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Sample records for asthma susceptibility gene

  1. Mapping and localization of susceptible genes in asthma

    Institute of Scientific and Technical Information of China (English)

    GU Ming-liang; ZHAO Jing

    2011-01-01

    Objective To elucidate the development of mapping and localization of susceptible genes on chromosomes to asthma related phenotypes.Data sources Published articles about susceptibility genes for asthma related phenotypes were selected using PubMed.Study selection Using methods of candidate gene positional clone and genome-wide scan with linkage and association analysis to determine the location in the genome of susceptibility genes to asthma and asthma related phenotypes.Results There are multiple regions in the genome harboring susceptibility genes to asthma and asthma relatedphenotypes, including chromosomes 5, 11, 12, 6, 2, 3, 13, 7, 14, 9, 19 and 17. Many of these regions contain candidate genes involved in asthma development and progression. Some susceptible genes may affect the phenotype expression or response to therapy. In addition, the interaction of multiple genes with the environment may contribute to the susceptibility to asthma.Conclusions As an essential step toward cloning the susceptible genes to asthma, fine mapping and localization onchromosomes are definitely needed. Novel powerful tools for gene discovery and the integration of genetics, biology and bioinformatics should be pursued.

  2. Asthma susceptible genes in Chinese population: A meta-analysis

    Directory of Open Access Journals (Sweden)

    He Chao

    2010-09-01

    Full Text Available Abstract Background Published data regarding the associations between genetic variants and asthma risk in Chinese population were inconclusive. The aim of this study was to investigate asthma susceptible genes in Chinese population. Methods The authors conducted 18 meta-analyzes for 18 polymorphisms in 13 genes from eighty-two publications. Results Seven polymorphisms were found being associated with risk of asthma, namely: A Disintegrin and Metalloprotease 33 (ADAM33 T1-C/T (odds ratio [OR] = 6.07, 95% confidence interval [CI]: 2.69-13.73, Angiotensin-Converting Enzyme (ACE D/I (OR = 3.85, 95%CI: 2.49-5.94, High-affinity IgE receptor β chain (FcεRIβ -6843G/A (OR = 1.49, 95%CI: 1.01-2.22, Interleukin 13(IL-13 -1923C/T (OR = 2.99, 95%CI: 2.12-4.24, IL-13 -2044A/G (OR = 1.49, 95%CI: 1.07-2.08, Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES -28C/G (OR = 1.64, 95%CI: 1.09-2.46, Tumor Necrosis Factor-α (TNF-α -308G/A(OR = 1.42, 95%CI: 1.09, 1.85. After subgroup analysis by age, the ACE D/I, β2-Adrenergic Receptor (β2-AR -79G/C, TNF-α -308G/A, Interleukin 4 receptor(IL-4R -1902G/A and IL-13 -1923C/T polymorphisms were found significantly associated with asthma risk in Chinese children. In addition, the ACE D/I, FcεRIβ -6843G/A, TNF-α -308G/A, IL-13 -1923C/T and IL-13 -2044A/G polymorphisms were associated with asthma risk in Chinese adults. Conclusion ADAM33, FcεRIβ, RANTES, TNF-α, ACE, β2-AR, IL-4R and IL-13 genes could be proposed as asthma susceptible genes in Chinese population. Given the limited number of studies, more data are required to validate these associations.

  3. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women

    NARCIS (Netherlands)

    Berube, Jean-Christophe; Gaudreault, Nathalie; Lavoie-Charland, Emilie; Sbarra, Laura; Henry, Cyndi; Madore, Anne-Marie; Pare, Peter D.; van den Berge, Maarten; Nickle, David; Laviolette, Michel; Laprise, Catherine; Boulet, Louis-Philippe; Bosse, Yohan

    2016-01-01

    Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study

  4. Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation

    DEFF Research Database (Denmark)

    White, Julia H; Chiano, Mathias; Wigglesworth, Mark

    2008-01-01

    Asthma is a multifactorial disease, in which the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Using a genome-wide scan for linkage in a population comprising of Danish families, we identified a novel linked locus on chromosome 1qter...... (LOD 3.6, asthma) and supporting evidence for this locus was identified for both asthma and atopic-asthma phenotypes in the GAIN (Genetics of Asthma International Network) families. The putative susceptibility gene was progressively localized to a 4.5 Mb region on chromosome 1q adjacent to the telomere...... and CHML genes wholly accounted for the original linkage in the Danish population and the genetic association was also confirmed in two separate studies involving the GAIN families. OPN3 and CHML are unique genes with no known function that are related to the pathophysiology of asthma. Significantly...

  5. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women.

    Science.gov (United States)

    Bérubé, Jean-Christophe; Gaudreault, Nathalie; Lavoie-Charland, Emilie; Sbarra, Laura; Henry, Cyndi; Madore, Anne-Marie; Paré, Peter D; van den Berge, Maarten; Nickle, David; Laviolette, Michel; Laprise, Catherine; Boulet, Louis-Philippe; Bossé, Yohan

    2016-01-01

    Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL) mapping study (n = 1035). Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P = 7.90E - 10). The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients.

  6. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women

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    Jean-Christophe Bérubé

    2016-01-01

    Full Text Available Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL mapping study (n=1035. Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P=7.90E-10. The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients.

  7. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women

    Science.gov (United States)

    Bérubé, Jean-Christophe; Gaudreault, Nathalie; Lavoie-Charland, Emilie; Sbarra, Laura; Henry, Cyndi; Madore, Anne-Marie; Paré, Peter D.; van den Berge, Maarten; Nickle, David; Laviolette, Michel; Laprise, Catherine; Boulet, Louis-Philippe; Bossé, Yohan

    2016-01-01

    Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL) mapping study (n = 1035). Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P = 7.90E − 10). The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients. PMID:27445529

  8. Asthma and atopy - a total genome scan for susceptibility genes

    DEFF Research Database (Denmark)

    Haagerup, A; Bjerke, T; Schiøtz, P O;

    2002-01-01

    atopy, allergic asthma and increased total IgE. We performed a total genome scan using 446 microsatellite markers and obtained nonparametric linkage results from the MAPMAKER/SIBS computer program. RESULTS: Our study revealed four candidate regions (MLS > 2) on chromosome 1p36, 3q21-q22, 5q31 and 6p24-p...

  9. Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

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    Alexey V. Polonikov

    2014-01-01

    Full Text Available Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE. We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase and PON2 (paraoxonase 2 as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma.

  10. Novel Gentic Variations Contributing to Asthma Susceptability in Saudi Arabia

    Science.gov (United States)

    2014-04-13

    Collection of Clinical Data That Will be Used in This Study and Will Form a Data Bank for Asthma in Saudi Arabia; Identify Known and NOVEL Genetic Risk Factors Contributing to Asthma Susceptibility; Study the Mechanistic Roles of the Genetic Variants Within Major Asthma Susceptibility Genes

  11. Association between HLA-DQA1, -DQB1 gene polymorphisms and susceptibility to asthma in northern Chinese subjects

    Institute of Scientific and Technical Information of China (English)

    高金明; 林耀广; 邱长春; 刘怡雯; 马毅; 刘英

    2003-01-01

    Objective Human leukocyte antigen (HLA) class Ⅱ genes, especially HLA-DQ genes, which are highly polymorphic, have been thought to be candidate loci for the etiology of asthma, and shown to be involved in antigenic presentation. This study was conducted to investigate whether susceptibility or resistance to asthma is associated with HLA-DQA1 and DQB1 genes polymorphism.Methods Venous blood samples were collected from northern Chinese population with Han ethnic. (1) One hundred and twenty-five unrelated asthmatic individuals and 52 subjects from 12 asthmatic pedigrees. (2) Ninety-six healthy controls without asthma and atopy with the same ethnic. Genomic DNA was extracted using standard phenol-chloroform method. The second exon of HLA-DQA1 and DQB1 genes were amplified by sequence-specific primer-polymerase chain reaction (SSP-PCR) method. All asthmatics had their serum IgE (total and specific) antibody or skin-prick test measured, bronchial reactivity to methacholine (Mch) and bronchial reversibility by β2-agonist evaluated.Results HLA-DQA1*0104 allele and HLA-DQB1*0201 allele were significantly higher in asthmatics than those in healthy controls (0.408 vs 0.177, P<0.01; 0.568 vs 0.198, P<0.01). Odds ratios (ORs) were 3.203 (95% CI 1.699-6.037), 5.328 (95% CI 2.883-9.849) respectively. Conversely, HLA-DQA1*0301 allele and HLA-DQB1*0301 were significantly decreased in asthmatics compared to healthy controls (0.296 vs 0.50, P<0.01; 0.4 vs 0.563, P<0.05); Logistic regression analysis showed that HLA-DQA1*0104 allele was associated independently with asthma etiology, OR [represented by Exp(B)] was 5.0942 with 95% CI 2.2520-21.1813; Spearman's analysis showed that HLA-DQA1*0104 allele and HLA-DQB1*0201 allele were positively associated with atopy, the correlation coefficient were 0.183 and 0.289 respectively, P<0.01. By contrast, HLA-DQA1*0301 allele was negatively related to atopy, the correlation coefficient was -0.168, P<0.05; linkage analysis did not support the

  12. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication.

    Science.gov (United States)

    Bochkov, Yury A; Watters, Kelly; Ashraf, Shamaila; Griggs, Theodor F; Devries, Mark K; Jackson, Daniel J; Palmenberg, Ann C; Gern, James E

    2015-04-28

    Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared with other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3) enables the cells normally unsusceptible to RV-C infection to support both virus binding and replication. A coding single nucleotide polymorphism (rs6967330, C529Y) was previously linked to greater cell-surface expression of CDHR3 protein, and an increased risk of wheezing illnesses and hospitalizations for childhood asthma. Compared with wild-type CDHR3, cells transfected with the CDHR3-Y529 variant had about 10-fold increases in RV-C binding and progeny yields. We developed a transduced HeLa cell line (HeLa-E8) stably expressing CDHR3-Y529 that supports RV-C propagation in vitro. Modeling of CDHR3 structure identified potential binding sites that could impact the virus surface in regions that are highly conserved among all RV-C types. Our findings identify that the asthma susceptibility gene product CDHR3 mediates RV-C entry into host cells, and suggest that rs6967330 mutation could be a risk factor for RV-C wheezing illnesses.

  13. Identifying novel genes contributing to asthma pathogenesis

    NARCIS (Netherlands)

    Holloway, John W.; Koppelman, Gerard H.

    2007-01-01

    Purpose of review To illustrate recent examples of novel asthma genes such as those encoding G-protein-coupled receptor for asthma susceptibility, filaggrin and tenascin-C, and to describe the process that is needed to translate these findings to the clinic. Recent findings Many hundreds of studies

  14. Interleukin 18 receptor 1 gene polymorphisms are associated with asthma

    DEFF Research Database (Denmark)

    Zhu, Guohua; Whyte, Moira K B; Vestbo, Jørgen;

    2008-01-01

    The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined...... by genotyping seven SNPs in 294, 342 and 100 families from Denmark, United Kingdom and Norway and conducting family-based association analyses for asthma, atopic asthma and bronchial hyper-reactivity (BHR) phenotypes. Three SNPs in IL18R1 were associated with asthma (0.01131 ... in IL18R1 and asthma....

  15. Vitamin D binding protein variants associate with asthma susceptibility in the Chinese han population

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    Zhang Youming

    2011-08-01

    Full Text Available Abstract Background Asthma is a genetically heterogeneous disease. Polymorphisms of genes encoding components of the vitamin D pathway have been reported to associate with the risk of asthma. We have previously demonstrated that vitamin D status was associated with lung function in Chinese asthma patients. In this study, we tested whether polymorphisms of genes encoding for vitamin D receptor (VDR, vitamin D 25-hydroxylase (CYP2R1 and vitamin D binding protein (GC were associated with asthma in the Chinese Han population. Methods We sequenced all 8 exons of VDR and all 5 exons of CYP2R1 in a Chinese case-control cohort of asthma consisting of 467 cases and 288 unrelated healthy controls. Two mutations were identified in these regions. These variants were specified as rs2228570 in exon 2 of VDR and rs12794714 in exon 1 of CYP2R1. We also genotyped two common polymorphisms in GC gene (rs4588 and rs7041 by a PCR-restriction fragment length polymorphism (RFLP method. We analyzed the association between these 4 polymorphisms and asthma susceptibility and asthma-related traits. Results Polymorphic markers in VDR and CYP2R1 were not associated with asthma in the Chinese Han cohort. Importantly, variants in GC gene, which give rise to the two most common electrophoretic isoforms of the vitamin D binding protein, were associated with asthma susceptibility. Compared with isoform Gc1, Gc2 was significantly associated with the risk of asthma (OR = 1.35, 95% CI = 1.01-1.78 p = 0.006. Conclusions The results provide supporting evidence for association between GC variants and asthma susceptibility in the Chinese Han population.

  16. Susceptibility Factors Relevant for the Association Between Long-Term Air Pollution Exposure and Incident Asthma.

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    Burte, Emilie; Nadif, Rachel; Jacquemin, Bénédicte

    2016-03-01

    In this review, we identified 15 studies in children and 10 studies in adults that assessed the association between long-term exposure to air pollution and incident asthma and that conducted stratified analyses to explore potential susceptibility factors. Overall, adult never-/former smokers seem to be at higher risk of incident asthma due to air pollution. Children without atopy and children from low socioeconomic status families also seem to be at higher risk of incident asthma due to air pollution. While interaction between air pollution and genes involved in the response to oxidative stress pathways have been explored, results are somewhat inconsistent and in need of replication. To evaluate interactions, large sample sizes are necessary, and much more research, including data pooling from existing studies, is needed to further explore susceptibility factors for asthma incidence due to long-term air pollution exposure.

  17. Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.

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    Ming-Wei Su

    Full Text Available BACKGROUND: The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 single-nucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1, the gene coding interleukin-4 receptor alpha chain (IL4Ra and the gene coding insulin induced gene 2 (INSIG2 on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83% with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2, signal transducer and activator of transcription 6 (STAT6. We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance. CONCLUSIONS/SIGNIFICANCE: The results of this study suggest that GSTP1, INSIG2 and IL4Ra may influence the lifetime asthma susceptibility through gene-gene interactions in schoolchildren. Home dampness combined with each one of the genes STAT6, IL13 and ADRB2 could raise the asthma risk.

  18. New insight into genes in association with asthma: literature-based mining and network centrality analysis

    Institute of Scientific and Technical Information of China (English)

    LIANG Rui; WANG Lei; WANG Gang

    2013-01-01

    Background Asthma is a heterogeneous disease for which a strong genetic basis has been firmly established.Until now no studies have been undertaken to systemically explore the network of asthma-related genes using an internally developed literature-based discovery approach.This study was to explore asthma-related genes by using literaturebased mining and network centrality analysis.Methods Literature involving asthma-related genes were searched in PubMed from 2001 to 2011.Integration of natural language processing with network centrality analysis was used to identify asthma susceptibility genes and their interaction network.Asthma susceptibility genes were classified into three functional groups by gene ontology (GO) analysis and the key genes were confirmed by establishing asthma-related networks and pathways.Results Three hundred and twenty-six genes related with asthma such as IGHE (IgE),interleukin (IL)-4,5,6,10,13,17A,and tumor necrosis factor (TNF)-alpha were identified.GO analysis indicated some biological processes (developmental processes,signal transduction,death,etc.),cellular components (non-structural extracellular,plasma membrane and extracellular matrix),and molecular functions (signal transduction activity) that were involved in asthma.Furthermore,22 asthma-related pathways such as the Toll-like receptor signaling pathway,hematopoietic cell lineage,JAK-STAT signaling pathway,chemokine signaling pathway,and cytokine-cytokine receptor interaction,and 17 hub genes,such as JAK3,CCR1-3,CCR5-7,CCR8,were found.Conclusions Our study provides a remarkably detailed and comprehensive picture of asthma susceptibility genes and their interacting network.Further identification of these genes and molecular pathways may play a prominent role in establishing rational therapeutic approaches for asthma.

  19. Interactions between genes and environmental factors in asthma and atopy: new developments

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    Sengler Claudia

    2001-10-01

    Full Text Available Abstract Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.

  20. Data-driven asthma endotypes defined from blood biomarker and gene expression data

    Science.gov (United States)

    The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes) driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-section...

  1. Perinatal Gene-Gene and Gene-Environment Interactions on IgE Production and Asthma Development

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    Jen-Chieh Chang

    2012-01-01

    Full Text Available Atopic asthma is a complex disease associated with IgE-mediated immune reactions. Numerous genome-wide studies identified more than 100 genes in 22 chromosomes associated with atopic asthma, and different genetic backgrounds in different environments could modulate susceptibility to atopic asthma. Current knowledge emphasizes the effect of tobacco smoke on the development of childhood asthma. This suggests that asthma, although heritable, is significantly affected by gene-gene and gene-environment interactions. Evidence has recently shown that molecular mechanism of a complex disease may be limited to not only DNA sequence differences, but also gene-environmental interactions for epigenetic difference. This paper reviews and summarizes how gene-gene and gene-environment interactions affect IgE production and the development of atopic asthma in prenatal and childhood stages. Based on the mechanisms responsible for perinatal gene-environment interactions on IgE production and development of asthma, we formulate several potential strategies to prevent the development of asthma in the perinatal stage.

  2. Leveraging gene-environment interactions and endotypes for asthma gene discovery.

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    Bønnelykke, Klaus; Ober, Carole

    2016-03-01

    Asthma is a heterogeneous clinical syndrome that includes subtypes of disease with different underlying causes and disease mechanisms. Asthma is caused by a complex interaction between genes and environmental exposures; early-life exposures in particular play an important role. Asthma is also heritable, and a number of susceptibility variants have been discovered in genome-wide association studies, although the known risk alleles explain only a small proportion of the heritability. In this review, we present evidence supporting the hypothesis that focusing on more specific asthma phenotypes, such as childhood asthma with severe exacerbations, and on relevant exposures that are involved in gene-environment interactions (GEIs), such as rhinovirus infections, will improve detection of asthma genes and our understanding of the underlying mechanisms. We will discuss the challenges of considering GEIs and the advantages of studying responses to asthma-associated exposures in clinical birth cohorts, as well as in cell models of GEIs, to dissect the context-specific nature of genotypic risks, to prioritize variants in genome-wide association studies, and to identify pathways involved in pathogenesis in subgroups of patients. We propose that such approaches, in spite of their many challenges, present great opportunities for better understanding of asthma pathogenesis and heterogeneity and, ultimately, for improving prevention and treatment of disease.

  3. Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients.

    Science.gov (United States)

    Žavbi, Mateja; Korošec, Peter; Fležar, Matjaž; Škrgat Kristan, Sabina; Marc Malovrh, Mateja; Rijavec, Matija

    2016-06-01

    One of the major asthma susceptibility loci is 17q12-17q21.1, but the relationship between this locus and adult asthma is unclear. Association analysis of 13 single nucleotide polymorphisms (SNPs) and haplotypes from 17q12-17q21.1 was performed in 418 adult patients with asthma and 288 controls from Slovenia. Single SNP analysis revealed only marginal associations with adult asthma for SNPs located in GSDMA, GSDMB, ORMDL3 and ZPBP2 genes, and rs7219080 was the most highly associated. Analyses of asthma phenotypes found no association with atopy or lung function, but rs2305480 and rs8066582 were associated with childhood asthma and rs9916279 was associated with asthma in smokers. Notably, haplotypes consisting of rs9916279, rs8066582, rs1042658, and rs2302777 harbouring PSMD3, CSF3 and MED24 genes were highly associated with asthma. The four most common haplotypes, TCCG, TTTA, CCCA and TTCA, were more frequent in patients with asthma, whereas TTCG, TCCA, TCTA and TTTG were more frequent in controls. Only 3% of asthma patients belonged to haplotypes TTCG, TCCA, TCTA and TTTG compared with nearly one-third (31%) of controls. Associations confirmed that the 17q12-17q21.1 locus harbours a genetic determinant for asthma risk in adults and suggest that in addition to the previously known ORMDL3-GSDM locus, CSF3-PSMD3-MED24 also plays a role in asthma pathogenesis.

