expressed from the same unique vlhA promoter by recruiting pseudogene sequences via site-specific recombination events, thus generating antigenic variability. Using a bacterial stock of M. synoviae WVU 1853 that had been colony purified thrice and maintained in our laboratory at low passage level, we previously identified a vlhA gene-related partial coding sequence, referred to as MS2/28.1. The E. coli-expressed product of this partial coding sequence was found to be immunodominant, suggesting that it might be expressed. Results Reverse transcription-PCR amplification (RT-PCR, using a sense primer located at the 5'-end region of the expected vlhA transcript and a reverse primer located at the 3' end of MS2/28.1 coding sequence, yielded a consistent amplification product showing that MS2/28.1 was indeed transcribed. Nucleotide sequence analysis of the RT-PCR product identified an 1815-nucleotide full-length open reading frame (ORF, immediately preceded by a nucleotide sequence identical to that previously reported for expressed vlhA genes. PCR amplifications using genomic DNA isolated from single colonies further confirmed that the full-length ORF of MS2/28.1 was located downstream of the unique vlhA promoter sequence. The deduced 604-amino acid (aa sequence showed a perfect sequence identity to the previously reported vlhA expressed genes along the first 224 residues, then highly diverged with only 37.6% aa identity. Despite the fact that this M. synoviae clone expressed a highly divergent and considerably shorter C-terminal haemagglutinin product, it was found to be expressed at the surface of the bacterium and was able to haemagglutinate chicken erythrocytes. Importantly, the E. coli-expressed C-terminal highly divergent 60 residues of MS2/28.1 proved

  11. DNA Fragmentation Factor 45 (DFF45 Gene at 1p36.2 Is Homozygously Deleted and Encodes Variant Transcripts in Neuroblastoma Cell Line

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    Hong Wei Yang

    2001-01-01

    Full Text Available Recently, loss of heterozygosity (LOH studies suggest that more than two tumor suppressor genes lie on the short arm of chromosome 1 (1p in neuroblastoma (NB. To identify candidate tumor suppressor genes in NB, we searched for homozygous deletions in 20 NB cell lines using a high-density STS map spanning chromosome 1 p36, a common LOH region in NB. We found that the 45-kDa subunit of the DNA fragmentation factor (DFF45 gene was homozygously deleted in an NB cell line, NB-1. DFF45 is the chaperon of DFF40, and both molecules are necessary for caspase 3 to induce apoptosis. DFF35, a splicing variant of DFF45, is an inhibitor of DFF40. We examined 20 NB cell lines for expression and mutation of DFF45 gene by reverse transcription (RT-polymerase chain reaction (PCR and RT-PCR-single-strand conformation polymorphism. Some novel variant transcripts of the DFF45 gene were found in NB cell lines, but not in normal adrenal gland and peripheral blood. These variants may not serve as chaperons of DFF40, but as inhibitors like DFF35, thus disrupting the balance between DFF45 and DFF40. No mutations of the DFF45 gene were found in any NB cell line, suggesting that the DFF45 is not a tumor suppressor gene for NB. However, homozygous deletion of the DFF45 gene in the NB-1 cell line may imply the presence of unknown tumor suppressor genes in this region.

  12. Low prevalence of connexin-40 gene variants in atrial tissues and blood from atrial fibrillation subjects

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    Tchou Gregory D

    2012-11-01

    Full Text Available Abstract Background The atrial gap junction protein connexin-40 (Cx40 has been implicated to play an important role in atrial conduction and development of atrial fibrillation (AF. However, the frequency of Cx40 mutations in AF populations and their impact on Cx40 expression remains unclear. In this study, we sought to identify polymorphisms in the Cx40 gene GJA5, investigate the potential functional role of these polymorphisms, and determine their allelic frequencies. The prevalence of nonsynonymous Cx40 mutations in blood and atrial tissue was also compared to mutation frequencies reported in prior studies. Methods We conducted direct sequencing of the GJA5 coding and 3′ UTR regions in blood samples from 91 lone AF subjects and 67 atrial tissue-derived samples from a lone cohort, a mixed AF cohort, and several transplant donors. Reporter gene transfection and tissue allelic expression imbalance assays were used to assess the effects of a common insertion/deletion polymorphism on Cx40 mRNA stability and expression. Results We identified one novel synonymous SNP in blood-derived DNA from a lone AF subject. In atrial tissue-derived DNA from lone and mixed AF subjects, we observed one novel nonsynonymous SNP, one rare previously reported synonymous SNP, and one novel 3′ UTR SNP. A previously noted 25 bp insertion/deletion polymorphism in the 3′ UTR was found to be common (minor allele frequency = 0.45 but had no effect on Cx40 mRNA stability and expression. The observed prevalence of nonsynonymous Cx40 mutations in atrial tissues derived from lone AF subjects differed significantly (p = 0.03 from a prior atrial tissue study reporting a high mutation frequency in a group of highly selected young lone AF subjects. Conclusions Our results suggest that Cx40 coding SNPs are uncommon in AF populations, although rare mutations in this gene may certainly lead to AF pathogenesis. Furthermore, a common insertion/deletion polymorphism in the Cx40 3