  4. A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity.

    Science.gov (United States)

    González, Juan R; Cáceres, Alejandro; Esko, Tonu; Cuscó, Ivon; Puig, Marta; Esnaola, Mikel; Reina, Judith; Siroux, Valerie; Bouzigon, Emmanuelle; Nadif, Rachel; Reinmaa, Eva; Milani, Lili; Bustamante, Mariona; Jarvis, Deborah; Antó, Josep M; Sunyer, Jordi; Demenais, Florence; Kogevinas, Manolis; Metspalu, Andres; Cáceres, Mario; Pérez-Jurado, Luis A

    2014-03-06

    The prevalence of asthma and obesity is increasing worldwide, and obesity is a well-documented risk factor for asthma. The mechanisms underlying this association and parallel time trends remain largely unknown but genetic factors may be involved. Here, we report on a common ~0.45 Mb genomic inversion at 16p11.2 that can be accurately genotyped via SNP array data. We show that the inversion allele protects against the joint occurrence of asthma and obesity in five large independent studies (combined sample size of 317 cases and 543 controls drawn from a total of 5,809 samples; combined OR = 0.48, p = 5.5 × 10(-6)). Allele frequencies show remarkable worldwide population stratification, ranging from 10% in East Africa to 49% in Northern Europe, consistent with discordant and extreme genetic drifts or adaptive selections after human migration out of Africa. Inversion alleles strongly correlate with expression levels of neighboring genes, especially TUFM (p = 3.0 × 10(-40)) that encodes a mitochondrial protein regulator of energy balance and inhibitor of type 1 interferon, and other candidates for asthma (IL27) and obesity (APOB48R and SH2B1). Therefore, by affecting gene expression, the ~0.45 Mb 16p11.2 inversion provides a genetic basis for the joint susceptibility to asthma and obesity, with a population attributable risk of 39.7%. Differential mitochondrial function and basal energy balance of inversion alleles might also underlie the potential selection signature that led to their uneven distribution in world populations.

  5. Susceptibility Genes in Thyroid Autoimmunity

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    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  6. Gene by environment interaction in asthma

    NARCIS (Netherlands)

    Koppelman, Gerard H.

    2006-01-01

    Asthma is a chronic inflammatory disease of the airways that is highly prevalent in the Western world. It is a genetically complex disease caused by multiple genetic and environmental factors, which may interact. Genetic research has recently incorporated environmental factors to investigate gene by

  7. Assessing the validity of asthma associations for eight candidate genes and age at diagnosis effects.

    Directory of Open Access Journals (Sweden)

    María Pino-Yanes

    Full Text Available BACKGROUND: Before the advent of genome-wide association studies (GWAS, ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B, IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: We systematically evaluated 286 common single nucleotide polymorphisms (SNPs of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls. We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R. CONCLUSIONS/SIGNIFICANCE: Our results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.

  8. Evaluation of a partial genome screening of two asthma susceptibility regions using bayesian network based bayesian multilevel analysis of relevance.

    Directory of Open Access Journals (Sweden)

    Ildikó Ungvári

    Full Text Available Genetic studies indicate high number of potential factors related to asthma. Based on earlier linkage analyses we selected the 11q13 and 14q22 asthma susceptibility regions, for which we designed a partial genome screening study using 145 SNPs in 1201 individuals (436 asthmatic children and 765 controls. The results were evaluated with traditional frequentist methods and we applied a new statistical method, called bayesian network based bayesian multilevel analysis of relevance (BN-BMLA. This method uses bayesian network representation to provide detailed characterization of the relevance of factors, such as joint significance, the type of dependency, and multi-target aspects. We estimated posteriors for these relations within the bayesian statistical framework, in order to estimate the posteriors whether a variable is directly relevant or its association is only mediated.With frequentist methods one SNP (rs3751464 in the FRMD6 gene provided evidence for an association with asthma (OR = 1.43(1.2-1.8; p = 3×10(-4. The possible role of the FRMD6 gene in asthma was also confirmed in an animal model and human asthmatics.In the BN-BMLA analysis altogether 5 SNPs in 4 genes were found relevant in connection with asthma phenotype: PRPF19 on chromosome 11, and FRMD6, PTGER2 and PTGDR on chromosome 14. In a subsequent step a partial dataset containing rhinitis and further clinical parameters was used, which allowed the analysis of relevance of SNPs for asthma and multiple targets. These analyses suggested that SNPs in the AHNAK and MS4A2 genes were indirectly associated with asthma. This paper indicates that BN-BMLA explores the relevant factors more comprehensively than traditional statistical methods and extends the scope of strong relevance based methods to include partial relevance, global characterization of relevance and multi-target relevance.

  9. Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility

    DEFF Research Database (Denmark)

    Fedulov, Alexey V; Leme, Adriana; Yang, Zhiping;

    2008-01-01

    Maternal immune responses can promote allergy development in offspring, as shown in a model of increased susceptibility to asthma in babies of ovalbumin (OVA)-sensitized and -challenged mother mice. We investigated whether inflammatory responses to air pollution particles (diesel exhaust particles...... inflammatory responses were evaluated 48 hours after exposure. Offspring of particle- or buffer-treated mothers were sensitized and aerosolized with OVA, followed by assays of airway hyperresponsiveness (AHR) and allergic inflammation (AI). Nonpregnant females had the expected minimal response to "inert" TiO(2......). In contrast, pregnant mice showed robust and persistent acute inflammation after both TiO(2) and DEP. Genomic profiling identified genes differentially expressed in pregnant lungs exposed to TiO(2). Neonates of mothers exposed to TiO(2) (and DEP, but not PBS) developed AHR and AI, indicating that pregnancy...

  10. The PCDH1-gene and asthma in early childhood

    DEFF Research Database (Denmark)

    Mortensen, Li J; Kreiner-Møller, Eskil; Hakonarson, Hakon;

    2014-01-01

    Previous studies suggests that variants in the protocadherin-1 (PCDH1) gene, important for cell-cell adhesion, are associated with asthma, bronchial, hyperresponsiveness and atopic dermatitis in school-children.To associate common variants of the PCDH1-gene to longitudinally assessed asthma......-phenotypes and atopic dermatitis in early childhood.We analysed 8 SNPs in PCDH1 from 411 children born to asthmatic mothers from the Copenhagen Prospective Studies on Asthma in Childhood birth-cohort.Asthma and atopic dermatitis were diagnosed prospectively to age seven and asthma was categorized by temporal pattern...... dermatitis and rs11167761-A (OR=1.85, CI: 1.24-2.75, p=0.0026).Common variations in PCDH1 increase the risk of developing both transient early asthma and atopic dermatitis in early childhood....

  11. Identification and Function of a Novel Candidate Gene for Asthma:ADAM 33

    Directory of Open Access Journals (Sweden)

    John W. Holloway

    2005-01-01

    Full Text Available Asthma is a complex disorder of inflammation and remodelling largely restricted to the conducting airways. It is a disorder where there are major genetics and environmental factors that interact together to initiate and propagate the disease into a chronic relapsing disorder. Until recently the genetic factors involved in disease pathogenesis have been restricted to variants in known molecules involved in the inflammatory or remodelling pathways. In this review evidence is presented for a new susceptibility gene for asthma, ADAM 33, that was identified by positional cloning. It is suggested that ADAM 33 plays a key role in predisposing to reduced lung function and bronchial hyperresponsiveness characteristic of asthma. Through an understanding of the disease-related SNPs(in ADAM 33it may be possible, not only to identify a gene based diagnostic test, but also to focus attention on developing a new treatment that reverses remodelling changes.

  12. Meta-Analysis on the Association of Interleukin-13(IL-13) Gene Polymorphism and the Genetic Susceptibility of Asthma in Chinese Population%中国人群白细胞介素-13基因多态性与哮喘易感性关系的Meta分析

    Institute of Scientific and Technical Information of China (English)

    汤兆明; 王琳; 胡丽华

    2011-01-01

    目的 评价白细胞介素-13基因多态性与中国人群哮喘易感性的关系.方法 检索中文及外文数据库,全面收集2010年8月之前发表的研究中国人群IL-13基因多态性与哮喘相关性的病例对照研究,对采纳的数据进行Meta分析.结果 9篇文献被纳入分析,其中涉及C1923T多态性的文献5篇、G2044A多态性的文献5篇.Meta分析计算合并比值比(95%可信区间):TT/CC基因型为4.15(2.83~6.09,P=0.000);CT/CC基因型为1.97(1.53~2.53,P=0.000);AA/GG基因型为1.92(1.00~3.72,P=0.051);GA/GG基因型为1.44(1.14~1.82,P=0.000).TY/CC、AA/GG、GA/GG研究数据不存在发表偏倚(P值分别为0.175、0.968、0.633);CT/CC研究数据存在发表偏倚(P=0.010).结论 当前的研究支持IL-13+1923位点基因型TT和+2044位点基因型GA是哮喘发病的危险因素,+1923位点基因型CT和+2044位点基因型AA与哮喘发病尚无明确关系.%Objective To investigate the association between Interleukin-13 (IL-13) gene polymorphism and the genetic susceptibility of asthma. Methods Published data relating to case-control studies reporting the link between IL-13 polymorphisms and asthma in Chinese population were retrieved through Chinese Bio-medicine Database(CBM) and PubMed. Meta-analysis was conducted to determine whether the IL-13 gene polymorphisms were associated with asthma.Results Night studies were finally accepted for analysis. There were four studies focused on C1923T polymorphism,and four studies focused on G2044A polymorphism. One study was focused on both polymorphisms. The odds ratio for asthma for TT/CC genotypes was 4.15 (95%CI 2.83~6.09, P=0.000), for CT/CC was 1.97 (95%CI 1.53~2.53, P=0.000). The odds for asthma for AA/GG genotypes was 1.92 (95%CI 1.00~3.72, P=0.051 ) and for GA/GG was 1.44 (95%CI 1.14~1.82, P=0.000). There is a publication bias regarding CT/CC genotype (P=0.010). No significant publication bias was found regarding TT

  13. Association of ADAM33 gene polymorphisms with allergic asthma

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Zand Karimi

    2014-09-01

    Conclusion: Polymorphisms of ADAM33 gene might be associated with severe asthma and sensitivity to aeroallergens in northeast of Iran, but further studies are needed to determine the polymorphisms in this area and other regions of our country.

  14. Evaluation of genetic susceptibility to childhood allergy and asthma in an African American urban population

    Directory of Open Access Journals (Sweden)

    Hudgens Edward E

    2011-02-01

    Full Text Available Abstract Background Asthma and allergy represent complex phenotypes, which disproportionately burden ethnic minorities in the United States. Strong evidence for genomic factors predisposing subjects to asthma/allergy is available. However, methods to utilize this information to identify high risk groups are variable and replication of genetic associations in African Americans is warranted. Methods We evaluated 41 single nucleotide polymorphisms (SNP and a deletion corresponding to 11 genes demonstrating association with asthma in the literature, for association with asthma, atopy, testing positive for food allergens, eosinophilia, and total serum IgE among 141 African American children living in Detroit, Michigan. Independent SNP and haplotype associations were investigated for association with each trait, and subsequently assessed in concert using a genetic risk score (GRS. Results Statistically significant associations with asthma were observed for SNPs in GSTM1, MS4A2, and GSTP1 genes, after correction for multiple testing. Chromosome 11 haplotype CTACGAGGCC (corresponding to MS4A2 rs574700, rs1441586, rs556917, rs502581, rs502419 and GSTP1 rs6591256, rs17593068, rs1695, rs1871042, rs947895 was associated with a nearly five-fold increase in the odds of asthma (Odds Ratio (OR = 4.8, p = 0.007. The GRS was significantly associated with a higher odds of asthma (OR = 1.61, 95% Confidence Interval = 1.21, 2.13; p = 0.001. Conclusions Variation in genes associated with asthma in predominantly non-African ethnic groups contributed to increased odds of asthma in this African American study population. Evaluating all significant variants in concert helped to identify the highest risk subset of this group.

  15. Susceptibility genes in movement disorders.

    Science.gov (United States)

    Scholz, Sonja; Singleton, Andrew

    2008-05-15

    During the last years, remarkable progress in our understanding of molecular genetic mechanisms underlying movement disorders has been achieved. The successes of linkage studies, followed by positional cloning, have dominated the last decade and several genes underlying monogenic disorders have been discovered. The pathobiological understanding garnered from these mutations has laid the foundation for much of the search for genetic loci that confer risk for, rather than cause, disease. With the introduction of whole genome association studies as a novel tool to investigate genetic variation underlying common, complex diseases, a new era in neurogenomics has just begun. As the field rapidly moves forward several new challenges and critical questions in clinical care have to be addressed. In this review, we summarize recent advances in the discovery of susceptibility loci underlying major movement disorders, explain the newest methodologies and tools employed for finding and characterizing genes and discuss how insights into the molecular genetic basis of neurological disorders will impact therapeutic concepts in patient care.

  16. Search for new breast cancer susceptibility genes

    NARCIS (Netherlands)

    Oldenburg, Rogier Abel

    2008-01-01

    This thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1 and BRCA2 breast cancer susceptibility genes. For the remaining families the genetic etiology is unknow

  17. Targeting of CD25 and glucocorticoid-induced TNF receptor family-related gene-expressing T cells differentially modulates asthma risk in offspring of asthmatic and normal mother mice.

    Science.gov (United States)

    Hubeau, Cedric; Apostolou, Irina; Kobzik, Lester

    2007-02-01

    Immunological mechanisms leading to increased asthma susceptibility in early life remain obscure. In this study, we examined the effects of neonatal Ab treatments targeting T cell populations on the development of an asthma syndrome. We used a model of increased asthma susceptibility where offspring of asthmatic BALB/c mother mice are more prone (than normal pups) to develop the disease. Neonatal pretreatment of naive pups with mAb directed against the IL-2Ralpha chain (CD25), the costimulatory molecule glucocorticoid-induced TNFR family related gene, and the inhibitory molecule CTLA-4 elicited contrasting effects in offspring depending on the mother's asthma status. Specifically, neonatal CD25(high) T cell depletion stimulated asthma susceptibility in normal offspring whereas it ameliorated the condition of pups born of asthmatic mothers. Conversely, glucocorticoid-induced TNFR family related gene ligation as a primary signal reduced the spleen cellularity and largely abrogated asthma susceptibility in asthma-prone offspring, without inducing disease in normal pups. Striking changes in Th1/Th2 cytokine levels, especially IL-4, followed mAb pretreatment and were consistent with the impact on asthma susceptibility. These results point to major differences in neonatal T cell population and responsiveness related to maternal asthma history. Interventions that temporarily remove and/or inactivate specific T cell subsets may therefore prove useful to attenuate early life asthma susceptibility and prevent the development of Th2-driven allergic airway disease.

  18. Data-driven asthma endotypes defined from blood biomarker and gene expression data.

    Directory of Open Access Journals (Sweden)

    Barbara Jane George

    Full Text Available The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-sectional study of asthmatic and non-asthmatic children from Detroit, MI. This study describes four distinct asthma endotypes identified via a purely data-driven method. Our method was specifically designed to integrate blood gene expression and clinical biomarkers in a way that provides new mechanistic insights regarding the different asthma endotypes. For example, we describe metabolic syndrome-induced systemic inflammation as an associated factor in three of the four asthma endotypes. Context provided by the clinical biomarker data was essential in interpreting gene expression patterns and identifying putative endotypes, which emphasizes the importance of integrated approaches when studying complex disease etiologies. These synthesized patterns of gene expression and clinical markers from our research may lead to development of novel serum-based biomarker panels.

  19. Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects.

    Science.gov (United States)

    Lee, Jong-Uk; Kim, Jeong Dong; Park, Choon-Sik

    2015-07-01

    Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for re-search on gene-environment interactions in asthma.

  20. HLA-DRB GENES POLYMORPHISM IN CHINESE NORTHERN PATIENTS WITH ATOPIC ASTHMA

    Institute of Scientific and Technical Information of China (English)

    高金明; 林耀广; 邱长春; 马毅

    1998-01-01

    Objective. Atopie asthma provides a usetul model for evaluating the genetic tactors that control human immune responsiveness. HLA class Ⅱ gene products are involved in the control of immune response. As HLA-DRB gene is the most polymorphic HLA class Ⅱ gene, we investigated whether susceptibility or resistance to the disease is associated with HLA-DRB. Methods. Blood samples were obtained from two groups of unrelated Chinese northern adults: (1) 50 atopic asthma (7 of them with familial aggregation) ; (2) 80 healthy controls without asthma or atopy and other HLA-associated diseases. Genomic DNA was extracted from peripheral venous blood leucocytes. The polymorphie second exon of HLA-DRB gene was amplified by sequence-specific primer polymerase chain reaction (SSP/PCR) methods. All patients had their serum IgE(total and spscifie) antibody levels by RAST, bronchial reactivity assessed by methaeholine brocho-provocation test and/or hronchodilation test. Results.There was an increased gene frequency of DR52 and DR52 in asthmatic subjects compared with healthy subjects(17% vs 4.3%, P<0. 01% 50% vs 17.5%, P<0. 01), and the decreased frequency of DR2(15) and DR52 in asthmatic patients(7% vs 18%, P<0. 05; 2% vs 33%, P<0. 01). We found the positive association between DR5(13)-DR52 and sIgE antibody responsiveness to d1 (from house dust mite allergen ); negative association between HLA-DRB alleles and TIgE or BHR ( bronchial hyperresponsiveness). Conclusion. The results suggested that HLA haplotype DR6(13)-DR52 was significantly implicated in suseeptibility to house dust mite induced-asthma, at least it would he more closely assocaated with atopic asthms. Conversely, alleles DR2(15) and DR51 might corder protection against the disease. HLA-DRB genes were particularly involved in regulating human atopie immune response in asthma.

  1. Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma

    Science.gov (United States)

    Singhania, Akul; Rupani, Hitasha; Jayasekera, Nivenka; Lumb, Simon; Hales, Paul; Gozzard, Neil; Davies, Donna E.

    2017-01-01

    Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study. Differences between central and peripheral airways were evaluated using transcriptomic analysis (Affymetrix HG U133 plus 2.0 GeneChips) of epithelial brushings obtained from severe asthma patients (N = 17) and healthy volunteers (N = 23). Results were validated in an independent cohort (N = 10) by real-time quantitative PCR. The IL-13 disease signature that is associated with an asthmatic phenotype was upregulated in severe asthmatics compared to healthy controls but was predominantly evident within the peripheral airways, as were genes related to mast cell presence. The gene expression response associated with glucocorticosteroid therapy (i.e. FKBP5) was also upregulated in severe asthmatics compared to healthy controls but, in contrast, was more pronounced in central airways. Moreover, an altered epithelial repair response (e.g. FGFBP1) was evident across both airway sites reflecting a significant aspect of disease in severe asthma unadressed by current therapies. A transcriptomic approach to understand epithelial activation in severe asthma has thus highlighted the need for better-targeted therapy to the peripheral airways in severe asthma, where the IL-13 disease signature persists despite treatment with currently available therapy. PMID:28045928

  2. Association of the interactions between TGF-1 and ADAM33 gene with susceptibility and severity in childhood asthma%TGF-1和ADAM33基因交互作用与儿童哮喘易感性及严重程度相关性

    Institute of Scientific and Technical Information of China (English)

    李宏彬; 徐光翠; 桂立辉; 冯宪军; 赵兵; 席景砖

    2012-01-01

    Objective:To verify the association of transforming growth factor-pl and a disintegrin and metalloprotein as e domain 33 polymorphisms with childhood asthma susceptibility and severity in a sample of patients with moderate and severe asthma. Methods: total of 144 controls and 110 asthmatic patients were recruited for this hospital-based case-control study. Three polymorphic sites (T869C, V4,T2)were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. The gene-gene interactions were analyzed with the MDR software. Results:There were no significant differences for both allele and genotype frequencies of T869C of TGF-pl gene between the childhood asthma and control group (P > 0. 05) . The allele frequencies of two SNPs ( V4, T2) of ADAM33 in childhood asthma group was significantly higher than that in control group (P <0. 01) . The nonsignificant differences were observed for the genotype CC of V4 locus and the genotype GA of Tl locus between moderate asthmatic groups and controls (P =0. 129 and 0. 084, respectively) , the genotype AA of T2 locus was no statistical significance between severe asthma and controls (P =0. 063) . There were significant differences in the interaction model between TGF-pl and ADAM33 gene (including 2 and 3 loci best model) analyzed by MDR (P<0.05). Conclusion; The results highlight the role of ADAM33 as a susceptibility gene for children asthma, and the interactions among TGF-βl T869C and ADAM33 V4 and T2 also have associations with children asthma in Chinese Han people.%目的:探讨转化生长因子β1(TGF-β1)和解整合素金属蛋白酶33(ADAM33)基因单核苷酸多态性与儿童哮喘易感性及严重程度相关性.方法:采用以医院为基础的病例对照研究(110例哮喘患儿和144例对照)方法,三个多态性位点(V4、T2、T869C)用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)技术进行基因分型,应用MDR软件分析基因各位点

  3. Novel susceptibility genes in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Colin Noble; Elaine Nimmo; Daniel Gaya; Richard K Russell; Jack Satsangi

    2006-01-01

    The inflammatory bowel disease, Crohn's disease and ulcerative colitis, are polygenic disorders with important environmental interactions. To date, the most widely adopted approach to identifying susceptibility genes in complex diseases has involved genome wide linkage studies followed by studies of positional candidate genes in loci of interest. This review encompasses data from studies into novel candidate genes implicated in the pathogenesis of inflammatory bowel disease. Novel techniques to identify candidate genes-genome wide association studies, yeast-two hybrid screening, microarray gene expression studies and proteomic profiling,are also reviewed and their potential role in unravelling the pathogenesis of inflammatory bowel disease are discussed.