  13. Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosa

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    Herpertz-Dahlmann Beate

    2008-11-01

    Full Text Available Abstract Background Several lines of evidence indicate that the central cannabinoid receptor 1 (CNR1 as well as the major endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH, N-acylethanolamine-hydrolyzing acid amidase (NAAA and monoglyceride lipase (MGLL are implicated in mediating the orexigenic effects of cannabinoids. The aim of this study was to analyse whether nucleotide sequence variations in the CNR1, FAAH, NAAA and MGLL genes are associated with anorexia nervosa (AN. Methods We analysed the association of a previously described (AATn repeat in the 3' flanking region of CNR1 as well as a total of 15 single nucleotide polymorphisms (SNPs representative of regions with restricted haplotype diversity in CNR1, FAAH, NAAA or MGLL in up to 91 German AN trios (patient with AN and both biological parents using the transmission-disequilibrium-test (TDT. One SNP was additionally analysed in an independent case-control study comprising 113 patients with AN and 178 normal weight controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, ARMS-PCR or using 3730xl capillary sequencers. Results The TDT revealed no evidence for association for any of the SNPs or the (AATn repeat with AN (all two-sided uncorrected p-values > 0.05. The lowest p-value of 0.11 was detected for the A-allele of the CNR1 SNP rs1049353 for which the transmission rate was 59% (95% confidence interval 47%...70%. Further genotyping of rs1049353 in 113 additional independent patients with AN and 178 normal weight controls could not substantiate the initial trend for association (p = 1.00. Conclusion As we found no evidence for an association of genetic variation in CNR1, FAAH, NAAA and MGLL with AN, we conclude that genetic variations in these genes do not play a major role in the etiology of AN in our study groups.

  14. Novel Pathogenic Variant (c.3178G>A) in the SMC1A Gene in a Family With Cornelia de Lange Syndrome Identified by Exome Sequencing

    OpenAIRE

    Jang, Mi-Ae; Lee, Chang-Woo; Kim, Jin-Kyung; Ki, Chang-Seok

    2015-01-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, moth...

  15. ALDH maintains the stemness of lung adenoma stem cells by suppressing the Notch/CDK2/CCNE pathway.

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    Zhongjun Li

    Full Text Available To evaluate the expression of ALDH1A1 in lung adenoma stem cells (LASCs and maintenance of their stemness through the Notch pathway.LASCs (A549s were isolated from lung adenoma cells (A549 and identified by their coexpression of CD133 and CD326 and their capacity formulti-directional differentiation. Expression of ALDH1A1 in A549 and A549s cells were evaluated by Real-time PCR. Effects of ALDH1A1 upregulation in A549 cells and its downregulation in A549s cells on the clonogenicity and cell cycle were assessed by colony-forming unit assay. Moreover, the effects of ALDH1A1 on the Notch pathway, and thus on the cell cycle, were studied.A549s cells were successfully isolated and identified.ALDH1A1expression was significantly higher in A549s than in A549 cells. Clonogenicity was significantly decreased in A549s cells treated with ALDH1A1 siRNA. Duration of the G1 stage of the cell cycle increased after ALDH1A1 was overexpressed, or decreased with ALDH1A1 siRNA. ALDH1A1, Notch1, -2, and -3, CDK2, and CCNE1 expression levels were higher in A549s cells than in A549 cells. Expression of Notch1, -2, and -3, CDK2, and CCNE1 was significantly decreased by upregulation of ALDH1A1 in A549 cells, but increased by its interruption in A549s cells. When Notch3 or CDK2 expression was downregulated, the expression levels of ALDH1A1, Notch1, -2, and -3, CDK2, and CCNE1 were reduced in all cell types.ALDH1A1 expression improved clonogenicity and inhibited the cell cycle, maintaining the stemness of the A549s cells; this may involve suppression of the Notch/CDK2/Cyclin pathway.

  16. Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk:A meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Akira; Yokoyama; Tetsuji; Yokoyama

    2010-01-01

    AIM:To evaluate the contribution of alcohol dehydrogenase-1B(ADH1B)and aldehyde dehydrogenase-2 (ALDH2)polymorphisms to the risk of esophageal cancer.METHODS:Nineteen articles were included by searching MEDLINE,EMBASE and the Chinese Biomedical Database,13 on ADH1B and 18 on ALDH2.We performed a meta-analysis of case-control studies including 13 studies on ADH1B(cases/controls:2390/7100)and 18 studies on ALDH2(2631/6030).RESULTS:The crude odds ratio[OR(95%confidence interval)]was 2.91(2.04-4.14)for ADH1B*1/...

  17. Variants in the Adiponectin Gene and Serum Adiponectin: The Coronary Artery Development in Young Adults (CARDIA) Study

    Science.gov (United States)

    Wassel, Christina L.; Pankow, James S.; Jacobs, David R.; Steffes, Michael W.; Li, Na; Schreiner, Pamela J.