  4. Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene.

    Directory of Open Access Journals (Sweden)

    Blanca E Himes

    Full Text Available Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR. The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS data. We used Efficient Mixed Model Association (EMMA analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG and two human AHR GWAS (i.e., SHARP, DAG, the Kv channel interacting protein 4 (KCNIP4 gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04, while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04. The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.

  5. Association of ADAM33 gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

    Indian Academy of Sciences (India)

    Priya Tripathi; Shally Awasthi; Rajendra Prasad; Nuzhat Husain; Subramaniam Ganesh

    2011-08-01

    ADAM33, a member of the ADAM (a disintegrin and metalloprotease) gene family, is an asthma susceptibility gene originally identified by positional cloning. In the present study, we investigated the possible association of five single-nucleotide polymorphisms (SNPs) in the ADAM33 (rs511898, rs528557, rs44707, rs597980 and rs2787094) with adult-onset asthma in an Indian population. The study included 175 patients with mild intermittent ($n = 44$), mild persistent ($n = 108$) or moderate persistent ($n = 23$) subgroups of asthma, and 253 nonasthmatic control individuals. SNPs were genotyped with the help of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method, and data were analysed using chi-square test and logistic regression model. Bonferroni’s correction for multiple comparisons was applied for each hypothesis. Genotypes and allele frequencies of SNPs rs511898 and rs528557 were significantly associated with adult-onset asthma ($P = 0.010-\\lt 0.001$). A significant association of the homozygous mutant genotype and mutant alleles of SNPs rs2787094, rs44707 and rs597980 with the asthma was also observed ($P = 0.020-\\lt 0.001$). A positive association between asthma and haplotypes AGCCT, GGCCT, AGACT, GCAGT, GGACT, ACCCC and AGACC were also found ($P = 0.036-\\lt 0.001$, OR $= 2.07-8.49$). Haplotypes AGCGT, GCAGC, ACAGC, ACAGT, GGAGC and GGCGT appear to protect against asthma ($P = 0.013-\\lt 0.0001$, OR $= 0.34-0.10$). Our data suggest that ADAM33 gene polymorphisms serve as genetic risk factors for asthma in Indian adult population.

  6. Asthma

    Directory of Open Access Journals (Sweden)

    Kim Harold

    2011-11-01

    Full Text Available Abstract Asthma is the most common respiratory disorder in Canada. Despite significant improvement in the diagnosis and management of this disorder, the majority of Canadians with asthma remain poorly controlled. In most patients, however, control can be achieved through the use of avoidance measures and appropriate pharmacological interventions. Inhaled corticosteroids (ICSs represent the standard of care for the majority of patients. Combination ICS/long-acting beta2-agonists (LABA inhalers are preferred for most adults who fail to achieve control with ICS therapy. Allergen-specific immunotherapy represents a potentially disease-modifying therapy for many patients with asthma, but should only be prescribed by physicians with appropriate training in allergy. Regular monitoring of asthma control, adherence to therapy and inhaler technique are also essential components of asthma management. This article provides a review of current literature and guidelines for the appropriate diagnosis and management of asthma.

  7. Asthma

    Science.gov (United States)

    ... 1.25 million of those individuals have severe asthma, a condition that can be difficult to control and treat. Learn more about his research by visiting the NHLBI Laboratory of Asthma and Lung Inflammation website: http://www.nhlbi.nih. ...

  8. Modification of the effect of ambient air pollution on pediatric asthma emergency visits: susceptible subpopulations

    Science.gov (United States)

    Strickland, Matthew J; Klein, Mitchel; Flanders, W Dana; Chang, Howard H; Mulholland, James A; Tolbert, Paige E; Darrow, Lyndsey A

    2016-01-01

    Background Children may have differing susceptibility to ambient air pollution concentrations depending on various background characteristics of the children. Methods Using emergency department (ED) data linked with birth records from Atlanta, Georgia, we identified ED visits for asthma or wheeze among children aged 2–16 years from 1 January 2002 through 30 June 2010 (n=109,758). We stratified by preterm delivery, term low birth weight, maternal race, Medicaid status, maternal education, maternal smoking, delivery method, and history of a bronchiolitis ED visit. Population-weighted daily average concentrations were calculated for 1-hour maximum carbon monoxide and nitrogen dioxide; 8-hour maximum ozone; and 24-hour average particulate matter less than 10 microns in diameter, particulate matter less than 2.5 microns in diameter (PM2.5), and the PM2.5 components sulfate, nitrate, ammonium, elemental carbon, and organic carbon, using measurements from stationary monitors. Poisson time-series models were used to estimate rate ratios for associations between three-day moving average pollutant concentrations and daily ED visit counts and to investigate effect-measure modification by the stratification factors. Results Associations between pollutant concentrations and asthma exacerbations were larger among children born preterm and among children born to African American mothers. Stratification by race and preterm status together suggested that both factors affected susceptibility. The largest estimated effect size (for an interquartile-range increase in pollution) was observed for ozone among preterm births to African American mothers: rate ratio=1.138 (95% confidence interval=1.077–1.203). In contrast, the rate ration for the ozone association among full-term births to mothers of other races was 1.025 (0.970–1.083). Conclusions Results support the hypothesis that children vary in their susceptibility to ambient air pollutants. PMID:25192402

  9. Harsh parent-child conflict is associated with decreased anti-inflammatory gene expression and increased symptom severity in children with asthma.

    Science.gov (United States)

    Ehrlich, Katherine B; Miller, Gregory E; Chen, Edith

    2015-11-01

    Asthma is a chronic respiratory disorder that affects over 7 million children in the United States. Evidence indicates that family stressors are associated with worsening of asthma symptoms, and some research suggests that these stressful experiences engender changes in children's immune systems in ways that exacerbate airway inflammation and contribute to both acute and chronic asthma symptoms. We examined the association between observed experiences of parent-child conflict and the expression of signaling molecules involved in the transduction of anti-inflammatory signals that regulate airway inflammation and obstruction. Fifty-seven children and their parents participated in a conflict task, and coders rated interactions for evidence of harsh and supportive behaviors. Children reported on their perceptions of parental support and reported on their daily asthma symptoms for 2 weeks. We collected peripheral blood in children to measure leukocyte expression of messenger RNA for the glucocorticoid receptor and the β2-adrenergic receptor. Analyses revealed that harsh conflict behaviors were associated with decreased expression of both messenger RNAs and more severe asthma symptoms. Neither supportive behaviors nor perceived parental support was associated with gene expression or asthma symptoms. These findings suggest that harsh interactions with parents are associated with downregulation of key anti-inflammatory signaling molecules and difficulties breathing in children with asthma. Children with asthma who are also victims of maltreatment may be particularly susceptible to transcriptional changes in immune cells that could worsen asthma over time.

  10. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying...... was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.Conclusion:Our results suggest...

  11. Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice.

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    Ian P Lewkowich

    Full Text Available Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs are important mediators of allergic asthma, yet the precise signals which render endogenous DCs "pro-asthmatic", and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J, or resistant (C3H to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23, whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

  12. Asthma

    OpenAIRE

    Kim, Harold; Mazza, Jorge

    2011-01-01

    Asthma is the most common respiratory disorder in Canada. Despite significant improvement in the diagnosis and management of this disorder, the majority of Canadians with asthma remain poorly controlled. In most patients, however, control can be achieved through the use of avoidance measures and appropriate pharmacological interventions. Inhaled corticosteroids (ICSs) represent the standard of care for the majority of patients. Combination ICS/long-acting beta2-agonists (LABA) inhalers are pr...

  13. Asthma

    OpenAIRE

    Kim Harold; Mazza Jorge

    2011-01-01

    Abstract Asthma is the most common respiratory disorder in Canada. Despite significant improvement in the diagnosis and management of this disorder, the majority of Canadians with asthma remain poorly controlled. In most patients, however, control can be achieved through the use of avoidance measures and appropriate pharmacological interventions. Inhaled corticosteroids (ICSs) represent the standard of care for the majority of patients. Combination ICS/long-acting beta2-agonists (LABA) inhale...

  14. Pathways: Strategies for Susceptibility Genes in SLE

    Science.gov (United States)

    Kelley, James M.; Edberg, Jeffrey C.; Kimberly, Robert P.

    2010-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disorder marked by an inappropriate immune response to nuclear antigens. Recent whole genome association and more focused studies have revealed numerous genes implicated in this disease process, including ITGAM, Fc gamma receptors, complement components, C-reactive protein, and others. One common feature of these molecules is their involvement in the immune opsonins pathway and phagocytic clearing of nuclear antigens and apoptotic debris which provide excessive exposure of lupus-related antigens to immune cells. Analysis of gene-gene interactions in the opsonin pathway and its relationship to SLE may provide a systems-based approach to identify additional candidate genes associated with disease able to account for a larger part of lupus susceptibility. PMID:20144911

  15. Association of beta 2 -adrenergic receptor gene polymorphisms and nocturnal asthma in Saudi patients

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    Al-Rubaish Abdullah

    2011-01-01

    Full Text Available Background and Objectives : Two polymorphisms of beta 2 -adrenergic receptor (β2 -AR gene, namely the substitution from arginine (Arg to glycine (Gly at codon 16 and from glutamine (Gln to glutamic (Glu at codon 27, are linked with functional changes in the β2 -AR in the respiratory system even though they are not deemed to be susceptibility genes for asthma per se. The objective of this study was to investigate this association in a subset of asthmatic patients, namely those with nocturnal asthma. Methods : The β2 -AR gene polymorphisms at codon 16 and 27 were assessed in 40 patients clinically diagnosed with nocturnal asthma and 96 normal controls. Genomic DNA was obtained from whole blood and genotyping was carried out by a PCR based restriction fragment length polymorphism technique. Results : There was a statistically significant difference in genotype frequencies at codon 16 (Arg/Gly between nocturnal asthmatic patients and normal control subjects (P < 0.05. However, there was no statistically significant difference in allele frequencies between the two groups. In addition, there was a significant association between Arg16-Gly genotype with nocturnal asthma compared to homozygous Gly16 (codominant model P = 0.0033, OR = 3.69: 95% CI: 1.49-9.12. However, there were no statistically significant differences in genotype and allele frequencies at codon 27 (Gln/Glu between the normal control and nocturnal asthmatic groups (χ2 = 1.81, P = 0.41. The results also indicate that linkage disequilibrium existed between the β2 -AR codon 16 and β2 -AR codon 27 polymorphism (/ D΄/ = 0.577. The data for all haplotypes did not show a statistically significant association. Conclusion : We present the genotype and allele frequencies of β2 -AR gene polymorphisms in normal Saudi subjects and nocturnal asthmatic patients. There was a significant difference in genotype frequencies at codon 16 (Arg/Gly. However, our study indicates a poor association of

  16. [Research advances in gene polymorphisms in biological pathways of drugs for asthma].

    Science.gov (United States)

    Guo, Dan-Dan; Zheng, Xiang-Rong

    2016-06-01

    The studies on gene polymorphisms in biological pathways of the drugs for the treatment of asthma refer to the studies in which pharmacogenetic methods, such as genome-wide association studies, candidate gene studies, genome sequencing, admixture mapping analysis, and linkage disequilibrium, are used to identify, determine, and repeatedly validate the effect of one or more single nucleotide polymorphisms on the efficacy of drugs. This can provide therapeutic strategies with optimal benefits, least side effects, and lowest costs to patients with asthma, and thus realize individualized medicine. The common drugs for asthma are β2 receptor agonists, glucocorticoids, and leukotriene modifiers. This article reviews the research achievements in polymorphisms in biological pathways of the common drugs for asthma, hoping to provide guidance for pharmacogenetic studies on asthma in future and realize individualized medicine for patients with asthma soon.

  17. Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences.

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    Melinda Butsch Kovacic

    Full Text Available BACKGROUND: Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes. METHODOLOGY/PRINCIPAL FINDINGS: Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05 in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05. Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049 or selected based on the literature alone (p = 0.0049, substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001 and increased the odds of allergic disease (OR = 1.8, p<0.008. Our data indicate that KIF3A rs7737031 (T-allele has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and

  18. Effect of TRPV1 gene mutation on bronchial asthma in children before and after treatment.

    Science.gov (United States)

    Chen, Chuan-Liang; Li, Hong; Xing, Xiao-Hong; Guan, Hai-Shan; Zhang, Jian-Hua; Zhao, Jun-Wu

    2015-01-01

    Bronchial asthma is a worldwide disease with high incidence. It not only harms children's physical and mental health, but it also brings a heavy burden to their families as well as the society. However, the trigger and pathogenesis of the disease remain unclear. This study aimed to analyze TRPV1 gene mutation and expression of cytokines in children with acute bronchial asthma before and after treatment, thus providing theoretical guidance for the diagnosis and treatment of bronchial asthma in children. Real-time quantitative polymerase chain reaction was adopted to detect TRPV1 mRNA expression level and enzyme-linked immuno sorbent assay was used to detect the serum total IgE level, eosinophil (EOS) number, IL-4, IL-5, and interferon (IFN) gamma levels in peripheral venous blood of children in the healthy control group and asthma group before and after treatment. Logistic regression analysis was applied to analyze the most essential factor inducing bronchial asthma in children. TRPV1 mRNA level of peripheral blood in the asthma group was higher than that in the control group before treatment (p asthma in children. TRPV1 gene mutation was closely related to bronchial asthma in children, which provided a theoretical basis for the treatment and prognosis of children with bronchial asthma.

  19. Genetic variants in the PSMA6, PSMC6 and PSMA3 genes associated with childhood asthma in Latvian and Taiwanese populations

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    Paramonova N.

    2014-09-01

    Full Text Available Proteasomes mediate functional realization of signaling proteins implicated in asthma pathogenesis. Aim. To evaluate main and sex-specific association between the PSMA6, PSMC6 and PSMA3 proteasomal genes variations and childhood asthma in Latvians and Taiwanese. Methods. SNPs rs2277460, rs1048990, rs2295826, rs2295827 and rs2348071 were genotyped in 102 Latvian and 159 Taiwanese cases for comparison with genetic diversity in populations (191 and 1097 subjects respectively. Results. Haplotype CGACG showed strong (P < 0.0001 association with asthma risk in both populations. All loci heterozygous genotypes and haplotype CCGTA were identified as asthma risk factors in Latvians; rs1048990 and rs2348071 GG homozygotes and rs2295826 and rs2295827 heterozygotes showed asthma risk and protective effect in Taiwanese females respectively. The multi locus genotypes homozygous for alleles being common in Latvian population were identified as protective in Latvians and disease susceptible in Taiwanese. Conclusions. Our results suggest an association of the 14q13-23 proteasomal genes polymorphisms with the childhood asthma in Latvians and Taiwanese and high-light risk and/or protective factors being the same or different between the populations.

  20. The impact of allergic rhinitis and asthma on human nasal and bronchial epithelial gene expression.

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    Ariane H Wagener

    Full Text Available BACKGROUND: The link between upper and lower airways in patients with both asthma and allergic rhinitis is still poorly understood. As the biological complexity of these disorders can be captured by gene expression profiling we hypothesized that the clinical expression of rhinitis and/or asthma is related to differential gene expression between upper and lower airways epithelium. OBJECTIVE: Defining gene expression profiles of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles. METHODS: This cross-sectional study included 18 subjects (6 allergic asthma and allergic rhinitis; 6 allergic rhinitis; 6 healthy controls. The estimated false discovery rate comparing 6 subjects per group was approximately 5%. RNA was extracted from isolated and cultured epithelial cells from bronchial brushings and nasal biopsies, and analyzed by microarray (Affymetrix U133+ PM Genechip Array. Data were analysed using R and Bioconductor Limma package. For gene ontology GeneSpring GX12 was used. RESULTS: The study was successfully completed by 17 subjects (6 allergic asthma and allergic rhinitis; 5 allergic rhinitis; 6 healthy controls. Using correction for multiple testing, 1988 genes were differentially expressed between healthy lower and upper airway epithelium, whereas in allergic rhinitis with or without asthma this was only 40 and 301 genes, respectively. Genes influenced by allergic rhinitis with or without asthma were linked to lung development, remodeling, regulation of peptidases and normal epithelial barrier functions. CONCLUSIONS: Differences in epithelial gene expression between the upper and lower airway epithelium, as observed in healthy subjects, largely disappear in patients with allergic rhinitis with or without asthma, whilst new differences emerge. The present data identify several pathways and genes that might be

  1. Prioritization of Disease Susceptibility Genes Using LSM/SVD.

    Science.gov (United States)

    Gong, Lejun; Yang, Ronggen; Yan, Qin; Sun, Xiao

    2013-12-01

    Understanding the role of genetics in diseases is one of the most important tasks in the postgenome era. It is generally too expensive and time consuming to perform experimental validation for all candidate genes related to disease. Computational methods play important roles for prioritizing these candidates. Herein, we propose an approach to prioritize disease genes using latent semantic mapping based on singular value decomposition. Our hypothesis is that similar functional genes are likely to cause similar diseases. Measuring the functional similarity between known disease susceptibility genes and unknown genes is to predict new disease susceptibility genes. Taking autism as an instance, the analysis results of the top ten genes prioritized demonstrate they might be autism susceptibility genes, which also indicates our approach could discover new disease susceptibility genes. The novel approach of disease gene prioritization could discover new disease susceptibility genes, and latent disease-gene relations. The prioritized results could also support the interpretive diversity and experimental views as computational evidence for disease researchers.

  2. Epigenetic Regulation: The Interface Between Prenatal and Early-Life Exposure and Asthma Susceptibility

    OpenAIRE

    De Planell-Saguer, Mariangels; Lovinsky-Desir, Stephanie; Miller, Rachel L.

    2013-01-01

    Asthma is a complex disease with genetic and environmental influences and emerging evidence suggests that epigenetic regulation is also a major contributor. Here, we focus on the developing paradigm that epigenetic dysregulation in asthma and allergy may start as early as in utero following several environmental exposures. We summarize the pathways important to the allergic immune response that are epigenetically regulated, the key environmental exposures associated with epigenetic changes in...

  3. FOXO3a Gene Polymorphism Associated with Asthma in Indian Population

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    Shravani Barkund

    2015-01-01

    Full Text Available Asthma is a chronic inflammatory disorder delineated by a heightened immunological response due to environmental or genetic factors. Single nucleotide polymorphism studies have shown that FOXO3a plays a pivotal role in maintaining immunoregulation. Polymorphism in FOXO3a has been linked to inflammatory diseases such as chronic obstructive pulmonary disease (COPD, Rheumatoid Arthritis, and Crohn’s disease suggesting that FOXO3a may be associated with asthma. Airway inflammation in asthma is characterized by activation of T helper type 2 (Th2 T cells and Foxo family members are reported to play critical roles in the suppression of T cell activation. Thus this study was undertaken to investigate an association between single nucleotide polymorphism of the FOXO3a (rs13217795, C>T transition gene and asthma in Indian population. To our knowledge we are the first ones reporting an association between FOXO3a and asthma.

  4. Advances in adult asthma diagnosis and treatment in 2012: potential therapeutics and gene-environment interactions.

    Science.gov (United States)

    Apter, Andrea J

    2013-01-01

    In the Journal of Allergy and Clinical Immunology in 2012, research reports related to asthma in adults clustered around mechanisms of disease, with a special focus on their potential for informing new therapies. There was also consideration of the effect of the environment on health from pollution, climate change, and epigenetic influences, underlining the importance of understanding gene-environment interactions in the pathogenesis of asthma and response to treatment.

  5. Profiling of differentially expressed genes using suppression subtractive hybridization in an equine model of chronic asthma.