    2016-01-01

    Circulating adiponectin is involved in the atherosclerotic process and has been associated with cardiovascular disease as well as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. The adiponectin gene (ADIPOQ) encodes the circulating protein adiponectin and affects its expression. Only a small proportion of all known ADIPOQ polymorphisms have been investigated in relation to circulating adiponectin concentrations. Using data from 3,355 African-American and white men and women aged 33–45 at the year 15 examination from the Coronary Artery Development in Young Adults (CARDIA) Study the association between 10 single-nucleotide polymorphisms (SNPs) within ADIPOQ and serum adiponectin was examined using linear regression. SNPs were chosen based on a tagSNP approach. Models were stratified by self-reported race to control for population stratification, and Bonferroni corrected for multiple comparisons. ADIPOQ SNPs rs17300539 (P Significant interactions were found between waist and rs182052 (P = 0.0029) and between rs9882505 and smoking (P = 0.001) in whites. Many ADIPOQ SNPs have not yet been examined, and additional studies are needed to determine whether these may be functional variants. PMID:20395949

  18. Multidrug Resistance 1 Gene Variants, Pesticide Exposure, and Increased Risk of DNA Damage

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    Chun-Chieh Chen

    2014-01-01

    Full Text Available The P-glycoprotein, encoded by the multidrug resistance (MDR1 gene, extrudes fat-soluble compounds to the extracellular environment. However, the DNA damage of pesticides in subjects with genetic variation in MDR1 has not been investigated. In this study, the comet assay was applied to examine the extent of DNA damage in the peripheral blood of 195 fruit growers who had been exposed to pesticides and 141 unexposed controls. The MDR1 polymorphisms were identified. Questionnaires were administered to obtain demographic data and occupational history. Results showed subjects experiencing high (2.14 μm/cell, P<0.01 or low pesticide exposure (2.18 μm/cell, P<0.01 had a significantly greater DNA tail moment than controls (1.28 μm/cell. Compared to the MDR1 T-129C (rs3213619 TC/CC carriers, the TT carriers had increased DNA tail moment in controls (1.30 versus 1.12 μm/cell, P<0.01. Similar results were observed in the high and low pesticide-exposed groups. Combined analysis revealed that pesticide-exposed fruit growers with MDR1 -129 TT genotype had the greatest DNA damage in the subjects with the combinations of pesticide exposure and MDR1 -129 genotypes. In conclusion, pesticide exposed individuals with susceptible MDR1 -129 genotypes may experience increased risk of DNA damage.

  19. Association of genetic variants in apoptosis genes FAS and FASL with radiation-induced late toxicity after prostate cancer radiotherapy

    International Nuclear Information System (INIS)

    Fas ligand (FASL) triggers apoptotic cell death by cross-linking with its receptor FAS, and after irradiation, expression of FAS and FASL is increased. In the present study, we investigated the association between common polymorphisms in the genes for FAS and FASL and the risk of late side effects after radiotherapy for prostate cancer. The role of FAS (- 1377G > A, rs2234767 and - 670A > G, rs1800682) and FASL (- 844C > T, rs763110) gene polymorphisms in the development of high-grade late rectal and/or urinary toxicity (defined as late toxicity EORTC/RTOG grade ≥ 2) was analyzed in 607 prostate cancer patients treated with radiotherapy. DNA was isolated and the selected polymorphisms were determined by 5'-nuclease (TaqMan) assays. After a median follow-up time of 82 months, high-grade late rectal and/or urinary toxicity was observed in 175 patients (29.7 %). Univariate analysis revealed a significantly decreased risk of high-grade late toxicity in carriers of the FASL - 844T allele. After adjusting for covariates, patients harboring at least one - 844T allele (CT or TT genotype) remained at decreased risk of high-grade late toxicity compared with patients harboring the CC genotype [hazard ratio (HR) 0.585, 95 %CI 0.39-0.878; p = 0.010]. For patients with the - 844TT genotype, the HR was 0.404 (95 %CI 0.171-0.956; p = 0.039) in multivariate analysis. No significant associations were found for the remaining polymorphisms analyzed. These results provide the first evidence that the presence of the FASL - 844T variant allele may have a protective effect against the development of high-grade late rectal and/or urinary side effects after prostate cancer radiotherapy. (orig.)

  20. Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study

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    Venojärvi Mika

    2011-01-01

    Full Text Available Abstract Background Adiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits. Methods Participants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507 were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs. Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34 years was analysed by Cox regression analysis. Results rs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p Conclusions These results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM. Trial registration number ClinicalTrials.gov NCT00518167

  1. Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models.

    Science.gov (United States)

    Spencer, E M; Chandler, K E; Haddley, K; Howard, M R; Hughes, D; Belyaev, N D; Coulson, J M; Stewart, J P; Buckley, N J; Kipar, A; Walker, M C; Quinn, J P

    2006-10-01

    Repressor element-1 silencing transcription factor (REST) is a candidate modulator of gene expression during status epilepticus in the rodent. In such models, full-length REST and the truncated REST4 variant are induced and can potentially direct differential gene expression patterns. We have addressed the regulation of these REST variants in rodent hippocampal seizure models and correlated this with expression of the proconvulsant, substance P encoding, PPT-A gene. REST and REST4 were differentially regulated following kainic acid stimulus both in in vitro and in vivo models. REST4 was more tightly regulated than REST in both models and its transient expression correlated with that of the differential regulation of PPT-A. Consistent with this, overexpression of a truncated REST protein (HZ4, lacking the C-terminal repression domain) increased expression of the endogenous PPT-A gene. Similarly the proximal PPT-A promoter reporter gene construct was differentially regulated by the distinct REST isoforms in hippocampal cells with HZ4 being the major inducer of increased reporter expression. Furthermore, REST and REST4 proteins were differentially expressed and compartmentalized within rat hippocampal cells in vitro following noxious stimuli. This differential localization of the REST isoforms was confirmed in the CA1 region following perforant path and kainic acid induction of status epilepticus in vivo. We propose that the interplay between REST and REST4 alter the expression of proconvulsant genes, as exemplified by the PPT-A gene, and may therefore regulate the progression of epileptogenesis. PMID:16828291