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    Jean-Pierre Lavoie

    Full Text Available BACKGROUND: Gene expression analyses are used to investigate signaling pathways involved in diseases. In asthma, they have been primarily derived from the analysis of bronchial biopsies harvested from mild to moderate asthmatic subjects and controls. Due to ethical considerations, there is currently limited information on the transcriptome profile of the peripheral lung tissues in asthma. OBJECTIVE: To identify genes contributing to chronic inflammation and remodeling in the peripheral lung tissue of horses with heaves, a naturally occurring asthma-like condition. METHODS: Eleven adult horses (6 heaves-affected and 5 controls were studied while horses with heaves were in clinical remission (Pasture, and during disease exacerbation induced by a 30-day natural antigen challenge during stabling (Challenge. Large peripheral lung biopsies were obtained by thoracoscopy at both time points. Using suppression subtractive hybridization (SSH, lung cDNAs of controls (Pasture and Challenge and asymptomatic heaves-affected horses (Pasture were subtracted from cDNAs of horses with heaves in clinical exacerbation (Challenge. The differential expression of selected genes of interest was confirmed using quantitative PCR assay. RESULTS: Horses with heaves, but not controls, developed airway obstruction when challenged. Nine hundred and fifty cDNA clones isolated from the subtracted library were screened by dot blot array and 224 of those showing the most marked expression differences were sequenced. The gene expression pattern was confirmed by quantitative PCR in 15 of 22 selected genes. Novel genes and genes with an already defined function in asthma were identified in the subtracted cDNA library. Genes of particular interest associated with asthmatic airway inflammation and remodeling included those related to PPP3CB/NFAT, RhoA, and LTB4/GPR44 signaling pathways. CONCLUSIONS: Pathways representing new possible targets for anti-inflammatory and anti

  6. Identification of Srp9 as a febrile seizure susceptibility gene

    NARCIS (Netherlands)

    Hessel, Ellen V S; de Wit, Marina; Wolterink-Donselaar, Inge G; Karst, Henk; de Graaff, Esther; van Lith, Hein A; de Bruijn, Ewart; de Sonnaville, Sophietje; Verbeek, Nienke E; Lindhout, Dick; de Kovel, Carolien G F; Koeleman, Bobby P C; van Kempen, Marjan; Brilstra, Eva; Cuppen, Edwin; Loos, Maarten; Spijker, Sabine S; Kan, Anne A; Baars, Susanne E; van Rijen, Peter C; Gosselaar, Peter H; Groot Koerkamp, Marian J A; Holstege, Frank C P; van Duijn, Cornelia; Vergeer, Jeanette; Moll, Henriette A; Taubøll, Erik; Heuser, Kjell; Ramakers, Geert M J; Pasterkamp, R Jeroen; van Nieuwenhuizen, Onno; Hoogenraad, Casper C; Kas, Martien J H; de Graan, Pierre N E

    2014-01-01

    OBJECTIVE: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. METHODS:

  7. Evaluation of multidrug resistance-1 gene C>T polymorphism frequency in patients with asthma

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    Ümran Toru

    2015-10-01

    Full Text Available OBJECTIVES:Asthma is a chronic inflammatory lung disease characterized by bronchial hyperresponsiveness and airflow obstruction. Genetic and oxidative stress factors, in addition to pulmonary and systemic inflammatory processes, play a pivotal role in the pathogenesis of asthma. The products of the multidrug resistance-1 gene protect lung tissue from oxidative stress. Here, we aimed to evaluate the association between the multidrug resistance-1 gene C>T polymorphism and asthma with regard to oxidative stress-related parameters of asthmatic patients.METHODS:Forty-five patients with asthma and 27 healthy age-matched controls were included in this study. Blood samples were collected in tubes with ethylenediaminetetraacetic acid. DNA was extracted from the blood samples. The multidrug resistance-1 gene polymorphism was detected by polymerase chain reaction and a subsequent enzyme digestion technique. The serum levels of total oxidant status and total antioxidant status were determined by the colorimetric measurement method.RESULTS:The heterozygous polymorphic genotype was the most frequent in both groups. A significant difference in the multidrug resistance-1 genotype frequencies between groups indicated an association of asthma with the TT genotype. A significant difference between groups was found for wild type homozygous participants and carriers of polymorphic allele participants. The frequency of the T allele was significantly higher in asthmatic patients. The increase in the oxidative stress index parameter was significant in the asthma group compared with the control group.CONCLUSIONS:The multidrug resistance-1 gene C/T polymorphism may be an underlying genetic risk factor for the development of asthma via oxidant-antioxidant imbalance, leading to increased oxidative stress.

  8. Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

    Science.gov (United States)

    Smolonska, Joanna; Koppelman, Gerard H.; Wijmenga, Cisca; Vonk, Judith M.; Zanen, Pieter; Bruinenberg, Marcel; Curjuric, Ivan; Imboden, Medea; Thun, Gian-Andri; Franke, Lude; Probst-Hensch, Nicole M.; Nürnberg, Peter; Riemersma, Roland A.; van Schayck, Onno; Loth, Daan W.; Bruselle, Guy G.; Stricker, Bruno H; Hofman, Albert; Uitterlinden, André G.; Lahousse, Lies; London, Stephanie J.; Loehr, Laura R.; Manichaikul, Ani; Barr, R. Graham; Donohue, Kathleen M.; Rich, Stephen S.; Pare, Peter; Bossé, Yohan; Hao, Ke; van den Berge, Maarten; Groen, Harry J.M.; Lammers, Jan-Willem J.; Mali, Willem; Boezen, H. Marike; Postma, Dirkje S.

    2014-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution. PMID:24993907

  9. Variation in conserved non-coding sequences on chromosome 5q and susceptibility to asthma and atopy

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    Dubchak Inna

    2005-12-01

    Full Text Available Abstract Background Evolutionarily conserved sequences likely have biological function. Methods To determine whether variation in conserved sequences in non-coding DNA contributes to risk for human disease, we studied six conserved non-coding elements in the Th2 cytokine cluster on human chromosome 5q31 in a large Hutterite pedigree and in samples of outbred European American and African American asthma cases and controls. Results Among six conserved non-coding elements (>100 bp, >70% identity; human-mouse comparison, we identified one single nucleotide polymorphism (SNP in each of two conserved elements and six SNPs in the flanking regions of three conserved elements. We genotyped our samples for four of these SNPs and an additional three SNPs each in the IL13 and IL4 genes. While there was only modest evidence for association with single SNPs in the Hutterite and European American samples (P IL4 gene (P IL13 gene was strongly associated with total IgE (P = 0.00022 and allergic sensitization to mold allergens (P = 0.00076 in the Hutterites, and more modestly associated with sensitization to molds in the European Americans and African Americans (P Conclusion These results indicate that there is overall little variation in the conserved non-coding elements on 5q31, but variation in IL4 and IL13, including possibly one SNP in a conserved element, influence asthma and atopic phenotypes in diverse populations.

  10. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    OpenAIRE

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wid...

  11. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    OpenAIRE

    Chang eShen; Jing eGao; Yu Jun Sheng; Jinfa eDou; Fusheng eZhou; Xiaodong eZheng; Randy eKo; Xianfa eTang; Caihong Hong Zhu; Xianyong Yong Yin; Liangdan Dan Sun; Yong eCui; Xue Jun Zhang

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association stud...

  12. Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma.

    Directory of Open Access Journals (Sweden)

    Lisa J Martin

    Full Text Available RATIONALE AND OBJECTIVE: Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated. METHODS: Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP. MEASUREMENTS AND MAIN RESULTS: We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively. In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05. We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls. CONCLUSION: Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.

  13. Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes.

    Science.gov (United States)

    Dozmorov, Mikhail G; Wren, Jonathan D; Alarcón-Riquelme, Marta E

    2014-02-01

    Genome-wide association studies have identified a number of autoimmune disease-susceptibility genes. Whether or not these loci share any regulatory or functional elements, however, is an open question. Finding such common regulators is of considerable research interest in order to define systemic therapeutic targets. The growing amount of experimental genomic annotations, particularly those from the ENCODE project, provide a wealth of opportunities to search for such commonalities. We hypothesized that regulatory commonalities might not only delineate a regulatory landscape predisposing to autoimmune diseases, but also define functional elements distinguishing specific diseases. We further investigated if, and how, disease-specific epigenomic elements can identify novel genes yet to be associated with the diseases. We evaluated transcription factors, histone modifications, and chromatin state data obtained from the ENCODE project for statistically significant over- or under-representation in the promoters of genes associated with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Systemic Sclerosis (SSc). We identified BATF, BCL11A, IRF4, NFkB, PAX5, and PU.1 as transcription factors over-represented in SLE- and RA-susceptibility gene promoters. H3K4me1 and H3K4me2 epigenomic marks were associated with SLE susceptibility genes, and H3K9me3 was common to both SLE and RA. In contrast to a transcriptionally active signature in SLE and RA, SSc-susceptibility genes were depleted in activating epigenomic elements. Using epigenomic elements enriched in SLE and RA, we identified additional immune and B cell signaling-related genes with the same elements in their promoters. Our analysis suggests common and disease-specific epigenomic elements that may define novel therapeutic targets for controlling aberrant activation of autoimmune susceptibility genes.

  14. Hereditary Breast Cancer: The Era of New Susceptibility Genes

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    Paraskevi Apostolou

    2013-01-01

    Full Text Available Breast cancer is the most common malignancy among females. 5%–10% of breast cancer cases are hereditary and are caused by pathogenic mutations in the considered reference BRCA1 and BRCA2 genes. As sequencing technologies evolve, more susceptible genes have been discovered and BRCA1 and BRCA2 predisposition seems to be only a part of the story. These new findings include rare germline mutations in other high penetrant genes, the most important of which include TP53 mutations in Li-Fraumeni syndrome, STK11 mutations in Peutz-Jeghers syndrome, and PTEN mutations in Cowden syndrome. Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such as CHEK2, ATM, PALB2, and BRIP1. This paper will summarize all current data on new findings in breast cancer susceptibility genes.

  15. Association and interaction analyses of eight genes under asthma linkage peaks

    DEFF Research Database (Denmark)

    Ferreira, M.A.R.; Zhao, Z.Z.; Thomsen, S.F.;

    2009-01-01

    Background: Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits. Methods: Ninety-five single nucleotide...... polymorphisms (SNP) located in eight genes (CD28, CTLA4, ICOS, ADAM23, ADAMTSL1, MS4A2, CDH26 and HRH3) were genotyped in > 5000 individuals from Australian (n = 1162), Dutch (n = 99) and Danish (n = 303) families. Traits tested included doctor-diagnosed asthma, atopy, airway obstruction, total serum...... immunoglobulin (Ig) E levels and eosinophilia. Association was tested using both multivariate and univariate methods, with gene-wide thresholds for significance determined through simulation. Gene-by-gene and gene-by-environment analyses were also performed. Results: There was no overall evidence for association...

  16. Rheumatoid arthritis susceptibility genes: An overview.

    Science.gov (United States)

    Korczowska, Izabela

    2014-09-18

    Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease sustained by genetic factors. Various aspects of the genetic contribution to the pathogenetics and outcome of RA are still unknown. Several genes have been indicated so far in the pathogenesis of RA. Apart from human leukocyte antigen, large genome wide association studies have identified many loci involved in RA pathogenesis. These genes include protein tyrosine phosphatase, nonreceptor type 22, Peptidyl Arginine Deiminase type IV, signal transducer and activator of transcription 4, cytotoxic T-lymphocyte-associated protein 4, tumor necrosis factor-receptor associated factor 1/complement component 5, tumor necrosis factor and others. It is important to determine whether a combination of RA risk alleles are able to identify patients who will develop certain clinical outcomes, such myocardium infarction, severe infection or lymphoma, as well as to identify patients who will respond to biological medication therapy.

  17. A methodology to establish a database to study gene environment interactions for childhood asthma

    Directory of Open Access Journals (Sweden)

    McCormick Jonathan

    2010-12-01

    Full Text Available Abstract Background Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES - Paediatric Asthma Gene Environment Study. Methods Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR, skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database. Results To date 1045 children have been invited to participate and data collected in 501 (48%. The mean age (SD of participants is 8.6 (3.9 years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD FEV1 97% (15 and median (IQR BDR is 5% (2, 9. There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024. Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part. Conclusions It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.

  18. [Susceptibility gene in multiple system atrophy (MSA)].

    Science.gov (United States)

    Tsuji, Shoji

    2014-01-01

    To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress.

  19. The -675 4G/5G polymorphism in plasminogen activator inhibitor-1 gene is associated with risk of asthma: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Wei Nie

    Full Text Available BACKGROUND: A number of studies assessed the association of -675 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor (PAI-1 gene with asthma in different populations. However, most studies reported inconclusive results. A meta-analysis was conducted to investigate the association between polymorphism in the PAI-1 gene and asthma susceptibility. METHODS: Databases including Pubmed, EMBASE, HuGE Literature Finder, Wanfang Database, China National Knowledge Infrastructure (CNKI and Weipu Database were searched to find relevant studies. Odds ratios (ORs with 95% confidence intervals (CIs were used to assess the strength of association in the dominant model, recessive model, codominant model, and additive model. RESULTS: Eight studies involving 1817 cases and 2327 controls were included. Overall, significant association between 4G/5G polymorphism and asthma susceptibility was observed for 4G4G+4G5G vs. 5G5G (OR = 1.56, 95% CI 1.12-2.18, P = 0.008, 4G/4G vs. 4G/5G+5G/5G (OR = 1.38, 95% CI 1.06-1.80, P = 0.02, 4G/4G vs. 5G/5G (OR = 1.80, 95% CI 1.17-2.76, P = 0.007, 4G/5G vs. 5G/5G (OR = 1.40, 95% CI 1.07-1.84, P = 0.02, and 4G vs. 5G (OR = 1.35, 95% CI 1.08-1.68, P = 0.008. CONCLUSIONS: This meta-analysis suggested that the -675 4G/5G polymorphism of PAI-1 gene was a risk factor of asthma.

  20. Polymorphisms in autophagy genes and susceptibility to tuberculosis.

    NARCIS (Netherlands)

    Songane, M.; Kleinnijenhuis, J.; Alisjahbana, B.; Sahiratmadja, E.; Parwati, I.; Oosting, M.; Plantinga, T.S.; Joosten, L.A.B.; Netea, M.G.; Ottenhoff, T.H.; Vosse, E. van de; Crevel, R. van

    2012-01-01

    Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana

  1. A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families : evidence for a major susceptibility locus on chromosome 2p

    NARCIS (Netherlands)

    Pillai, SG; Chiano, MN; White, NJ; Speer, M; Barnes, KC; Carlsen, K; Gerritsen, Jorrit; Helms, P; Lenney, W; Silverman, M; Sly, P; Sundy, J; Tsanakas, J; von Berg, A; Whyte, M; Varsani, S; Skelding, P; Hauser, M; Vance, J; Pericak-Vance, M; Burns, DK; Middleton, LT; Brewster, [No Value; Anderson, WH; Riley, JH

    2006-01-01

    Asthma is a complex disease and the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Families with at least two siblings with asthma were collected from Europe, Australia and the US. A genome scan using a set of 364 families with a panel o

  2. Candidate Genes for Inherited Autism Susceptibility in the Lebanese Population

    Science.gov (United States)

    Kourtian, Silva; Soueid, Jihane; Makhoul, Nadine J.; Guisso, Dikran Richard; Chahrour, Maria; Boustany, Rose-Mary N.

    2017-01-01

    Autism spectrum disorder (ASD) is characterized by ritualistic-repetitive behaviors and impaired verbal/non-verbal communication. Many ASD susceptibility genes implicated in neuronal pathways/brain development have been identified. The Lebanese population is ideal for uncovering recessive genes because of shared ancestry and a high rate of consanguineous marriages. Aims here are to analyze for published ASD genes and uncover novel inherited ASD susceptibility genes specific to the Lebanese. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33) and 100 unaffected Lebanese controls. Cytogenetics 2.7 M Microarrays/CytoScan™ HD arrays allowed mapping of homozygous regions of the genome. The CNTNAP2 gene was screened by Sanger sequencing. Homozygosity mapping uncovered DPP4, TRHR, and MLF1 as novel candidate susceptibility genes for ASD in the Lebanese. Sequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 ASD patients. This mutation was present in unaffected family members and unaffected Lebanese controls. Although a slight increase in number was observed in ASD patients and family members compared to controls, there were no significant differences in allele frequencies between affecteds and controls (C/TTCTG: γ2 value = 0.014; p = 0.904). The CNTNAP2 polymorphism identified in this population, hence, is not linked to the ASD phenotype. PMID:28358038

  3. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci.

    Science.gov (United States)

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo.

  4. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    Directory of Open Access Journals (Sweden)

    Chang eShen

    2016-02-01

    Full Text Available Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association studies (GWASs. More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWASs. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo, such as immunoregulatory function, melanocyte regulation and so on. A number of susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in vitiligo development.

  5. Genetic factors and asthma in aluminum smelter workers.

    Science.gov (United States)

    Arnaiz, Nilo O; Kaufman, Joel D; Daroowalla, Feroza M; Quigley, Sean; Farin, Federico; Checkoway, Harvey

    2003-04-01

    An asthma-like condition has been reported among aluminum smelter potroom workers. The pathophysiologic mechanisms and the causative agent involved are unknown. Inasmuch as gene polymorphisms are associated with asthma in the general population, the authors of this case-control study examined whether polymorphisms were associated with the development of potroom asthma. Genotyping was performed for the beta2-adrenoreceptor, high-affinity Ig (immunoglobulin) E receptor, and Tumor Necrosis Factor on potroom workers who developed a new asthma-like condition and on individuals who did not develop respiratory problems. No associations were found between potroom asthma case status and genotype. The asthma-like condition associated with potroom work remains poorly understood. Future investigations of genetic susceptibility and occupational asthma may provide pathophysiologic insights into these work-related conditions, but larger numbers of subjects will be required.

  6. Effects of maternal exposure to di(2-ethylhexyl)phthalate (DEHP) during pregnancy on susceptibility to neonatal asthma

    Energy Technology Data Exchange (ETDEWEB)

    Shin, In-Sik; Lee, Mee-Young [Basic Herbal Medicine Research Group, Korea Institute of Oriental Medicine, 483 Expo-ro, Yusung-gu, Daejeon 305-811 (Korea, Republic of); Cho, Eun-Sang [College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764 (Korea, Republic of); Choi, Eun-young [College of Nursing and Health, Kongju National University, 56 Gongju Daehak-ro, Gongju, Chungnam 314-701 (Korea, Republic of); Son, Hwa-Young [College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764 (Korea, Republic of); Lee, Kyoung-Youl, E-mail: youl10@hanmail.net [College of Nursing and Health, Kongju National University, 56 Gongju Daehak-ro, Gongju, Chungnam 314-701 (Korea, Republic of)

    2014-02-01

    Di(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer and is widely dispersed in the environment. In this study, we investigated the effects of maternal exposure to DEHP during pregnancy on neonatal asthma susceptibility using a murine model of asthma induced by ovalbumin (OVA). Pregnant BALB/c mice received DEHP from gestation day 13 to lactation day 21. Their offspring were sensitized on postnatal days (PNDs) 9 and 15 by intraperitoneal injection of 0.5 μg OVA with 200 μg aluminum hydroxide. On PNDs 22, 23 and 24, live pups received an airway challenge of OVA for 30 min. Offspring from pregnant mice that received DEHP showed reductions in inflammatory cell count, interleukin (IL)-4, IL-13, and eotaxin in their bronchoalveolar lavage fluid and in total immunoglobulin E and OVA-specific IgE in their plasma compared with offspring from pregnant mice that did not receive DEHP treatment. These results were consistent with histological analysis and immunoblotting. Maternal exposure to DEHP reduces airway inflammation and mucus production in offspring, with a decrease in inducible nitric oxide synthase (iNOS) in the lung tissue. This study suggests that maternal exposure to DEHP during pregnancy reduces asthmatic responses induced by OVA challenge in offspring. These effects were considered to be closely related to the suppression of Th2 immune responses and iNOS expression. - Highlights: • Maternal exposure to di(2-ethylhexyl)phthalate reduces asthmatic response in pups. • Di(2-ethylhexyl)phthalate reduces eosinophilia induced by ovalbumin exposure. • Di(2-ethylhexyl)phthalate reduces T-helper type 2 cytokine production. • Di(2-ethylhexyl)phthalate attenuates airway inflammation and mucus production. • Di(2-ethylhexyl)phthalate suppresses inducible nitric oxide synthase in lung tissue.

  7. Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections.

    Directory of Open Access Journals (Sweden)

    Ettie M Lipner

    Full Text Available Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects.