  2. Genetic variants in DNA double-strand break repair genes and risk of salivary gland carcinoma: a case-control study.

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    Li Xu

    Full Text Available DNA double strand break (DSB repair is the primary defense mechanism against ionizing radiation-induced DNA damage. Ionizing radiation is the only established risk factor for salivary gland carcinoma (SGC. We hypothesized that genetic variants in DSB repair genes contribute to individual variation in susceptibility to SGC. To test this hypothesis, we conducted a case-control study in which we analyzed 415 single nucleotide polymorphisms (SNPs in 45 DSB repair genes in 352 SGC cases and 598 controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs and 95% confidence intervals (CIs. Rs3748522 in RAD52 and rs13180356 in XRCC4 were significantly associated with SGC after Bonferroni adjustment; ORs (95% CIs for the variant alleles of these SNPs were 1.71 (1.40-2.09, P = 1.70 × 10(-7 and 0.58 (0.45-0.74, P = 2.00 × 10(-5 respectively. The genetic effects were modulated by histological subtype. The association of RAD52-rs3748522 with SGC was strongest for mucoepidermoid carcinoma (OR = 2.21, 95% CI: 1.55-3.15, P = 1.25 × 10(-5, n = 74, and the association of XRCC4-rs13180356 with SGC was strongest for adenoid cystic carcinoma (OR = 0.60, 95% CI: 0.42-0.87, P = 6.91 × 10(-3, n = 123. Gene-level association analysis revealed one gene, PRKDC, with a marginally significant association with SGC risk in non-Hispanic whites. To our knowledge, this study is the first to comprehensively evaluate the genetic effect of DSB repair genes on SGC risk. Our results indicate that genetic variants in the DSB repair pathways contribute to inter-individual differences in susceptibility to SGC and show that the impact of genetic variants differs by histological subtype. Independent studies are warranted to confirm these findings.

  3. Resequencing of genes for transforming growth factor β1 (TGFB1 type 1 and 2 receptors (TGFBR1, TGFBR2, and association analysis of variants with diabetic nephropathy

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    Patterson Chris C

    2007-02-01

    Full Text Available Abstract Background Diabetic nephropathy is the leading cause of end stage renal failure in the western world. There is substantial epidemiological evidence supporting a genetic predisposition to diabetic nephropathy, however the exact molecular mechanisms remain unknown. Transforming growth factor (TGFβ1 is a crucial mediator in the pathogenesis of diabetic nephropathy. Methods We investigated the role of five known single nucleotide polymorphisms (SNPs in the TGFB1 gene for their association with diabetic nephropathy in an Irish, type 1 diabetic case (n = 272 control (n = 367 collection. The activity of TGFβ1 is facilitated by the action of type 1 and type 2 receptors, with both receptor genes (TGFBR1 and TGFBR2 shown to be upregulated in diabetic kidney disease. We therefore screened TGFBR1 and TGFBR2 genes for genomic variants using WAVE™ (dHPLC technology and confirmed variants by direct capillary sequencing. Allele frequencies were determined in forty-eight healthy individuals. Data for all SNPs was assessed for Hardy Weinberg equilibrium, with genotypes and allele frequencies compared using the χ2 test for contingency tables. Patterns of linkage disequilibrium were established and common haplotypes estimated. Results Fifteen variants were identified in these genes, seven of which are novel, and putatively functional SNPs were subsequently genotyped using TaqMan™, Invader™ or Pyrosequencing® technology. No significant differences (p > 0.1 were found in genotype or allele distributions between cases and controls for any of the SNPs assessed. Conclusion Our results suggest common variants in TGFB1, TGFBR1 and TGFBR2 genes do not strongly influence genetic susceptibility to diabetic nephropathy in an Irish Caucasian population.

  4. Variants in multiple genes polymorphism association analysis of COPD in the Chinese Li population

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    Ding Y

    2015-07-01

    Full Text Available Yipeng Ding,1,* Danlei Yang,2,3,* Long Zhou,4 Junxu Xu,5 Yu Chen,5 Ping He,1 Jinjian Yao,1 Jiannan Chen,1 Huan Niu,1 Pei Sun,1 Tianbo Jin4 1Department of Emergency, People’s Hospital of Hainan Province, Haikou, Hainan, 2Department of Respiratory and Critical Care Medicine, Tongji Hospital, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Medical College, 3Department of Science and Technology, Huazhong University, Wuhan, 4School of Life Sciences, Northwest University, Xi’an, 5Department of Respiration Emergency, The Third People’s Hospital of Haikou, Haikou, Hainan, People’s Republic of China *These authors contributed equally to this work Background: It is known that the contribution of risk alleles to chronic obstructive pulmonary disease (COPD may vary between populations. Further, previous studies involving various ethnic groups have revealed associations between COPD and genetic polymorphisms in families with sequence similarity 13, member A (FAM13A, micro-RNA 2054 (MIR2054, SET domain containing protein 7 (SETD7, ring finger protein 150 (RNF150, hedgehog interacting protein (HHIP, and vascular endothelial growth factor A (VEGFA. Our objective was to explore the association between these gene polymorphism and COPD in members of Chinese Li minority population.Materials and methods: The Chinese Li population case–control study was conducted to assess genetic associations with COPD risk. Seven single nucleotide polymorphisms (SNPs located on chromosome 4, including FAM13A, MIR2054, SETD7, RNF150, and HHIP, and nine SNPs in the VEGFA gene were genotyped among 234 cases and 240 controls using Sequenom Mass-ARRAY® platform. Linkage disequilibrium (LD analysis was performed using Haploview software and the associations of the SNP frequencies with COPD were analyzed using chi-square (χ2 tests, genetic models analysis, and haplotype analysis.Results: By χ2 we found the minor allele “G” of rs17050782 was with increased

  5. Gender differences in associations of glutamate decarboxylase 1 gene (GAD1 variants with panic disorder.

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    Heike Weber

    Full Text Available BACKGROUND: Panic disorder is common (5% prevalence and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. METHODOLOGY/PRINCIPAL FINDINGS: Nineteen single nucleotide polymorphisms (SNPs tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584. Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165 in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. CONCLUSIONS/SIGNIFICANCE: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.

  6. Role of 5-HT2C receptor gene variants in antipsychotic-induced weight gain

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    Brandl EJ

    2011-08-01

    Full Text Available Tessa JM Wallace, Clement C Zai, Eva J Brandl, Daniel J MüllerNeurogenetics Section, Center for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, CanadaAbstract: Antipsychotic-induced weight gain is a serious side effect of antipsychotic medication that can lead to increased morbidity, mortality, and non-compliance in patients. Numerous single nucleotide polymorphisms have been studied for association with antipsychotic-induced weight gain in an attempt to find genetic predictors of this side effect. An ability to predict this side effect could lead to personalized treatment plans for predisposed individuals, which could significantly decrease the prevalence and severity of weight gain. Variations in the serotonin receptor 2c gene (HTR2C have emerged as promising candidates for prediction of antipsychotic-induced weight gain. Specifically, the well-studied -759C/T promoter polymorphism has been associated with weight gain in diverse populations, although some studies have reported no association. This discrepancy is likely due to heterogeneity in study design with respect to ethnicity, treatment duration, and other variables. Notably, the association between HTR2C and antipsychotic-induced weight gain appears strongest in short-term studies on patients with limited or no previous antipsychotic treatment. Other, less extensively studied promoter polymorphisms (-697C/G, -997G/A, and -1165A/G have also emerged as potential predictors of antipsychotic-induced weight gain. Conversely, the well-studied intronic polymorphism Cys23Ser does not appear to be associated. With further research on both HTR2C and other genetic and environmental predictors of antipsychotic-induced weight gain, a predictive test could one day be created to screen patients and provide preventative or alternative treatment for those who are predisposed to this serious side effect.Keywords: HTR2C, pharmacogenomics, promoter polymorphism

  7. Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern.

    Directory of Open Access Journals (Sweden)

    Moisés Selman

    Full Text Available BACKGROUND: Idiopathic pulmonary fibrosis (IPF is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of "rapid" and "slow" progressors with IPF. METHODS AND FINDINGS: 26 patients with 24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006 and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04 in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238+/-98% versus 123+/-29% (p<0.05 and 30+/-17% (p<0.01]. CONCLUSIONS/SIGNIFICANCE: A subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.

  8. Moringa oleifera Gold Nanoparticles Modulate Oncogenes, Tumor Suppressor Genes, and Caspase-9 Splice Variants in A549 Cells.

    Science.gov (United States)

    Tiloke, Charlette; Phulukdaree, Alisa; Anand, Krishnan; Gengan, Robert M; Chuturgoon, Anil A

    2016-10-01

    Gold nanoparticles (AuNP's) facilitate cancer cell recognition and can be manufactured by green synthesis using nutrient rich medicinal plants such as Moringa oleifera (MO). Targeting dysregulated oncogenes and tumor suppressor genes is crucial for cancer therapeutics. We investigated the antiproliferative effects of AuNP synthesized from MO aqueous leaf extracts (MLAuNP ) in A549 lung and SNO oesophageal cancer cells. A one-pot green synthesis technique was used to synthesise MLAuNP . A549, SNO cancer cells and normal peripheral blood mononuclear cells (PBMCs) were exposed to MLAuNP and CAuNP to evaluate cytotoxicity (MTT assay); apoptosis was measured by phosphatidylserine (PS) externalization, mitochondrial depolarization (ΔΨm) (flow cytometry), caspase-3/7, -9 activity, and ATP levels (luminometry). The mRNA expression of c-myc, p53, Skp2, Fbw7α, and caspase-9 splice variants was determined using qPCR, while relative protein expression of c-myc, p53, SRp30a, Bax, Bcl-2, Smac/DIABLO, Hsp70, and PARP-1 were determined by Western blotting. MLAuNP and CAuNP were not cytotoxic to PBMCs, whilst its pro-apoptotic properties were confirmed in A549 and SNO cells. MLAuNP significantly increased caspase activity in SNO cells while MLAuNP significantly increased PS externalization, ΔΨm, caspase-9, caspase-3/7 activities, and decreased ATP levels in A549 cells. Also, p53 mRNA and protein levels, SRp30a (P = 0.428), Bax, Smac/DIABLO and PARP-1 24 kDa fragment levels were significantly increased. Conversely, MLAuNP significantly decreased Bcl-2, Hsp70, Skp2, Fbw7α, c-myc mRNA, and protein levels and activated alternate splicing with caspase-9a splice variant being significantly increased. MLAuNP possesses antiproliferative properties and induced apoptosis in A549 cells by activating alternate splicing of caspase-9. J. Cell. Biochem. 117: 2302-2314, 2016. © 2016 Wiley Periodicals, Inc. PMID:26923760