  8. Identification of candidate genes for dyslexia susceptibility on chromosome 18.

    Directory of Open Access Journals (Sweden)

    Thomas S Scerri

    Full Text Available Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s conferring susceptibility by a two stage strategy of linkage and association analysis.Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R, dymeclin (DYM and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L.Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

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

    Science.gov (United States)

    Torgerson, Dara G.; Giri, Tusar; Druley, Todd E.; Zheng, Jie; Huntsman, Scott; Seibold, Max A.; Young, Andrew L.; Schweiger, Toni; Yin-Declue, Huiqing; Sajol, Geneline D.; Schechtman, Kenneth B; Hernandez, Ryan D.; Randolph, Adrienne G.; Bacharier, Leonard B.; Castro, Mario

    2015-01-01

    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. PMID:26587832

  10. 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.

  11. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility

    OpenAIRE

    Simmons, J.; Mullighan, C; Welsh, K; JEWELL, D

    2000-01-01

    BACKGROUND—The vitamin D receptor (VDR) gene represents a strong positional candidate susceptibility gene for inflammatory bowel disease (IBD). The VDR gene maps to a region on chromosome 12 that has been shown to be linked to IBD by genome screening techniques. It is the cellular receptor for 1,25(OH)2 vitamin D3 (calcitriol) which has a wide range of different regulatory effects on the immune system. IBD is characterised by activation of the mucosal immune system.
AIM—To determine if polymo...

  12. Prioritisation and network analysis of Crohn's disease susceptibility genes.

    Directory of Open Access Journals (Sweden)

    Daniele Muraro

    Full Text Available Recent Genome-Wide Association Studies (GWAS have revealed numerous Crohn's disease susceptibility genes and a key challenge now is in understanding how risk polymorphisms in associated genes might contribute to development of this disease. For a gene to contribute to disease phenotype, its risk variant will likely adversely communicate with a variety of other gene products to result in dysregulation of common signaling pathways. A vital challenge is to elucidate pathways of potentially greatest influence on pathological behaviour, in a manner recognizing how multiple relevant genes may yield integrative effect. In this work we apply mathematical analysis of networks involving the list of recently described Crohn's susceptibility genes, to prioritise pathways in relation to their potential development of this disease. Prioritisation was performed by applying a text mining and a diffusion based method (GRAIL, GPEC. Prospective biological significance of the resulting prioritised list of proteins is highlighted by changes in their gene expression levels in Crohn's patients intestinal tissue in comparison with healthy donors.

  13. GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma : The Traffic, Asthma and Genetics (TAG) Study

    NARCIS (Netherlands)

    MacIntyre, Elaina A.; Brauer, Michael; Melen, Erik; Bauer, Carl Peter; Bauer, Mario; Berdel, Dietrich; Bergstroem, Anna; Brunekreef, Bert; Chan-Yeung, Moira; Kluemper, Claudia; Fuertes, Elaine; Gehring, Ulrike; Gref, Anna; Heinrich, Joachim; Herbarth, Olf; Kerkhof, Marjan; Koppelman, Gerard H.; Kozyrskyj, Anita L.; Pershagen, Goran; Postma, Dirkje S.; Thiering, Elisabeth; Tiesler, Carla M. T.; Carlsten, Christopher

    2014-01-01

    Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma. Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and i

  14. Relationship between measles HI titers and an MS susceptibility gene.

    Science.gov (United States)

    Haile, R W; Visscher, B R; Detels, R; Valdiviezo, N L; Sever, J L; Madden, D L

    1981-01-01

    Recently published studies of formal linkage analyses strongly suggest that a multiple sclerosis susceptibility (MSS) gene is linked to the HLA region of the sixth chromosome. The objective of this analysis was to investigate whether or not the gene has any demonstrable relationship to the immune status with regard to measles within members of multiple-case MS families. Family members were HLA-typed, and levels of antibodies to measles were determined using the hemagglutination inhibition assay. Since a specific, HLA-defined haplotype within each family is presumably a marker for the MSS gene, family members were characterized as either carrying [(+) controls] or not carrying [(-) controls] the MSS gene by the presence of this specific haplotype. Twenty families were entered into the analyses. Results revealed that the mean titer to measles was not different between (+) and (-) controls, and that MS cases had significantly higher titers than both control groups combined.

  15. Identification of Pseudomonas aeruginosa genes associated with antibiotic susceptibility

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Pseudomonas aeruginosa causes acute and chronic infections in humans and these infections are difficult to treat due to the bacteria’s high-level of intrinsic and acquired resistance to antibiotics. To address this problem, it is crucial to investigate the molecular mechanisms of antibiotic resistance in this organism. In this study, a P. aeruginosa transposon insertion library of 17000 clones was constructed and screened for altered susceptibility to seven antibiotics. Colonies grown on agar plates con- taining antibiotics at minimum inhibitory concentrations (MICs) and those unable to grow at ? MIC were collected. The transposon-disrupted genes in 43 confirmed mutants that showed at least a three-fold increase or a two-fold decrease in suscep- tibility to at least one antibiotic were determined by semi-random PCR and subsequent sequencing analysis. In addition to nine genes known to be associated with antibiotic resistance, including mexI, mexB and mexR, 24 new antibiotic resis- tance-associated genes were identified, including a fimbrial biogenesis gene pilY1 whose disruption resulted in a 128-fold in- crease in the MIC of carbenicillin. Twelve of the 43 genes identified were of unknown function. These genes could serve as targets to control or reverse antibiotic resistance in this important human pathogen.

  16. Association and interaction analyses of eight genes under asthma linkage peaks

    DEFF Research Database (Denmark)

    Ferreira, M A R; Zhao, Z Z; Thomsen, S F;

    2009-01-01

    BACKGROUND: Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits. METHODS: Ninety-five single nucleotide...... polymorphisms (SNP) located in eight genes (CD28, CTLA4, ICOS, ADAM23, ADAMTSL1, MS4A2, CDH26 and HRH3) were genotyped in >5000 individuals from Australian (n = 1162), Dutch (n = 99) and Danish (n = 303) families. Traits tested included doctor-diagnosed asthma, atopy, airway obstruction, total serum...... after accounting for the number of tests performed. CONCLUSIONS: The individual variants genotyped in the 2q33, 9p21 and 20q13 regions do not explain a large fraction of the variation in the quantitative traits tested or have a major impact on asthma or atopy risk. Our results are consistent with a weak...

  17. Increased asthma and adipose tissue inflammatory gene expression with obesity and Inuit migration to a western country

    DEFF Research Database (Denmark)

    Backer, Vibeke; Baines, Katherine J; Powell, Heather;

    2016-01-01

    BACKGROUND: An overlap between obesity and asthma exists, and inflammatory cells in adipose tissue could drive the development of asthma. Comparison of adipose tissue gene expression among Inuit living in Greenland to those in Denmark provides an opportunity to assess how changes in adipose tissue...... inflammation can be modified by migration and diet. OBJECTIVE: To examine mast cell and inflammatory markers in adipose tissue and the association with asthma. METHODS: Two Inuit populations were recruited, one living in Greenland and another in Denmark. All underwent adipose subcutaneous biopsy, followed...... by clinical assessment of asthma, and measurement of AHR. Adipose tissue biopsies were homogenised, RNA extracted, and PCR was performed to determine the relative gene expression of mast cell (tryptase, chymase, CPA3) and inflammatory markers (IL-6, IL-1β, and CD163). RESULTS: Of the 1059 Greenlandic Inuit...

  18. Genes associated with RSV lower respiratory tract infection and asthma: the application of genetic epidemiological methods to understand causality

    Science.gov (United States)

    Larkin, Emma K; Hartert, Tina V

    2015-01-01

    Infants with respiratory syncytial virus (RSV) lower respiratory tract infections (LRIs) are at increased risk for childhood asthma. The objectives of this article are to review the genes associated with both RSV LRI and asthma, review analytic approaches to assessing shared genetic risk and propose a future perspective on how these approaches can help us to understand the role of infant RSV infection as both an important risk factor for asthma and marker of shared genetic etiology between the two conditions. The review of shared genes and thus pathways associated with severity of response to RSV infection and asthma risk can help us to understand mechanisms of disease and ultimately propose new and novel targets for primary prevention of both diseases. PMID:26478738

  19. GIMAP GTPase family genes: potential modifiers in autoimmune diabetes, asthma, and allergy.

    Science.gov (United States)

    Heinonen, Mirkka T; Laine, Antti-Pekka; Söderhäll, Cilla; Gruzieva, Olena; Rautio, Sini; Melén, Erik; Pershagen, Göran; Lähdesmäki, Harri J; Knip, Mikael; Ilonen, Jorma; Henttinen, Tiina A; Kere, Juha; Lahesmaa, Riitta

    2015-06-15

    GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differentiation and have been previously connected to immune-mediated disorders in animal studies. GIMAP4 is believed to contribute to the Th cell subtype-driven immunological balance via its role in T cell survival. GIMAP5 has a key role in BB-DR rat and NOD mouse lymphopenia. To elucidate GIMAP4 and GIMAP5 function and role in human immunity, we conducted a study combining genetic association in different immunological diseases and complementing functional analyses. Single nucleotide polymorphisms tagging the GIMAP haplotype variation were genotyped in Finnish type 1 diabetes (T1D) families and in a prospective Swedish asthma and allergic sensitization birth cohort. Initially, GIMAP5 rs6965571 was associated with risk for asthma and allergic sensitization (odds ratio [OR] 3.74, p = 0.00072, and OR 2.70, p = 0.0063, respectively) and protection from T1D (OR 0.64, p = 0.0058); GIMAP4 rs13222905 was associated with asthma (OR 1.28, p = 0.035) and allergic sensitization (OR 1.27, p = 0.0068). However, after false discovery rate correction for multiple testing, only the associations of GIMAP4 with allergic sensitization and GIMAP5 with asthma remained significant. In addition, transcription factor binding sites surrounding the associated loci were predicted. A gene-gene interaction in the T1D data were observed between the IL2RA rs2104286 and GIMAP4 rs9640279 (OR 1.52, p = 0.0064) and indicated between INS rs689 and GIMAP5 rs2286899. The follow-up functional analyses revealed lower IL-2RA expression upon GIMAP4 knockdown and an effect of GIMAP5 rs2286899 genotype on protein expression. Thus, the potential role of GIMAP4 and GIMAP5 as modifiers of immune-mediated diseases cannot be discarded.

  20. Stress and asthma: novel insights on genetic, epigenetic, and immunologic mechanisms.

    Science.gov (United States)

    Rosenberg, Stacy L; Miller, Gregory E; Brehm, John M; Celedón, Juan C

    2014-11-01

    In the United States the economically disadvantaged and some ethnic minorities are often exposed to chronic psychosocial stressors and disproportionately affected by asthma. Current evidence suggests a causal association between chronic psychosocial stress and asthma or asthma morbidity. Recent findings suggest potential mechanisms underlying this association, including changes in the methylation and expression of genes that regulate behavioral, autonomic, neuroendocrine, and immunologic responses to stress. There is also evidence suggesting the existence of susceptibility genes that predispose chronically stressed youth to both post-traumatic stress disorder and asthma. In this review we critically examine published evidence and suggest future directions for research in this field.

  1. Th17-Related Genes and Celiac Disease Susceptibility

    Science.gov (United States)

    Medrano, Luz María; García-Magariños, Manuel; Dema, Bárbara; Espino, Laura; Maluenda, Carlos; Polanco, Isabel; Figueredo, M. Ángeles; Fernández-Arquero, Miguel; Núñez, Concepción

    2012-01-01

    Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD), recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs), mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA), were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk. PMID:22359581

  2. Th17-related genes and celiac disease susceptibility.

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    Luz María Medrano

    Full Text Available Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD, recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs, mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA, were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk.

  3. Asthma pharmacotherapy.

    Science.gov (United States)

    Schofield, Minka L

    2014-02-01

    Asthma is a chronic inflammatory disease of the airway that leads to airway obstruction via bronchoconstriction, edema, and mucus hypersecretion. The National Asthma Education and Prevention Program has outlined evidence-based guidelines to standardize asthma therapy and improve outcomes. The initial recommendation of choice for persistent asthmatic patients is an inhaled corticosteroid (ICS). Long-acting beta-2 agonists in combination with ICS, oral corticosteroids, leukotriene modifiers, and anti-IgE therapeutic options can be considered for patients with persistent or worsening symptoms. Many novel therapies are being developed, with an emphasis on anti-inflammatory mechanisms, gene expression, and cytokine modification.

  4. Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma.

    Science.gov (United States)

    Campbell, Catarina D; Mohajeri, Kiana; Malig, Maika; Hormozdiari, Fereydoun; Nelson, Benjamin; Du, Gaixin; Patterson, Kristen M; Eng, Celeste; Torgerson, Dara G; Hu, Donglei; Herman, Catherine; Chong, Jessica X; Ko, Arthur; O'Roak, Brian J; Krumm, Niklas; Vives, Laura; Lee, Choli; Roth, Lindsey A; Rodriguez-Cintron, William; Rodriguez-Santana, Jose; Brigino-Buenaventura, Emerita; Davis, Adam; Meade, Kelley; LeNoir, Michael A; Thyne, Shannon; Jackson, Daniel J; Gern, James E; Lemanske, Robert F; Shendure, Jay; Abney, Mark; Burchard, Esteban G; Ober, Carole; Eichler, Evan E

    2014-01-01

    Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.

  5. Plasma Adiponectin Concentrations and Adiponectin Gene Polymorphisms Are Associated with Bronchial Asthma in the Chinese Li Population

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    Yipeng Ding

    2015-10-01

    Full Text Available The purpose of this study was to determine the clinical significance of changes in the plasma  adiponectin  concentration  in  patients  with  bronchial  asthma  and  to  test  the association between the single nucleotide polymorphisms (SNPs rs2241766 and rs1501299 in the ADIPOQ gene and bronchial asthma in the Chinese Li population.We selected 120 cases and 120 controls, and plasma adiponectin, interleukin (IL-6, and tumor  necrosis  factor-alpha  (TNF-α  levels  were  measured  by  enzyme-linked immunosorbent assay (ELISA. In addition, we genotyped two tag single nucleotide polymorphisms (tSNPs and evaluated their association with bronchial asthma using the χ2 test and genetic model analysis.Compared to controls, patients with acute exacerbation of bronchial asthma showedsignificantly lower adiponectin and significantly higher IL-6 and TNF-α levels (p<0.01. Apositive association was found between the rs1501299 SNP and acute exacerbation (OR =1.62; 95% CI= 1.08-2.43; p= 0.019.The inverse correlation between the plasma adiponectin concentration and asthma exacerbation indicates that adiponectin may play a protective role in the pathogenesis of asthma. Meanwhile, our findings suggest that ADIPOQ polymorphisms influence the risk of developing bronchial asthma in Chinese Li population.

  6. Susceptibility genes for schizophrenia: mutant models, endophenotypes and psychobiology.

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    O'Tuathaigh, Colm M P; Desbonnet, Lieve; Moran, Paula M; Waddington, John L

    2012-01-01

    Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models.

  7. Polymorphisms in autophagy genes and susceptibility to tuberculosis.

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    Mario Songane

    Full Text Available Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1β, IL-6, IL-8, IFN-γ and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02 and MTOR (p = 0.02 and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04. All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production.

  8. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

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    Anne M L Jansen

    Full Text Available Lynch Syndrome (LS is caused by pathogenic germline variants in one of the mismatch repair (MMR genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history.Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants.Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG. Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29% cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32% with one pathogenic somatic variant (n = 8 or one VUS predicted to be pathogenic (n = 1.This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%. In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.

  9. Associations of Toll-like receptor 7 and 8 Polymorphisms with Asthma and Asthma-related Phenotypes in a Chinese Han Population.

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    Zhang, Qian; Qian, Fen-Hong; Yin, Xiao-Wei; Cao, Qi; Bai, Jian-Ling; Du, Qiang; Shi, Yi

    2015-12-01

    Toll-like receptor (TLR) 7 and 8 mediate anti-virus immunity and are of particular relevance to asthma. However, very little information about genetic association on TLR7/8 and asthma are available. This study aimed to evaluate the effects of polymorphisms in TLR7 and 8 on asthma risk and asthma-related phenotypes in a Chinese Han population. We enrolled 462 unrelated adult asthmatic patients and 398 healthy volunteers. The genotypes of tagging single nucleotide polymorphisms (SNPs) in TLR7 and 8 genes were determined using multiplex SNaPshot SNP genotyping assay. We used case-control and case-only studies to assess any links with asthma and asthma-related phenotypes. There was no association between the variants in TLR7 and 8 and asthma susceptibility. However, our results revealed that the genetic variants in TLR7 and 8 were associated with asthma-related phenotypes, including eosinophil counts, serum immunoglobulin E levels, lung function, and asthma severity as well. Our study suggests that TLR7 and 8 polymorphisms may play a considerable role in the pathogenesis of asthma. It will help in better understanding the pathogenesis of asthma and development of more effective strategies for asthma prevention, prediction, and therapy.

  10. Associations between nitric oxide synthase genes and exhaled NO-related phenotypes according to asthma status.

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    Emmanuelle Bouzigon

    Full Text Available BACKGROUND: The nitric oxide (NO pathway is involved in asthma, and eosinophils participate in the regulation of the NO pool in pulmonary tissues. We investigated associations between single nucleotide polymorphisms (SNPs of NO synthase genes (NOS and biological NO-related phenotypes measured in two compartments (exhaled breath condensate and plasma and blood eosinophil counts. METHODOLOGY: SNPs (N = 121 belonging to NOS1, NOS2 and NOS3 genes were genotyped in 1277 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA. Association analyses were conducted on four quantitative phenotypes: the exhaled fraction of NO (Fe(NO, plasma and exhaled breath condensate (EBC nitrite-nitrate levels (NO2-NO3 and blood eosinophils in asthmatics and non-asthmatics separately. Genetic heterogeneity of these phenotypes between asthmatics and non-asthmatics was also investigated. PRINCIPAL FINDINGS: In non-asthmatics, after correction for multiple comparisons, we found significant associations of Fe(NO levels with three SNPs in NOS3 and NOS2 (P ≤ 0.002, and of EBC NO2-NO3 level with NOS2 (P = 0.002. In asthmatics, a single significant association was detected between Fe(NO levels and one SNP in NOS3 (P = 0.004. Moreover, there was significant heterogeneity of NOS3 SNP effect on Fe(NO between asthmatics and non-asthmatics (P = 0.0002 to 0.005. No significant association was found between any SNP and NO2-NO3 plasma levels or blood eosinophil counts. CONCLUSIONS: Variants in NO synthase genes influence Fe(NO and EBC NO2-NO3 levels in adults. These genetic determinants differ according to asthma status. Significant associations were only detected for exhaled phenotypes, highlighting the critical relevance to have access to specific phenotypes measured in relevant biological fluid.

  11. Polymorphisms of IL-4, IL-4Rα, and AICDA Genes in Adult Allergic Asthma

    Institute of Scientific and Technical Information of China (English)

    崔天盆; 王琳; 吴健民; 胡丽华; 谢俊刚

    2003-01-01

    Summary: The relationship between 3 polymorphisms sites [interleulin-4 (IL-4), IL-4 receptor (IL-4R) α chain and activation-induced cytidine deaminase (AICDA)] and adult allergic asthma in Chinawas studied. By using case-control method, DNA and clinical data were obtained from allergic asth-matic patients and compared with those in the control subjects. The subjects were genotyped for theIL-4 C-589T promoter polymorphism, the IL-4R α chain Q576R and the AICDA C8408T by poly-merase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The resultsshowed that the IL-4 C-589T was not associated with adult allergic asthma in China. However, theIL-4R α chain 576R/R and AICDA 8408T/T frequency was significantly increased in allergic asthmagroup as compared with that in the control group [odd ratio (OR)= 3. 797 and 9. 127, respectively;P<0.01)] and was correlated with the increased plasma total IgE. These data suggested that theIL-4R α chain 576R/R and AICDA 8408T/T genotypes confer genetic susceptibility to adult allergicasthma in China.

  12. IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study

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    Kurukulaaratchy Ramesh

    2008-01-01

    Full Text Available Abstract Background Tobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13 polymorphisms and tobacco smoke on persistent childhood wheezing and asthma. Methods In the Isle of Wight birth cohort (UK, 1989–1999, five IL13 single nucleotide polymorphisms (SNPs: rs1800925 (-1112C/T, rs2066960, rs1295686, rs20541 (R130Q and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy. Results Maternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair. However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014. Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02. Comparable results were observed for persistent childhood asthma (p for interaction = 0.03. Conclusion This is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.