  9. Common Variants in the ATP2B1 Gene Are Associated With Susceptibility to Hypertension

    Science.gov (United States)

    Tabara, Yasuharu; Kohara, Katsuhiko; Kita, Yoshikuni; Hirawa, Nobuhito; Katsuya, Tomohiro; Ohkubo, Takayoshi; Hiura, Yumiko; Tajima, Atsushi; Morisaki, Takayuki; Miyata, Toshiyuki; Nakayama, Tomohiro; Takashima, Naoyuki; Nakura, Jun; Kawamoto, Ryuichi; Takahashi, Norio; Hata, Akira; Soma, Masayoshi; Imai, Yutaka; Kokubo, Yoshihiro; Okamura, Tomonori; Tomoike, Hitonobu; Iwai, Naoharu; Ogihara, Toshio; Inoue, Itsuro; Tokunaga, Katsushi; Johnson, Toby; Caulfield, Mark; Munroe, Patricia; Umemura, Satoshi; Ueshima, Hirotsugu; Miki, Tetsuro

    2016-01-01

    Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10−5; allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10−11). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10−4). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10−18). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10−7) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. PMID:20921432

  10. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Lawrenson, Kate; Iversen, Edwin S; Tyrer, Jonathan;

    2015-01-01

    Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair...

  11. Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization

    NARCIS (Netherlands)

    van der Velde, K. Joeri; Kuiper, Joel; Thompson, Bryony A.; Plazzer, John-Paul; van Valkenhoef, Gert; de Haan, Mark; Jongbloed, Jan D. H.; Wijmenga, Cisca; de Koning, Tom J.; Abbott, Kristin M.; Sinke, Richard; Spurdle, Amanda B.; Macrae, Finlay; Genuardi, Maurizio; Sijmons, Rolf H.; Swertz, Morris A.

    2015-01-01

    Next-generation sequencing in clinical diagnostics is providing valuable genomic variant data, which can be used to support healthcare decisions. In silico tools to predict pathogenicity are crucial to assess such variants and we have evaluated a new tool, Combined Annotation Dependent Depletion (CA

  12. Analysis of coding variants in the betacellulin gene in type 2 diabetes and insulin secretion in African American subjects

    Directory of Open Access Journals (Sweden)

    Karim Mohammad A

    2006-07-01

    Full Text Available Abstract Background Betacellulin is a member of the epidermal growth factor family, expressed at the highest levels predominantly in the pancreas and thought to be involved in islet neogenesis and regeneration. Nonsynonymous coding variants were reported to be associated with type 2 diabetes in African American subjects. We tested the hypotheses that these previously identified variants were associated with type 2 diabetes in African Americans ascertained in Arkansas and that they altered insulin secretion in glucose tolerant African American subjects. Methods We typed three variants, exon1 Cys7Gly (C7G, exon 2 Leu44Phe (L44F, and exon 4 Leu124Met (L124M, in 188 control subjects and 364 subjects with type 2 diabetes. We tested for altered insulin secretion in 107 subjects who had undergone intravenous glucose tolerance tests to assess insulin sensitivity and insulin secretion. Results No variant was associated with type 2 diabetes, and no variant altered insulin secretion or insulin sensitivity. However, an effect on lipids was observed for all 3 variants, and variant L124M was associated with obesity measures. Conclusion We were unable to confirm a role for nonsynonymous variants of betacellulin in the propensity to type 2 diabetes or to impaired insulin secretion.

  13. Human CRF2 α and β splice variants: pharmacological characterization using radioligand binding and a luciferase gene expression assay

    International Nuclear Information System (INIS)