  13. Bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008049 Activation ralated genes of memory CD+4 T cells in asthma patients. PI Weifeng(皮卫峰),et al. Dept Respir Med, Xinhua Hosp, Sch Med, Shanghai Jiaotong Univ, Shanghai 200092. Chin J Tuberc Respir Dis 2007;30(12):932-935. Objective To screen and identify the genes of activated memory CD+4 T cells in asthma. Methods Differential display polymerase chain reaction(DDPCR) was utilized to identify genes of memory CD+4 T cells after activation from asthmatic patients and normal individuals,

  14. Treating psoriasis by targeting its susceptibility gene Rel.

    Science.gov (United States)

    Fan, Tingting; Wang, Shaowen; Yu, Linjiang; Yi, Huqiang; Liu, Ruiling; Geng, Wenwen; Wan, Xiaochun; Ma, Yifan; Cai, Lintao; Chen, Youhai H; Ruan, Qingguo

    2016-04-01

    Psoriasis is a chronic inflammatory disorder of the skin. Accumulating evidence indicates that the Rel gene, a member of the NF-κB family, is a risk factor for the disease. We sought to investigate whether psoriasis can be prevented by directly targeting the Rel gene transcript, i.e., the c-Rel mRNA. Using chemically-modified c-Rel specific siRNA (siRel) and poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) micelles, we successfully knocked down the expression of c-Rel, and showed that the expression of cytokine IL-23, a direct target of c-Rel that can drive the development of IL-17-producing T cells, was markedly inhibited. More importantly, treating mice with siRel not only prevented but also ameliorated imiquimod (IMQ)-induced psoriasis. Mechanistic studies showed that siRel treatment down-regulated the expression of multiple inflammatory cytokines. Taken together, these results indicate that the susceptibility gene Rel can be targeted to treat and prevent psoriasis.

  15. HLA genes and other candidate genes involved in susceptibility for (pre)neoplastic cervical disease

    NARCIS (Netherlands)

    Zoodsma, M; Nolte, IM; Meerman, GJT; De Vries, EGE; Van Der Zee, AGJ

    2005-01-01

    This review focuses on common and genetic risk factors such as HLA and other genes that may be involved in susceptibility for (pre)neoplastic cervical disease. The goal of this review is the evaluation of polymorphisms that are either associated with cervical intraepithelial neoplasia (CIN) and/or c

  16. Prioritization of Susceptibility Genes for Ectopic Pregnancy by Gene Network Analysis.

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    Liu, Ji-Long; Zhao, Miao

    2016-02-01

    Ectopic pregnancy is a very dangerous complication of pregnancy, affecting 1%-2% of all reported pregnancies. Due to ethical constraints on human biopsies and the lack of suitable animal models, there has been little success in identifying functionally important genes in the pathogenesis of ectopic pregnancy. In the present study, we developed a random walk-based computational method named TM-rank to prioritize ectopic pregnancy-related genes based on text mining data and gene network information. Using a defined threshold value, we identified five top-ranked genes: VEGFA (vascular endothelial growth factor A), IL8 (interleukin 8), IL6 (interleukin 6), ESR1 (estrogen receptor 1) and EGFR (epidermal growth factor receptor). These genes are promising candidate genes that can serve as useful diagnostic biomarkers and therapeutic targets. Our approach represents a novel strategy for prioritizing disease susceptibility genes.

  17. Whole-exome sequencing of a pedigree segregating asthma

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    DeWan Andrew T

    2012-10-01

    Full Text Available Abstract Background Despite the success of genome-wide association studies for asthma, few, if any, definitively causal variants have been identified and there is still a substantial portion of the heritability of the disease yet to be discovered. Some of this “missing heritability” may be accounted for by family-specific coding variants found to be segregating with asthma. Methods To identify family-specific variants segregating with asthma, we recruited one family from a previous study of asthma as reporting multiple asthmatic and non-asthmatic children. We performed whole-exome sequencing on all four children and both parents and identified coding variants segregating with asthma that were not found in other variant databases. Results Ten novel variants were identified that were found in the two affected offspring and affected mother, but absent in the unaffected father and two unaffected offspring. Of these ten, variants in three genes (PDE4DIP, CBLB, and KALRN were deemed of particular interest based on their functional prediction scores and previously reported function or asthma association. We did not identify any common risk variants segregating with asthma, however, we did observe an increase in the number of novel, nonsynonymous variants in asthma candidate genes in the asthmatic children compared to the non-asthmatic children. Conclusions This is the first report applying exome sequencing to identify asthma susceptibility variants. Despite having sequenced only one family segregating asthma, we have identified several potentially functional variants in interesting asthma candidate genes. This will provide the basis for future work in which more families will be sequenced to identify variants across families that cluster within genes.

  18. Association of polymorphisms in the human IL4 and IL5 genes with atopic bronchial asthma and severity of the disease.

    Science.gov (United States)

    Freidin, Maxim B; Kobyakova, Olga S; Ogorodova, Ludmila M; Puzyrev, Valery P

    2003-01-01

    Two polymorphisms in the IL4 (G/C 3'-UTR) and IL5 (C-703T) genes were studied in a sample of families whose probands had atopic bronchial asthma (BA) (66 families, n = 183) and in a group of non-cognate individuals with the severe form of the disease (n = 34). The samples were collected from the Russian population in the city of Tomsk (Russia). Using the transmission/disequilibrium test (TDT), a significant association of allele C-703 IL5 with BA was established (TDT = 4.923, p = 0.007 +/- 0.0007). The analysis of 40 individuals with mild asthma and 49 patients with the severe form of the disease revealed a negative association of genotype GG IL4 (OR = 0.39, 95% CI = 0.15-0.99, p = 0.035), and also a trend towards a positive association of the GC IL4 genotype (OR = 2.52, 95% CI = 0.98-6.57, p = 0.052) with mild BA. There was a concordance of the clinical classification of BA severity with the 'genotype' (McNemar's chi(2) test with continuity correction constituted 0.03, d.f. = 1, p = 0.859). These results suggest that polymorphisms in the IL4 and IL5 genes contribute to the susceptibility to atopic BA and could determine the clinical course of the disease.

  19. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

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    Valentina Escott-Price

    Full Text Available Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6 and 14 (IGHV1-67 p = 7.9×10-8 which indexed novel susceptibility loci.The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

  20. Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

    Science.gov (United States)

    Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Jun, Gyungah; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Denning, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Vronskaya, Maria; Johnson, Andrew D.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Hernández, Isabel; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick C.; Hardy, John; Naranjo, Maria Candida Deniz; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Scarpini, Elio; Bonuccelli, Ubaldo; Mancuso, Michelangelo; Siciliano, Gabriele; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Frank-García, Ana; Panza, Francesco; Solfrizzi, Vincenzo; Caffarra, Paolo; Nacmias, Benedetta; Perry, William; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F. A. G.; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John S. K.; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Van Broeckhoven, Christine; Farrer, Lindsay A.; van Duijn, Cornelia M.; Ramirez, Alfredo

    2014-01-01

    Background Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. PMID:24922517

  1. 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

  2. Toll-like receptors:function and roles in asthma

    Institute of Scientific and Technical Information of China (English)

    周林福; 殷凯生

    2004-01-01

    @@ Asthma is a chronic airway inflammatory disease involved with multiple susceptible genes for atopy. Toll-like receptors (TLRs), an ancient though newly characterized and evolutionarily conserved immune receptor family, activate the mononuclear phagocyte system via both myeloid differentiation marker 88 (MyD88)-dependent and -independent signaling pathways. TLRs might play a key role in asthma by recognition of pathogenic microorganisms, activation of innate immunity, regulation of adaptive immunity, and induction of immune tolerance. For future immunotherapy of asthma, it is promising to develop novel immune regulators by selectively targeting blockade of TLRs.

  3. Gene-network analysis identifies susceptibility genes related to glycobiology in autism.

    Directory of Open Access Journals (Sweden)

    Bert van der Zwaag

    Full Text Available The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD, and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.

  4. Epigenetics of asthma.

    Science.gov (United States)

    Durham, Andrew L; Wiegman, Coen; Adcock, Ian M

    2011-11-01

    Asthma is caused by both heritable and environmental factors. It has become clear that genetic studies do not adequately explain the heritability and susceptibility to asthma. The study of epigenetics, heritable non-coding changes to DNA may help to explain the heritable component of asthma. Additionally, epigenetic modifications can be influenced by the environment, including pollution and cigarette smoking, which are known asthma risk factors. These environmental trigger-induced epigenetic changes may be involved in skewing the immune system towards a Th2 phenotype following in utero exposure and thereby enhancing the risk of asthma. Alternatively, they may directly or indirectly modulate the immune and inflammatory processes in asthmatics via effects on treatment responsiveness. The study of epigenetics may therefore play an important role in our understanding and possible treatment of asthma and other allergic diseases. This article is part of a Special Issue entitled: Biochemistry of Asthma.

  5. Asthma Basics

    Science.gov (United States)

    ... Old Feeding Your 1- to 2-Year-Old Asthma Basics KidsHealth > For Parents > Asthma Basics A A ... Asthma Categories en español Asma: aspectos fundamentales About Asthma Asthma is a common lung condition in kids ...

  6. Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium

    Science.gov (United States)

    Postma, D. S.; Moffatt, M. F.; Jarvis, D.; Ramasamy, A.; Wjst, M.; Omenaas, E. R.; Bouzigon, E.; Demenais, F.; Nadif, R.; Siroux, V.; Polonikov, A. V.; Solodilova, M.; Ivanov, V. P.; Curjuric, I.; Imboden, M.; Kumar, A.; Probst-Hensch, N.; Ogorodova, L. M.; Puzyrev, V. P.; Bragina, E. Yu; Freidin, M. B.; Nolte, I. M.; Farrall, A. M.; Cookson, W. O. C. M.; Strachan, D. P.; Koppelman, G. H.; Boezen, H. M.

    2017-01-01

    Background Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. Methods We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. Results First approach: 50 SNPs were selected based on an overall interaction effect at p<10−4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10−5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10−4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10−4; replication: ORint = 1.40, p = 0.03). Conclusions Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma. PMID:28253294

  7. Distinct microRNA Expression in Human Airway Cells of Asthmatic Donors Identifies a Novel Asthma-associated Gene

    Science.gov (United States)

    Airway inflammation is the hallmark of asthma and suggests a dysregulation of homeostatic mechanisms. MicroRNAs (miRNAs) are key regulators of gene expression, necessary for the proper function of cellular processes. Here, we tested the hypothesis that differences between healthy...

  8. Schizophrenia susceptibility gene locus at Xp22.3.

    Science.gov (United States)

    Milunsky, J; Huang, X L; Wyandt, H E; Milunsky, A

    1999-06-01

    Multiple genetic loci have been implicated in the search for schizophrenia susceptibility genes, none having been proven as causal. Genetic heterogeneity is probable in the polygenic etiology of schizophrenia. We report on two unrelated Caucasian women with paranoid schizophrenia (meeting Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria) who have an Xp22.3 overlapping deletion characterized by fluorescence in situ hybridization (FISH). Patient 1 was previously reported by us (Wyandt HE, Bugeau-Michaud L, Skare JC, Milunsky A. Partial duplication of Xp: a case report and review of previously reported cases. Amer J Med Genet 1991: 40: 280-283) to have a de novo partial duplication of Xp. At that time, she was a 24-year-old woman with short stature, irregular menses, other abnormalities suggestive of Turner syndrome, and paranoid schizophrenia. Recently, FISH analysis demonstrated that she has an inverted duplication (X)(p22.1p11.2) and a microscopic deletion (X)(p22.2p22.3) between DXS1233 and DXS7108 spanning approximately 16-18 cM. Patient 2 is a 14-year-old girl with short stature, learning disabilities, and paranoid schizophrenia. High-resolution chromosome analysis revealed a de novo deletion involving Xp22. FISH analysis showed that the deletion (X)(p22.2p22.3) spanned 10-12 cM between AFMB290XG5 and DXS1060. Given that deletions of Xp22 are not common events, the occurrence of two unrelated schizophrenia patients with an overlapping deletion of this region would be extraordinarily rare. Hence, the deletion within Xp22.3 almost certainly contains a gene involved in the pathogenesis of paranoid schizophrenia.

  9. Mucin 1 Gene (MUC1 and Gastric-Cancer Susceptibility

    Directory of Open Access Journals (Sweden)

    Norihisa Saeki

    2014-05-01

    Full Text Available Gastric cancer (GC is one of the major malignant diseases worldwide, especially in Asia. It is classified into intestinal and diffuse types. While the intestinal-type GC (IGC is almost certainly caused by Helicobacter pylori (HP infection, its role in the diffuse-type GC (DGC appears limited. Recently, genome-wide association studies (GWAS on Japanese and Chinese populations identified chromosome 1q22 as a GC susceptibility locus which harbors mucin 1 gene (MUC1 encoding a cell membrane-bound mucin protein. MUC1 has been known as an oncogene with an anti-apoptotic function in cancer cells; however, in normal gastric mucosa, it is anticipated that the mucin 1 protein has a role in protecting gastric epithelial cells from a variety of external insults which cause inflammation and carcinogenesis. HP infection is the most definite insult leading to GC, and a protective function of mucin 1 protein has been suggested by studies on Muc1 knocked-out mice.

  10. Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway

    Directory of Open Access Journals (Sweden)

    Bahnweg Margret

    2006-04-01

    Full Text Available Abstract The vitamin D prophylaxis of rickets in pregnant women and newborns may play a role in early allergic sensitization. We now asked if an already diseased population may have inherited genetic variants in the vitamin D turnover or signalling pathway. Serum levels of calcidiol (25-OH-D3 and calcitriol (1,25-(OH2-D3 were retrospectively assessed in 872 partipants of the German Asthma Family Study. 96 DNA single base variants in 13 different genes were genotyped with MALDI-TOF and a bead array system. At least one positive SNP with a TDT of p Genetic analysis of biological pathways seem to be a promising approach where this may be a first entry point into effects of a polygenic inherited vitamin D sensitivity that may affect also other metabolic, immunological and cancerous diseases.

  11. Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour

    NARCIS (Netherlands)

    Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

    2015-01-01

    The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive en

  12. Gene-Gene Associations with the Susceptibility of Kawasaki Disease and Coronary Artery Lesions.

    Directory of Open Access Journals (Sweden)

    Ho-Chang Kuo

    Full Text Available Kawasaki disease (KD is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL formation. We examined 384 single-nucleotide polymorphisms (SNPs for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73, KD patients without CAL (n = 153, and cohort controls (n = 575. Individual SNPs were first assessed by univariate analysis (UVA and multivariate analysis (MVA. We used multifactor dimensionality reduction (MDR to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10, while 35 individual SNPs were significantly associated using MVA (p ≤ 0.05. Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ≤ 0.05. In logistic regression, combined possession of PDE2A (rs341058 and CYFIP2 (rs767007 significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10(-7, while combinations of LOC100133214 (rs2517892 and IL2RA (rs3118470 significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10(-5. Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

  13. Variants of DENND1B associated with asthma in children

    DEFF Research Database (Denmark)

    Sleiman, Patrick M A; Flory, James; Imielinski, Marcin;

    2010-01-01

    Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.......Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown....

  14. Genetic influence on the age at onset of asthma

    DEFF Research Database (Denmark)

    Thomsen, Simon Francis; Duffy, David Lorenzo; Kyvik, Kirsten Ohm;

    2010-01-01

    Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma.......Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma....

  15. Pediatric Asthma

    Science.gov (United States)

    ... Plan Asthma Epidemic Eating with Asthma Helping Your Child Cope With a Medical Condition Nasal Wash Guide Cleaning Dirty Items Impact on Families Asthma & Pets Peak Flow Meter Athletes & Asthma Helpful Tools for ...

  16. Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation.

    Science.gov (United States)

    Favre, G; Banta Lavenex, P; Lavenex, P

    2012-10-23

    The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

  17. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Notaridou, Maria; Quaye, Lydia; Dafou, Dimitra;

    2011-01-01

    Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines...

  18. Association of TNF-α and IL-13 genes polymorphisms with bronchial asthma%TNF-α及IL-13基因的多态性与哮喘的相关性研究

    Institute of Scientific and Technical Information of China (English)

    梁文华; 周兆山; 吉中强; 王燕青; 薛卫林; 张小燕

    2015-01-01

    目的 探讨肿瘤坏死因子-α (tumor necrosis factor-α,TNF-α)基因和白细胞介素13(interleukin-13,IL-13)基因多态性与青岛地区汉族成人哮喘的相关性.方法 应用SNaPshot方法对400例哮喘患者和200名正常对照的TNF-α基因的rs1799724、rs1800630、rs1799964和rs769178以及IL-13基因的rs2158177和rs1295687共6个多态位点的多态性进行检测.结果 相对于AA-GA基因型,rs2158177位点GG基因型频率在对照组为5%,哮喘组为2.8%,差异有统计学意义(OR=0.31,95%CI:0.12-0.82,P=0.021).其余5个位点的基因型频率在哮喘组与对照组间差异无统计学意义(P>0.05).结论 IL-13基因rs2158177多态性与青岛地区汉族成人哮喘具有相关性.未发现TNF-α基因的多态性与青岛地区汉族成人哮喘存在相关性.%Objective To assess the association of polymorphisms of TNF-α gene (rs1799724, rs1800630, rs1799964 and rs769178) and IL-13 gene (rs2158177 and rs1295687) with susceptibility to asthma among ethnic Chinese in Qingdao region.Methods For 400 asthma patients and 200 healthy subjects, above polymorphisms were detected with a SNaPshot method.Results For rs2158177, thefrequency of genotype of GG in the asthma group was significantly lower than the control group (2.8% vs.5%, OR=0.31, 95%CI: 0.12-0.82,P=0.021).No significant difference was detected in the genotypic frequencies for the remaining 5 polymorphisms between the two groups (All P>0.05).Conclusion The study has indicated that rs2158177 polymorphism of the IL-13 gene is associated with asthma in ethnic Han Chinese from Qingdao.No association has been found between polymorphisms of TNF-α gene with susceptibility to asthma.

  19. Difficult Asthma

    Directory of Open Access Journals (Sweden)

    Ahmet Uslu

    2003-03-01

    Full Text Available Difficult asthma is a distinct entity of asthma, comprising approximately %5 of asthmatic patients. There is no agreed definition of difficult asthma. It will include asthma uncontrolled by new standard therapy, steroid dependent, steroid resistant and severe asthma. In this study difficult asthma; clinical features, risk factors, pathophysiology and novel therapies are summarized by literatures.

  20. Difficult asthma

    OpenAIRE

    Ahmet Uslu; Tülay Özdemir

    1989-01-01

    Difficult asthma is a distinct entity of asthma, comprising approximately %5 of asthmatic patients. There is no agreed definition of difficult asthma. It will include asthma uncontrolled by new standard therapy, steroid dependent, steroid resistant and severe asthma. In this study difficult asthma; clinical features, risk factors, pathophysiology and novel therapies are summarized by literatures.

  1. Management Features of Asthma in Children Under the Deletion Polymorphism of Genes Gstt1 and Gstm1

    Directory of Open Access Journals (Sweden)

    Elena C. Koloskova

    2015-03-01

    Full Text Available It has been performed complex examination of 50 school-aged children with bronchial asthma, which included a study of acetylation phenotype and a determination of deletions in the genes of glutathione-S-transferase (GSTM1 and GSTT1. The study has shown that in children with slow acetylation phenotype and the absence of deletions in genes GSTT1 and GSTM1 аssociates with poor control of the disease that requires increased anti-inflammatory therapy with an emphasis on higher "step". When using the ACT test for the assessment of asthma control often determined by the underestimation of their child's condition, indicating that about the need for the objectification of control of the disease with the help of spirographic method and subsequent correction of the basic therapy.

  2. Association of the variants in AGT gene with modified drug response in Korean aspirin-intolerant asthma patients.

    Science.gov (United States)

    Pasaje, Charisse Flerida A; Kim, Jeong-Hyun; Park, Byung-Lae; Cheong, Hyun Sub; Park, Tae-Joon; Lee, Jin-Sol; Kim, Yongha; Bae, Joon Seol; Kim, Jin Moo; Park, Jong Sook; Park, Choon-Sik; Shin, Hyoung Doo

    2011-10-01

    The angiotensinogen (AGT) gene enhances the effect of several bronchoconstrictors and produces a peptide that is accumulated in the airways of asthma patients; events that may underpin the pathogenesis of aspirin-intolerant asthma (AIA). To carry out a case-control analysis between AGT and aspirin-induced bronchospasm following treatment with an anti-asthma drug, montelukast (MLK), 38 single nucleotide polymorphisms (SNPs) in AGT were genotyped in 56 AIA cohort. Genotyping was performed with TaqMan assay and haplotypes were inferred using PHASE algorithm ver. 2.0. Statistical analyses of each SNPs and haplotypes were performed using SAS version 9.1. Among 13 variants displaying significant signals, two SNPs (+2401C>G and +2476C>T) in the intronic region of AGT were significantly associated with modification of drug response even after correction for multiple testing (P=0.0009-0.002; P(corr)=0.02-0.03). Furthermore, the two variants also exhibited associations with MLK response rate (P=0.0003-0.0006; P(corr)=0.006-0.01). Although our results are preliminary and further replication in a larger-scale group of subjects should be warranted, these observations provide evidence that AGT variants might be one of genetic factors involved in the response of anti-asthma drugs in AIA patients.