    Corticotropin releasing factor (CRF) receptors belong to the super-family of G protein-coupled receptors. These receptors are classified into two subtypes (CRF1 and CRF2). Both receptors are positively coupled to adenylyl cyclase but they have a distinct pharmacology and distribution in brain. Two isoforms belonging to the CRF2 subtype receptors, CRF2α and CRF2β, have been identified in rat and man. The neuropeptides CRF and urocortin mediate their actions through this CRF G protein-coupled receptor family. In this report, we describe the pharmacological characterization of the recently identified hCRF2β receptor. We have used radioligand binding with [125I]-tyr0-sauvagine and a gene expression assay in which the firefly luciferase gene expression is under the control of cAMP responsive elements. Association kinetics of [125I]-tyr0-sauvagine binding to the hCRF2β receptor were monophasic while dissociation kinetics were biphasic, in agreement with the kinetics results obtained with the hCRF2α receptor. Saturation binding analysis revealed two affinity states in HEK 293 cells with binding parameters in accord with those determined kinetically and with parameters obtained with the hCRF2α receptor. A non-hydrolysable GTP analog, Gpp(NH)p, reduced the high affinity binding of [125I]-tyr0-sauvagine to both hCRF2 receptor isoforms in a similar manner. The rank order of potency of CRF agonist peptides in competition experiments was identical for both hCRF2α-helical CRF(9-41)oCRF). Similarly, agonist potency was similar for the two isoforms when studied using the luciferase gene reporter system. The peptide antagonist α-helical CRF(9-41) exhibited a non-competitive antagonism of urocortin-stimulated luciferase expression with both hCRF2 receptor isoforms. Taken together, these results indicate that the pharmacological profiles of the CRF2 splice variants are identical. This indicates that the region of the N-terminus that varies between the receptors is probably

  14. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer.

    Science.gov (United States)

    Ayub, Tiyasha H; Keyver-Paik, Mignon-Denise; Debald, Manuel; Rostamzadeh, Babak; Thiesler, Thore; Schröder, Lars; Barchet, Winfried; Abramian, Alina; Kaiser, Christina; Kristiansen, Glen; Kuhn, Walther; Kübler, Kirsten

    2015-06-30

    Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes. PMID:25999351

  15. Recombinant interferon gamma augments phagocyte superoxide production and X-chronic granulomatous disease gene expression in X-linked variant chronic granulomatous disease.

    OpenAIRE

    Ezekowitz, R A; Orkin, S H; Newburger, P E

    1987-01-01

    We examined the potential of interferon gamma (IFN-gamma) to ameliorate the physiologic defect of chronic granulomatous disease (CGD) by studying its effects on CGD phagocyte superoxide generation, NADPH oxidase kinetics, cytochrome b559 content, and expression of X-CGD (the gene for the X-linked disease). Granulocytes and macrophages from three patients in two kindreds with "variant" X-linked CGD (i.e., with very low, but detectable, baseline superoxide-generating activity) responded to IFN-...

  16. A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study

    Directory of Open Access Journals (Sweden)

    E. Dounousi

    2016-01-01

    Full Text Available Background. Oxidative stress is a hallmark of CKD and this alteration is strongly implicated in LV hypertrophy and in LV dysfunction. Methods and Patients. We resorted to the strongest genetic biomarker of paraoxonase-1 (PON1 activity, the Q192R variant in the PON1 gene, to unbiasedly assess (Mendelian randomization the cross-sectional and longitudinal association of this gene-variant with LV mass and function in 206 CKD patients with a 3-year follow-up. Results. The R allele of Q192R polymorphism associated with oxidative stress as assessed by plasma 8-isoPGF2α (P=0.03 and was dose-dependently related in a direct fashion to LVMI (QQ: 131.4 ± 42.6 g/m2; RQ: 147.7 ± 51.1 g/m2; RR: 167.3 ± 41.9 g/m2; P=0.001 and in an inverse fashion to systolic function (LV Ejection Fraction (QQ: 79 ± 12%; RQ: 69 ± 9%; RR: 65 ± 10% P=0.002. On longitudinal observation, this gene variant associated with the evolution of the same echocardiographic indicators [LVMI: 13.40 g/m2 per risk allele, P=0.005; LVEF: −2.96% per risk allele, P=0.001]. Multivariate analyses did not modify these associations. Conclusion. In CKD patients, the R allele of the Q192R variant in the PON1 gene is dose-dependently related to the severity of LVH and LV dysfunction and associates with the longitudinal evolution of these cardiac alterations. These results are compatible with the hypothesis that oxidative stress is implicated in cardiomyopathy in CKD patients.

  17. Analysis of the interferon gamma (rs2430561, +874T/A) functional gene variant in relation to the presence of cardiovascular events in rheumatoid arthritis

    OpenAIRE

    Mercedes García-Bermúdez; Raquel López-Mejías; Carlos González-Juanatey; Alfonso Corrales; Gema Robledo; Santos Castañeda; Miranda-Filloy, José A.; Ricardo Blanco; Benjamín Fernández-Gutiérrez; Alejandro Balsa; Isidoro González-Alvaro; Carmen Gómez-Vaquero; Javier Llorca; Javier Martín; Miguel A. González-Gay

    2012-01-01

    Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) morbidity and mortality. Since interferon-gamma (IFN-γ) has a direct effect on inflammation, in this study we assessed the potential association of the IFNG functional gene variant rs2430561 with CV disease in patients with RA. Methods: One thousand six hundred and thirty-five patients fulfilling the 1987 American College of Rheumatology classification criteria for RA were geno...

  18. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease

    OpenAIRE

    Ward, Lucas D.; Kellis, Manolis

    2015-01-01

    More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. This has increased the urgency of understanding the regulatory genome as a key component for translating genetic results into mechanistic insights and ultimately therapeutics. To address this challenge, we developed HaploReg (http://compbio.mit.edu/HaploReg) to aid the functional dissection of genome-wide association study (GWAS) results, the ...