  3. Pharmacogenomics of pediatric asthma

    Directory of Open Access Journals (Sweden)

    Gupta Sarika

    2010-01-01

    Full Text Available Context: Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below. Evidence Acquisition: A search of PubMed, Google scholar, E-Medicine, BMJ and Mbase was done using the key words "pharmacogenomics of asthma", "pharmacogenomics of β-agonist, glucocorticoids, leukotriene modifiers, theophylline, muscarinic antagonists in asthma". Results: Presently, there are limited examples of gene polymorphism that can influence response to asthma therapy. Polymorphisms that alter response to asthma therapy include Arg16Gly, Gln27Glu, Thr164Ile for β-agonist receptor, polymorphism of glucocorticoid receptor gene, CRHR1 variants and polymorphism of LTC4S, ALOX5. Polymorphic variants of muscarinic receptors, PDE4 and CYP450 gene variants. Conclusion: It was concluded that genetic variation can improve the response to asthma therapy. However, no gene polymorphism has been associated with consistent results in different populations. Therefore, asthma pharmacogenomic studies in different populations with a large number of subjects are required to make possible tailoring the asthma therapy according to the genetic characteristic of individual patient.

  4. Identification of susceptibility genes for bipolar affective disorder and schizophrenia on chromosome 22q13

    DEFF Research Database (Denmark)

    Severinsen, Jacob Eg

    2006-01-01

    Linkage analyses suggest that chromosome 22q12-13 may harbor one or more shared susceptibility loci for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of distantly related cases and control individuals from the Faeroe Islands our group has previously reported that chromosome 22......q13 may harbor two shared susceptibility loci for BPD and SZ. The aim of the Ph.D. project was to identify and characterize susceptibility genes for BPD and SZ located in these two loci on 22q13, primarily by association analyses of selected positional candidate genes in a number of population...... samples (total of 1,751 individuals), and by bioinformatic and expression analyses of a subset of disease associated genes and gene variants. In total 67 single nucleotide polymorphisms (SNPs) located in 18 positional candidate genes, and 4 microsattelite markers were investigated, using a Scottish case...

  5. Microsatellite Scan Identifies New Candidate Genes for Susceptibility to Alcoholic Chronic Pancreatitis in Japanese Patients

    Directory of Open Access Journals (Sweden)

    Kei Kitahara

    2008-01-01

    Full Text Available Alcohol abuse is one of the most common risk factor for chronic pancreatitis, but the underlying pathophysiological mechanisms remain unclear. The aim of this study was to identify genes that contribute to susceptibility or resistance for alcoholic chronic pancreatitis by screening the whole genome. Sixty-five patients with alcoholic chronic pancreatitis (63 men and 2 women, mean age 55.2 years and 99 healthy Japanese controls were enrolled in this study. This was an association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. This search revealed 10 candidate susceptibility regions and 5 candidate resistant regions throughout the genome. No specific microsatellite markers were detected in association with previously reported susceptibility genes for chronic pancreatitis, such as PRSS1, PRSS2, CTRC, SPINK1, CFTR, ALDH2, and CYP2E1. Among the statistically significant markers, D15S1007 on chromosome 15q14 showed strong evidence for disease susceptibility (70.8% vs. 35.1%, Pc = 0.0001. Within 500 kb of D15S1007, several genes were candidate genes for susceptibility, including FMN1, DKFZP686C2281, LOC440268, RYR3, and AVEN, This study identified 10 candidate susceptibility and 5 candidate resistant regions that may contain genes involved in ACP pathogenesis.

  6. Relationship between the Cholesterol Level in Children with Asthma and Susceptibility of Mycoplasma Pneumoniae%哮喘患儿血清胆固醇水平与易感肺炎支原体的关系

    Institute of Scientific and Technical Information of China (English)

    张长娟; 段全纪; 周清霞

    2014-01-01

    目的:探讨支气管哮喘(简称哮喘)患儿血清胆固醇水平与易感肺炎支原体( MP )的关系。方法60例哮喘患儿分为哮喘组,40例健康儿童被分为正常对照组,检测两组血清总胆固醇水平,并进行1年的随访,记录随访期内肺炎支原体感染的次数。结果哮喘患儿血清总胆固醇水平及随访期内哮喘患儿肺炎支原体感染次数明显高于对照组,( P<0.05)。结论哮喘患儿存在血清胆固醇水平升高,其可致哮喘患儿更易感染肺炎支原体。%[ ABSTRACT] Objective To discuss the relationship between the cholesterol level in children with asthma and susceptibility of Mycoplasma pneumonia ( MP ) .Methods Sixty children with asthma were divided into the asthma group,and 40 healthy volunteers were divided into the healthy control group,then the cholesterol level was contrasted be-tween the two groups.Children with asthma and healthy volunteers were followed up for 1 year,and the number of MP in-fection during the follow-up period was recorded.Results The cholesterol level and the number of MP infection in the asthma group were significantly higher than those in the healthy control group.Conclusion High cholesterol exists in children with asthma and it can make children with asthma more vulnerable to infection MP.

  7.  Possible gene dosage effect of glutathione-S-transferases on atopic asthma: Using real-time PCR for quantification of GSTM1 and GSTT1 gene copy numbers

    DEFF Research Database (Denmark)

    Andersen, Charlotte Brasch; Christiansen, Lene; Tan, Qihua;

    2004-01-01

    Asthma is a complex genetic disorder characterized by chronic inflammation in the airways. As oxidative stress is a key component of inflammation, variations in genes involved in antioxidant defense could therefore be likely candidates for asthma. Three enzymes from the superfamily glutathione-S-...

  8. Plasminogen activator inhibitor-1 gene 4G/5G polymorphism in Turkish children with asthma and allergic rhinitis.

    Science.gov (United States)

    Ozbek, Ozlem Yilmaz; Ataç, F Belgin; Ogus, Ersin; Ozbek, Namik

    2009-01-01

    Plasminogen activator inhibitor (PAI-1) has an essential role in tissue remodeling after inflammation. Recent literature revealed only one study evaluating PAI-1 4G/5G gene polymorphism in children with asthma and none in children with allergic rhinitis. We aimed to investigate distribution of PAI-1 4G/5G polymorphism in a group of Turkish children with asthma and allergic rhinitis and compare these findings with those obtained in normal peers. Patients with physician-diagnosed asthma (n = 106) and allergic rhinitis (n = 99) and 83 healthy peers were included in this study. We evaluated PAI-1 4G/5G polymorphism genotype as well as the possible association between PAI-1 4G/5G polymorphism and pulmonary function tests, serum total immunoglobulin E (IgE), total eosinophil count, and skin-prick test positivity in our study. The prevalence of the 4G allele significantly exceeded the values found in the controls both in patients with asthma (p = 0.001) and in patients with allergic rhinitis (p = 0.002). Interestingly, comparison of asthmatic patients revealed that mean baseline percent forced expiratory volume in 1 second and forced vital capacity were significantly higher in patients who bear 5G/5G genotype than in those who have 4G/4G or 4G/5G genotypes. No statistically significant relationship were found between PAI-1 polymorphism and total serum IgE levels, total eosinophil count, or selected skin test responses to aeroallergens. Our study suggests that Turkish children with asthma or allergic rhinitis have a higher prevalence of PAI-1 4G allele compared with their healthy peers.

  9. Differences in intestinal gene expression proflies in broiler lines varying in susceptibility to malabsorption syndrome

    NARCIS (Netherlands)

    Hemert, van S.; Hoekman, A.J.W.; Smits, M.A.; Rebel, J.M.J.

    2004-01-01

    Examination of the host gene expression response upon encounters with pathogens may provide insights into the cellular events following an infection. In addition, it may shed light on the basic mechanisms underlying differences in the susceptibility of the host. In this study gene expression in the

  10. Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Okamoto, Koji; Iwasaki, Naoko; Nishimura, Chisa

    2010-01-01

    , member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the beta cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals...

  11. Defining asthma in genetic studies

    NARCIS (Netherlands)

    Koppelman, GH; Postma, DS; Meijer, G.

    1999-01-01

    Genetic studies have been hampered by the lack of a gold standard to diagnose asthma. The complex nature of asthma makes it more difficult to identify asthma genes. Therefore, approaches to define phenotypes, which have been successful in other genetically complex diseases, may be applied to define

  12. NRAMP1 and VDR Gene Polymorphisms in Susceptibility to Tuberculosis in Venezuelan Population

    Directory of Open Access Journals (Sweden)

    Mercedes Fernández-Mestre

    2015-01-01

    Full Text Available Natural resistance-associated macrophage protein (Nramp1 and the vitamin D receptor (VDR are central components of the innate and adaptive immunity against Mycobacterium tuberculosis, and associations between susceptibility to tuberculosis and polymorphisms in the genes NRAMP and VDR have been sought in geographically diverse populations. We investigated associations of NRAMP1 and VDR gene polymorphisms with susceptibility to TB in the Venezuelan population. The results suggest the absence of any association between VDR variants FokI, ApaI, and TaqI and susceptibility to tuberculosis. In contrast, the NRAMP1 3′UTR variants were associated with susceptibility to M. tuberculosis infection, as seen in the comparisons between TST+ and TST− controls, and also with progression to TB disease, as shown in the comparisons between TB patients and TST+ controls. This study confirms the previously described association of the NRAMP1 3′UTR polymorphism with M. tuberculosis infection and disease progression.

  13. NRAMP1 and VDR Gene Polymorphisms in Susceptibility to Tuberculosis in Venezuelan Population

    Science.gov (United States)

    Fernández-Mestre, Mercedes; Villasmil, Ángel; Takiff, Howard; Fuentes Alcalá, Zhenia

    2015-01-01

    Natural resistance-associated macrophage protein (Nramp1) and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis, and associations between susceptibility to tuberculosis and polymorphisms in the genes NRAMP and VDR have been sought in geographically diverse populations. We investigated associations of NRAMP1 and VDR gene polymorphisms with susceptibility to TB in the Venezuelan population. The results suggest the absence of any association between VDR variants FokI, ApaI, and TaqI and susceptibility to tuberculosis. In contrast, the NRAMP1 3′UTR variants were associated with susceptibility to M. tuberculosis infection, as seen in the comparisons between TST+ and TST− controls, and also with progression to TB disease, as shown in the comparisons between TB patients and TST+ controls. This study confirms the previously described association of the NRAMP1 3′UTR polymorphism with M. tuberculosis infection and disease progression. PMID:26578819

  14. Mapping Interactive Cancer Susceptibility Genes in Prostate Cancer

    Science.gov (United States)

    2007-04-01

    further analysis around this FHIT marker. Under the assumption of a recessive model, we attempted to narrow the disease interval by examining key meiotic ...examining key meiotic recombinants. A and B, physical map illustrating marker and FHIT exon locations. Solid bar, FHIT gene boundary; vertical bars, exons 5...gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 1996;84

  15. Natural selection on genes that underlie human disease susceptibility

    Science.gov (United States)

    Blekhman, Ran; Man, Orna; Herrmann, Leslie; Boyko, Adam R.; Indap, Amit; Kosiol, Carolin; Bustamante, Carlos D.; Teshima, Kosuke M.; Przeworski, Molly

    2008-01-01

    What evolutionary forces shape genes that contribute to the risk of human disease? Do similar selective pressures act on alleles that underlie simple vs. complex disorders? [1-3]. Answers to these questions will shed light on the origin of human disorders (e.g., [4]), and help to predict the population frequencies of alleles that contribute to disease risk, with important implications for the efficient design of mapping studies [5-7]. As a first step towards addressing them, we created a hand-curated version of the Mendelian Inheritance in Man database (OMIM). We then examined selective pressures on Mendelian disease genes, genes that contribute to complex disease risk and genes known to be essential in mouse, by analyzing patterns of human polymorphism and of divergence between human and rhesus macaque. We find that Mendelian disease genes appear to be under widespread purifying selection, especially when the disease mutations are dominant (rather than recessive). In contrast, the class of genes that influence complex disease risk shows little signs of evolutionary conservation, possibly because this category includes both targets of purifying and positive selection. PMID:18571414

  16. Schizophrenia susceptibility genes on chromosome 13q32

    Institute of Scientific and Technical Information of China (English)

    胡颖; 许琪; 鞠桂芝; 刘树铮; 史杰萍; 于雅琴; 尉军

    2004-01-01

    @@Schizophrenia is a complex mental disorder affecting approximately 1% of the general population worldwide.1 It has a high incidence in the general population, a poor prognosis and a poor outcome, in that it has become a major social problem. Family, twin, and adoption studies have clearly shown that a genetic component is quite likely to play an important role in determining susceptibility to schizophrenia. The genome-wide scan indicates that several chromosomal regions are linked to schizophrenia, some of which have been replicated independently including 6p21-24, 8p21-22, 13q14-33 and 22q11-12.2,3 This study was designed to detect two single nucleotide polymorphisms (SNPs) located in the 13q14-33 region, rs188608 at the STK24 locus and rs2892679 at the GPC6 locus, among Chinese population.

  17. Identification of a T1D Susceptibility Gene

    Directory of Open Access Journals (Sweden)

    Grant Morahan

    2001-01-01

    Full Text Available It is not known what causes type 1 diabetes (T1D, which affects over 1 million people in the U.S. alone. Each year, 30,000 young people in the U.S. develop this disease and depend on insulin injections thereafter. Because of the huge cost to the individual, the family, and to society in increased health care costs, it is important to find what makes these people susceptible. The disease process itself is clear: the individual’s immune system — T lymphocytes in particular — attack and destroy the body’s insulin-producing cells. But how and why this autoimmune process starts or proceeds unregulated is still not known.

  18. Evidence for an asthma risk locus on chromosome Xp: a replication linkage study

    DEFF Research Database (Denmark)

    Brasch-Andersen, C; Møller, M U; Haagerup, A;

    2008-01-01

    BACKGROUND: Asthma is a complex genetic disorder characterized by chronic inflammation in the airways. Identification of genetic risk factors for asthma has been complicated due to genetic heterogeneity and influence from environmental risk factors. Despite the fact that multiple genetic linkage...... studies have been carried out the results are still conflicting and call for replication experiments. A Danish genome-wide scan has prior reported evidence for candidate regions for asthma susceptibility genes on chromosomes 1p, 5q, 6p, 12q and Xp. Linkage to chromosome 12q was later confirmed in the same...... replication sample as used in the present study. The aim of the study was to replicate linkage to candidate regions for asthma in an independent Danish sample. METHODS: We performed a replication study investigating linkage to candidate regions for asthma on chromosomes 1p36.31-p36.21, 5q15-q23.2, 6p24.3-p22...

  19. MDM2 SNP309, gene-gene interaction, and tumor susceptibility: an updated meta-analysis

    Directory of Open Access Journals (Sweden)

    Wu Wei

    2011-05-01

    Full Text Available Abstract Background The tumor suppressor gene p53 is involved in multiple cellular pathways including apoptosis, transcriptional control, and cell cycle regulation. In the last decade it has been demonstrated that the single nucleotide polymorphism (SNP at codon 72 of the p53 gene is associated with the risk for development of various neoplasms. MDM2 SNP309 is a single nucleotide T to G polymorphism located in the MDM2 gene promoter. From the time that this well-characterized functional polymorphism was identified, a variety of case-control studies have been published that investigate the possible association between MDM2 SNP309 and cancer risk. However, the results of the published studies, as well as the subsequent meta-analyses, remain contradictory. Methods To investigate whether currently published epidemiological studies can clarify the potential interaction between MDM2 SNP309 and the functional genetic variant in p53 codon72 (Arg72Pro and p53 mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls. Results The data we reviewed indicated that variant homozygote 309GG and heterozygote 309TG were associated with a significant increased risk of all tumor types (homozygote comparison: odds ratio (OR = 1.25, 95% confidence interval (CI = 1.13-1.37; heterozygote comparison: OR = 1.10, 95% CI = 1.03-1.17. We also found that the combination of GG and Pro/Pro, TG and Pro/Pro, GG and Arg/Arg significantly increased the risk of cancer (OR = 3.38, 95% CI = 1.77-6.47; OR = 1.88, 95% CI = 1.26-2.81; OR = 1.96, 95% CI = 1.01-3.78, respectively. In a stratified analysis by tumor location, we also found a significant increased risk in brain, liver, stomach and uterus cancer (OR = 1.47, 95% CI = 1.06-2.03; OR = 2.24, 95%CI = 1.57-3.18; OR = 1.54, 95%CI = 1.04-2.29; OR = 1.34, 95%CI = 1.07-1.29, respectively. However, no association was seen between MDM2 SNP309 and tumor susceptibility

  20. Beta 2-adrenergic receptor gene association with overweight and asthma in children and adolescents and its relationship with physical fitness

    Directory of Open Access Journals (Sweden)

    Neiva Leite

    2015-12-01

    Full Text Available Objective: To investigate the association of Arg16Gly and Gln27Glu polymorphisms of β2-adrenergic receptor gene (ADRB2 with the occurrence of asthma and overweight and the gene's influence on anthropometric, clinic, biochemical and physical fitness variables in children and adolescents. Methods: Subjects were evaluated for allelic frequencies of the β2-adrenergic receptor gene, height, weight, body mass index (BMI, BMI Z-score, waist circumference (WC, pubertal stage, resting heart rate (HRres, blood pressure (BP, total cholesterol (TC, glucose, insulin, high density lipoprotein (HDL-C, low density lipoprotein (LDL-C, triglyceride (TG, Homeostasis Metabolic Assessment (HOMA2-IR, Quantitative Insulin Sensitivity Check Index (QUICKI and maximal oxygen uptake (VO2max. The participants were divided in four groups: overweight asthmatic (n=39, overweight non-asthmatic (n=115, normal weight asthmatic (n=12, and normal weight non-asthmatic (n=40. Results: Regarding the Gln27Glu polymorphism, higher total cholesterol was observed in usual genotype individuals than in genetic variant carriers (p=0.04. No evidence was found that the evaluated polymorphisms are influencing the physical fitness. The Arg16 allele was found more frequently among the normal weight asthmatic group when compared to the normal weight non-asthmatic group (p=0.02, and the Glu27 allele was more frequently found in the overweight asthmatics group when compared to the normal weight non-asthmatic group (p=0.03. Conclusions: The association of Arg16 allele with the occurrence of asthma and of the Glu27 allele with overweight asthmatic adolescents evidenced the contribution of the β2-adrenergic receptor gene to the development of obesity and asthma.

  1. Identification of susceptibility genes and genetic modifiers of human diseases

    Science.gov (United States)

    Abel, Kenneth; Kammerer, Stefan; Hoyal, Carolyn; Reneland, Rikard; Marnellos, George; Nelson, Matthew R.; Braun, Andreas

    2005-03-01

    The completion of the human genome sequence enables the discovery of genes involved in common human disorders. The successful identification of these genes is dependent on the availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform technology based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology, we generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes. We also established a large DNA sample bank comprised of more than 50,000 consented healthy and diseased individuals. This combination of reagents and technology allows the execution of large-scale genome-wide association studies. Taking advantage of MassARRAY"s capability for quantitative analysis of nucleic acids, allele frequencies are estimated in sample pools containing large numbers of individual DNAs. To compare pools as a first-pass "filtering" step is a tremendous advantage in throughput and cost over individual genotyping. We employed this approach in numerous genome-wide, hypothesis-free searches to identify genes associated with common complex diseases, such as breast cancer, osteoporosis, and osteoarthritis, and genes involved in quantitative traits like high density lipoproteins cholesterol (HDL-c) levels and central fat. Access to additional well-characterized patient samples through collaborations allows us to conduct replication studies that validate true disease genes. These discoveries will expand our understanding of genetic disease predisposition, and our ability for early diagnosis and determination of specific disease subtype or progression stage.

  2. Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil

    OpenAIRE

    Castellucci, Léa; Jamieson, Sarra E; Almeida, Lucas; Oliveira, Joyce; Guimarães, Luiz Henrique; Lessa, Marcus; Fakiola, Michaela; Jesus, Amélia Ribeiro de; Miller, E. Nancy; Carvalho, Edgar M.; Blackwell, Jenefer M.