  19. The Association of a Variant in the Cell Cycle Control Gene CCND1 and Obesity on the Development of Asthma in the Swiss SAPALDIA Study

    OpenAIRE

    Thun, Gian Andri; Imboden, Medea; Berger, Wolfgang; Rochat, Thierry; Probst-Hensch, Nicole M

    2013-01-01

    OBJECTIVE: The molecular mechanisms underlying the association between obesity (BMI ≥ 30 kg/m(2)) and asthma are poorly understood. Since shifts in the fate of bronchial cells due to low-grade systemic inflammation may provide a possible explanation, we investigated whether two of the best documented functional variants in cell cycle control genes modify the obesity-asthma association. METHODS: We genotyped 5930 SAPALDIA cohort participants for the single-nucleotide polymorphisms (SNPs) rs...

  20. Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial

    OpenAIRE

    Langefeld, Carl D.; Divers, Jasmin; Nicholas M. Pajewski; Hawfield, Amret T.; Reboussin, David M.; Bild, Diane E.; Kaysen, George A.; Kimmel, Paul L; Raj, Dominic; Ricardo, Ana C.; Wright, Jackson T; Sedor, John R.; Rocco, Michael V.; Freedman, Barry I.

    2014-01-01

    Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans. Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2,571 African Americans from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logist...

  1. IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents

    OpenAIRE

    E. M. Queiroz; Cândido, A.P.C.; CASTRO I.M.; A.Q.A. Bastos; Machado-Coelho, G. L. L.; Freitas, R.N.

    2015-01-01

    Association studies of genetic variants and obesity and/or obesity-related risk factors have yielded contradictory results. The aim of the present study was to determine the possible association of five single-nucleotide polymorphisms (SNPs) located in the IGF2, LEPR, POMC, PPARG, and PPARGC1 genes with obesity or obesity-related risk phenotypes. This case-control study assessed overweight (n=192) and normal-weight (n=211) children and adolescents. The SNPs were analyzed using minisequencing ...

  2. A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study

    Science.gov (United States)

    Bouba, I.; Spoto, B.; Pappas, K.; Tripepi, G.; Georgiou, I.; Tselepis, A.; Elisaf, M.; Tsakiris, D.; Zoccali, C.; Siamopoulos, K.

    2016-01-01

    Background. Oxidative stress is a hallmark of CKD and this alteration is strongly implicated in LV hypertrophy and in LV dysfunction. Methods and Patients. We resorted to the strongest genetic biomarker of paraoxonase-1 (PON1) activity, the Q192R variant in the PON1 gene, to unbiasedly assess (Mendelian randomization) the cross-sectional and longitudinal association of this gene-variant with LV mass and function in 206 CKD patients with a 3-year follow-up. Results. The R allele of Q192R polymorphism associated with oxidative stress as assessed by plasma 8-isoPGF2α (P = 0.03) and was dose-dependently related in a direct fashion to LVMI (QQ: 131.4 ± 42.6 g/m2; RQ: 147.7 ± 51.1 g/m2; RR: 167.3 ± 41.9 g/m2; P = 0.001) and in an inverse fashion to systolic function (LV Ejection Fraction) (QQ: 79 ± 12%; RQ: 69 ± 9%; RR: 65 ± 10% P = 0.002). On longitudinal observation, this gene variant associated with the evolution of the same echocardiographic indicators [LVMI: 13.40 g/m2 per risk allele, P = 0.005; LVEF: −2.96% per risk allele, P = 0.001]. Multivariate analyses did not modify these associations. Conclusion. In CKD patients, the R allele of the Q192R variant in the PON1 gene is dose-dependently related to the severity of LVH and LV dysfunction and associates with the longitudinal evolution of these cardiac alterations. These results are compatible with the hypothesis that oxidative stress is implicated in cardiomyopathy in CKD patients.

  3. ALDH2 Genotype Has No Effect on Salivary Acetaldehyde without the Presence of Ethanol in the Systemic Circulation

    OpenAIRE

    Helminen, Andreas; Väkeväinen, Satu; Salaspuro, Mikko

    2013-01-01

    Background Acetaldehyde associated with alcoholic beverages was recently classified as carcinogenic (Group 1) to humans based on uniform epidemiological and biochemical evidence. ALDH2 (aldehyde dehydrogenase 2) deficient alcohol consumers are exposed to high concentrations of salivary acetaldehyde and have an increased risk of upper digestive tract cancer. However, this interaction is not seen among ALDH2 deficient non-drinkers or rare drinkers, regardless of their smoking status or consumpt...

  4. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.

    Science.gov (United States)

    Ward, Lucas D; Kellis, Manolis

    2016-01-01

    More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. This has increased the urgency of understanding the regulatory genome as a key component for translating genetic results into mechanistic insights and ultimately therapeutics. To address this challenge, we developed HaploReg (http://compbio.mit.edu/HaploReg) to aid the functional dissection of genome-wide association study (GWAS) results, the prediction of putative causal variants in haplotype blocks, the prediction of likely cell types of action, and the prediction of candidate target genes by systematic mining of comparative, epigenomic and regulatory annotations. Since first launching the website in 2011, we have greatly expanded HaploReg, increasing the number of chromatin