    2012-01-01

    Leishmania braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. In the mouse, Fli1 was identified as a gene influencing enhanced wound healing and resistance to CL caused by L. major. Polymorphism at FLI1 is associated with CL caused by L. braziliensis in humans, with an inverse association observed for ML disease. Here we extend the analysis to look at other wound healing genes, including CTGF, TGFB1, TGFBR1/2, SMADS 2/3/4/7 and FLII, all functionally linked along with FLI1 in ...

  3. Chromosomal Abnormalities and Putative Susceptibility Genes in Autism Spectrum Disorders

    DEFF Research Database (Denmark)

    Nielsen, Mette Gilling

    Autism spectrum disorders (ASDs) is a heterogeneous group of neurodevelopmental disorders with a significant genetic component as shown by family and twin studies. However, only a few genes have repeatedly been shown to be involved in the development of ASDs. The aim of this study has been...

  4. Influence of doxorubicin on fluconazole susceptibility and efflux pump gene expression of Candida dubliniensis.

    LENUS (Irish Health Repository)

    Schulz, Bettina

    2012-05-01

    The effect of doxorubicin (DOX) on the fluconazole (FLU) susceptibility of C. dubliniensis was investigated. Isolates were exposed to DOX and FLU in a chequerboard assay and resistance gene expressions were analysed after DOX exposure. The susceptibility of the yeast to FLU was decreased in the presence of DOX in the chequerboard assay with FIC indices suggesting an antagonistic effect. Gene expression analyses showed an overexpression of CdCDR2. Hence, DOX was found to have an impact on resistance mechanisms in C. dubliniensis isolates.

  5. Occupational asthma

    Science.gov (United States)

    ... Names Asthma - occupational exposure; Irritant-induced reactive airways disease Images Spirometry Respiratory system References Lemiere C, Vandenplas O. Occupational allergy and asthma. In: Adkinson NF Jr., Bochner ...

  6. Protein-protein interaction and pathway analyses of top schizophrenia genes reveal schizophrenia susceptibility genes converge on common molecular networks and enrichment of nucleosome (chromatin) assembly genes in schizophrenia susceptibility loci.

    Science.gov (United States)

    Luo, Xiongjian; Huang, Liang; Jia, Peilin; Li, Ming; Su, Bing; Zhao, Zhongming; Gan, Lin

    2014-01-01

    Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.

  7. Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns.

    Science.gov (United States)

    Yao, Gen-Dong; Li, Shou-Xia; Chen, Ding-Li; Feng, Hai-Qin; Zhao, Su-Bin; Liu, Yong-Jie; Guo, Li-Li; Yang, Zhi-Ming; Zhang, Xiao-Fang; Sun, Cai-Xia; Wang, Ze-Hui; Zhang, Wei-Yong

    2014-01-01

    The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss.

  8. The role of ERBB2 gene polymorphisms in leprosy susceptibility

    Directory of Open Access Journals (Sweden)

    Jamile Leão Rêgo

    2015-04-01

    Full Text Available Mycobacterium lepraeinfects skin and peripheral nerves causing deformities and disability. The M. lepraebacterium binds to ErbB2 on the Schwann cell surface causing demyelination and favoring spread of the bacilli and causing nerve injury. Polymorphisms at the ERBB2 gene were previously investigated as genetic risk factors for leprosy in two Brazilian populations but with inconsistent results. Herein we extend the analysis of ERBB2 variants to a third geographically distinct population in Brazil. Our results show that there is no association between the genotyped SNPs and the disease (p> 0.05 in this population. A gene set or pathway analysis under the genomic region of ERBB2 will be necessary to clarify its regulation under M. lepraestimulus.

  9. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility

    Directory of Open Access Journals (Sweden)

    Pradhan V

    2010-01-01

    Full Text Available Systemic lupus erythematosus (SLE is a prototype autoimmune disease. SLE is a result of one or more immune mechanisms, like autoantibody production, complement activation, multiple inflammation and immune complex deposition leading to organ tissue damage. SLE affected patients are susceptible to common and opportunistic infections. There are several reports suggesting that Mycobacterium tuberculosis infection precipitates SLE in patients from endemic areas. Genetic factors and environmental factors also play an important role in the overall susceptibility to SLE pathophysiology. Recently, protein tyrosine phosphatase, non-receptor type 22 (PTPN22 gene, has been found to be associated with several autoimmune diseases like SLE, Grave′s disease and Hashimoto thyroiditis. The missense R620W polymorphism, rs 2476601, in PTPN22 gene at the nucleotide 1858 in codon 620 (620Arg > Trp has been associated with autoimmune diseases. The PTPN22 locus is also found to be responsible for development of pulmonary tuberculosis in certain populations. The PTPN22 1858C/T gene locus will be ideal to look for SLE susceptibility to tuberculosis in the Indian population. In this review, we focus on human PTPN22 gene structure and function as well as the association of PTPN22 gene polymorphisms with SLE susceptibility

  10. Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method

    Institute of Scientific and Technical Information of China (English)

    SUN Xiangqing; JIA Yanbin; ZHANG Xuegong; XU Qi; SHEN Yan; LI Yanda

    2005-01-01

    Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world's population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions of COMTand ALDH3B1 genes was detected to be significantly susceptible to schizophrenia.

  11. Distinct regulation of murine lupus susceptibility genes by the IRF5/Blimp-1 axis.

    Science.gov (United States)

    Panchanathan, Ravichandran; Liu, Hongzhu; Liu, Hongqi; Fang, Chee-Mun; Erickson, Loren D; Pitha, Paula M; Choubey, Divaker

    2012-01-01

    Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for IFN regulatory factor 5 [IRF]5 and Blimp-1) in the human genome. Accordingly, the murine Irf5 and Prdm1 genes have been shown to play a role in lupus susceptibility. However, it remains unclear how IRF5 and Blimp-1 (a transcriptional target of IRF5) contribute to lupus susceptibility. Given that the murine lupus susceptibility locus Nba2 includes the IFN-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5/Blimp-1 axis could regulate the expression of these genes. We found that an Irf5 deficiency in mice decreased the expression of Blimp-1 and reduced the expression of the Ifi202. However, the deficiency increased the expression of Aim2 and Fcgr2b. Correspondingly, increased expression of IRF5 in cells increased levels of Blimp-1 and p202 protein. Moreover, Blimp-1 expression increased the expression of Ifi202, whereas it reduced the expression of Aim2. Interestingly, an Aim2 deficiency in female mice increased the expression of IRF5. Similarly, the Fcgr2b-deficient mice expressed increased levels of IRF5. Moreover, increased expression of IRF5 and Blimp-1 in lupus-prone C57BL/6.Nba2, New Zealand Black, and C57BL/6.Sle123 female mice (as compared with age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Taken together, our observations demonstrate that the IRF5/Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and they suggest an important role for the IRF5/Blimp-1/p202 axis in murine lupus susceptibility.

  12. Distinct regulation of murine lupus susceptibility genes by the IRF5-Blimp-1 axis

    Science.gov (United States)

    Panchanathan, Ravichandran; Liu, Hongzhu; Liu, Hongqi; Fang, Chee-Mun; Erickson, Loren D.; Pitha, Paula M.; Choubey, Divaker

    2011-01-01

    Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for the IRF5 and Blimp-1) in the human genome. Accordingly, the murine Irf5 and Prdm1 genes have been shown to play a role in lupus susceptibility. However, it remains unclear how IRF5 and Blimp-1 (a transcriptional target of IRF5) contribute to lupus susceptibility. Given that the murine lupus susceptibility locus Nba2 includes the interferon-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5-Blimp-1 axis could regulate the expression of these genes. We found that an Irf5-deficiency in mice decreased the expression of Blimp-1 and reduced the expression of the Ifi202. However, the deficiency increased the expression of Aim2 and Fcgr2b. Correspondingly, increased expression of IRF5 in cells increased levels of Blimp-1 and p202 protein. Moreover, Blimp-1 expression increased the expression of Ifi202, whereas it reduced the expression of Aim2. Interestingly, an Aim2-deficiency in female mice increased the expression of IRF5. Similarly, the Fcgr2b-deficient mice expressed increased levels of IRF5. Moreover, increased expression of IRF5 and Blimp-1 in lupus-prone B6.Nba2, NZB, and B6.Sle123 female mice (as compared to age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Together, our observations demonstrate that the IRF5-Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and suggest an important role for the IRF5-Blimp-1-p202 axis in murine lupus susceptibility. PMID:22116829

  13. Xerosis is associated with asthma in men independent of atopic dermatitis and filaggrin gene mutations

    DEFF Research Database (Denmark)

    Engebretsen, K A; Linneberg, Allan René; Thuesen, B H

    2015-01-01

    that asthma (either current or at some point in life) was significantly associated with reporting generalized xerosis (OR 1.32; 95% CI 1.02-1.72). The association was stronger in men (OR 1.79; 95% CI 1.13-2.84) when compared to women (OR 1.18; 95% CI 0.86-1.62). Furthermore, a significant association...... was observed between xerosis and 'allergic asthma' in men (OR 2.13; 95% CI 1.08-4.19). CONCLUSION: Our findings indicate an association between xerosis and asthma in men independent of atopic dermatitis and FLG mutations. Both facilitated allergen sensitization and secondary degradation of filaggrin following...... T-helper cell 2 inflammation might be key elements to understanding this relationship....

  14. Ischemic stroke susceptibility gene in a Northern Han Chinese population

    Institute of Scientific and Technical Information of China (English)

    Haiping Wang; Shujuan Shi; Wenjing Yan; Yan Song; Jingjing Zhan; Chen Zhang; Haiji Wang

    2013-01-01

    Interleukin-18 gene promoter polymorphisms are potential risk factors for ischemic cerebrovascular disease, and the-607C al ele may increase ischemic stroke risk in the Han Chinese population. In the present study, we recruited 291 patients with ischemic cerebrovascular disease from the Affi-liated Hospital of Qingdao University Medical Col ege, China, and 226 healthy controls. Both pa-tients and controls were from the Han population in northern China. Immunoresonance scattering assays detected increased serum amyloid A protein, C-reactive protein, and interleukin-18 levels in ischemic cerebrovascular disease patients compared with healthy controls. Analysis of the-607C/A (rs1946518) polymorphism in the interleukin-18 gene promoter showed ischemic cerebrovascular disease patients exhibited increased frequencies of the CC genotype and C al eles than healthy controls. Genotype and al ele frequencies of the interleukin-18-137G/C (rs187238) polymorphism and the-13T/C (rs11024595) polymorphism in the 5'-flanking region of serum amyloid A, showed no significant difference between the two groups. Multivariate logistic regression analysis on the interleukin-18 promoter A/C genetic locus, for correction of age, gender, history of smoking, hyper-tension, diabetes mel itus, hypercholesteremia, and an ischemic stroke family history, showed ischemic cerebrovascular disease risk in individuals without the A al ele (C homozygotes) was 2.2-fold greater than in A al ele carriers. Overal , our findings suggest that the-13T/C (rs11024595) polymorphism in the 5′-flanking region of serum amyloid A has no correlation with ischemic cere-brovascular disease, but the C al ele of the-607C/A (rs1946518) polymorphism in the interleukin-18 promoter is a high-risk factor for ischemic cerebrovascular disease in the Han population of northern China. In addition, the A al ele is likely a protective gene for ischemic cerebrovascular disease.

  15. Asthma in childhood.

    Science.gov (United States)

    de Benedictis, Fernando Maria; Attanasi, Marina

    2016-03-01

    Several topics on childhood asthma were addressed in the Paediatric Clinical Year in Review session at the 2015 European Respiratory Society International Congress. With regard to the relationship between lower respiratory tract infections and asthma, it emerges that is the number of respiratory episodes in the first years of life, but not the particular viral trigger, to be associated with later asthma development. Understanding which characteristics of individual patients are associated with an increased risk for asthma exacerbation is a critical step to implement strategies preventing these seasonal events. Recent data suggest the possibility that exhaled volatile organic compounds may qualify as biomarkers in detecting early signs of asthma. Adding information of exhaled volatile organic compounds and expression of inflammation genes to a clinical tool significantly improves asthma prediction in preschool wheezy children. Personal communication with children and adolescents is likely more important than the tools actually used for monitoring asthma. Systemic corticosteroids do not affect the long-term prognosis in children with first viral-induced wheezing episode and should be used cautiously during acute episodes. Finally, stress and a polymorphism upstream of a specific gene are both associated with reduced bronchodilator response in children with asthma.

  16. Asthma in childhood

    Directory of Open Access Journals (Sweden)

    Fernando Maria de Benedictis

    2016-03-01

    Full Text Available Several topics on childhood asthma were addressed in the Paediatric Clinical Year in Review session at the 2015 European Respiratory Society International Congress. With regard to the relationship between lower respiratory tract infections and asthma, it emerges that is the number of respiratory episodes in the first years of life, but not the particular viral trigger, to be associated with later asthma development. Understanding which characteristics of individual patients are associated with an increased risk for asthma exacerbation is a critical step to implement strategies preventing these seasonal events. Recent data suggest the possibility that exhaled volatile organic compounds may qualify as biomarkers in detecting early signs of asthma. Adding information of exhaled volatile organic compounds and expression of inflammation genes to a clinical tool significantly improves asthma prediction in preschool wheezy children. Personal communication with children and adolescents is likely more important than the tools actually used for monitoring asthma. Systemic corticosteroids do not affect the long-term prognosis in children with first viral-induced wheezing episode and should be used cautiously during acute episodes. Finally, stress and a polymorphism upstream of a specific gene are both associated with reduced bronchodilator response in children with asthma.

  17. In Search of the Genes of Asthma on the Island of Tristan da Cunha

    Directory of Open Access Journals (Sweden)

    Noe Zamel

    1995-01-01

    of interbreeding and a high prevalence of asthma should be helpful. One such community has been described in the medical literature, the island of Tristan da Cunha. The University of Toronto Genetics of Asthma Project decided to study this community. It sent a team to the island to construct a geneology, obtain a history of respiratory and allergy symptoms by questionnaire, perform allergy skin testing and methocholine challenge, and obtain blood for white cell genetic studies. The initial results of this study are presented here, together with a historical perspective on the people of Tristan da Cunha.

  18. EFFECTS OF VITAMIN D RECEPTOR GENE POLYMORPHISMS ON SUSCEPTIBILITY TO TYPE 1 DIABETES MELLITUS

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To investigate the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes mellitus (T1DM) in the Chinese Han population.Method One hundred and thirty-six Chinese Han people, including 54 T1DM patients and 82 unrelated healthy subjects as control were genotyped by polymerase chain reaction-restriction fragment length polymorphism for three restriction sites in the VDR gene, which were ApaI, TaqI, and BamI.Results The frequency of B allele of BsmI site in VDR gene was significantly higher in T1DM patients than in healthy subjects (P=0.033) while no difference was found between the two groups in the distribution of ApaI and TaqI polymorphisms.Conclusion The BsmI polymorphism of VDR gene may be associated with the susceptibility to T1DM in the Chinese Hah population of Beijing.

  19. Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

    NARCIS (Netherlands)

    Cenit, M.C.; Simeon, C.P.; Vonk, M.C.; Callejas-Rubio, J.L.; Espinosa, G.; Carreira, P.; Blanco, F.J.; Narvaez, J.; Tolosa, C.; Roman-Ivorra, J.A.; Gomez-Garcia, I.; Garcia-Hernandez, F.J.; Gallego, M.; Garcia-Portales, R.; Egurbide, M.V.; Fonollosa, V.; Garcia de la Pena, P.; Lopez-Longo, F.J.; Gonzalez-Gay, M.A.; The Spanish Scleroderma, G.; Hesselstrand, R.; Riemekasten, G.; Witte, T.; Voskuyl, A.E.; Schuerwegh, A.J.; Madhok, R.; Fonseca, C.; Denton, C.; Nordin, A.; Palm, O.; Laar, J.M. van; Hunzelmann, N.; Distler, J.H.; Kreuter, A.; Herrick, A.; Worthington, J.; Koeleman, B.P.; Radstake, T.R.D.J.; Martin, J.

    2012-01-01

    OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotyp

  20. ALTERED HEPATIC GENE EXPRESSION IN MORBIDLY OBESE WOMEN AND ITS IMPLICATIONS FOR SUSCEPTIBILITY TO OTHER DISEASES

    Science.gov (United States)

    The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women un...

  1. A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility

    DEFF Research Database (Denmark)

    Damotte, V; Guillot-Noel, L; Patsopoulos, N A;

    2014-01-01

    Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in in...

  2. Detection of vanC 1 gene transcription in vancomycin-susceptible Enterococcus faecalis

    Directory of Open Access Journals (Sweden)

    Tiane Martin de Moura

    2013-06-01

    Full Text Available Here we report the presence and expression levels of the vanC 1 and vanC 2/3 genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC 1 and vanC 2/3 genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC 1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis.

  3. Detection of vanC1 gene transcription in vancomycin-susceptible Enterococcus faecalis.

    Science.gov (United States)

    Moura, Tiane Martin de; Cassenego, Ana Paula Vaz; Campos, Fabrício Souza; Ribeiro, Andrea Machado Leal; Franco, Ana Cláudia; d'Azevedo, Pedro Alves; Frazzon, Jeverson; Frazzon, Ana Paula Guedes

    2013-06-01

    Here we report the presence and expression levels of the vanC1 and vanC(2/3) genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC1 and vanC(2/3) genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis.

  4. Detection of vanC1 gene transcription in vancomycin-susceptible Enterococcus faecalis

    Science.gov (United States)

    de Moura, Tiane Martin; Cassenego, Ana Paula Vaz; Campos, Fabrício Souza; Ribeiro, Andrea Machado Leal; Franco, Ana Cláudia; d'Azevedo, Pedro Alves; Frazzon, Jeverson; Frazzon, Ana Paula Guedes

    2013-01-01

    Here we report the presence and expression levels of the vanC 1 and vanC 2/3 genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC 1 and vanC 2/3 genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC 1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis. PMID:23828012

  5. Association of PTGDR gene polymorphisms with asthma in two Caucasian populations

    DEFF Research Database (Denmark)

    Zhu, G; Vestbo, J; Lenney, W;

    2007-01-01

    The prostanoid DP receptor (PTGDR) is shown to be involved in the asthma patho-physiology and the results from the published genetic association studies are inconsistent. Four single nucleotide polymorphisms (SNPs) in PTGDR were genotyped in 342 and 294 families from UK and Denmark respectively. ...

  6. 17q21 gene variation is not associated with asthma in adulthood

    DEFF Research Database (Denmark)

    Kreiner-Møller, E.; Strachan, D P; Linneberg, A;

    2015-01-01

    function in adulthood. The aim was to examine the association between the 17q21 region and current adult asthma and lung function, and interaction with active smoking. METHODS: We investigated the single nucleotide polymorphism rs7216389 at the 17q21 locus in 3471 adults from the Health2006 cross...

  7. Gene Expression Analysis of Plum pox virus (Sharka Susceptibility/Resistance in Apricot (Prunus armeniaca L..

    Directory of Open Access Journals (Sweden)

    Manuel Rubio

    Full Text Available RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925, which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein PPVres region could also be involved in the resistance.

  8. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.).

    Science.gov (United States)

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance.

  9. Genetics of canine diabetes mellitus: are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs?

    Science.gov (United States)

    Catchpole, Brian; Adams, Jamie P; Holder, Angela L; Short, Andrea D; Ollier, William E R; Kennedy, Lorna J

    2013-02-01

    Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population.

  10. Transposon insertional mutagenesis in mice identifies human breast cancer susceptibility genes and signatures for stratification

    Science.gov (United States)

    Chen, Liming; Jenjaroenpun, Piroon; Pillai, Andrea Mun Ching; Ivshina, Anna V.; Ow, Ghim Siong; Efthimios, Motakis; Zhiqun, Tang; Lee, Song-Choon; Rogers, Keith; Ward, Jerrold M.; Mori, Seiichi; Adams, David J.; Jenkins, Nancy A.; Copeland, Neal G.; Ban, Kenneth Hon-Kim; Kuznetsov, Vladimir A.; Thiery, Jean Paul

    2017-01-01

    Robust prognostic gene signatures and therapeutic targets are difficult to derive from expression profiling because of the significant heterogeneity within breast cancer (BC) subtypes. Here, we performed forward genetic screening in mice using Sleeping Beauty transposon mutagenesis to identify candidate BC driver genes in an unbiased manner, using a stabilized N-terminal truncated β-catenin gene as a sensitizer. We identified 134 mouse susceptibility genes from 129 common insertion sites within 34 mammary tumors. Of these, 126 genes were orthologous to protein-coding genes in the human genome (hereafter, human BC susceptibility genes, hBCSGs), 70% of which are previously reported cancer-associated genes, and ∼16% are known BC suppressor genes. Network analysis revealed a gene hub consisting of E1A binding protein P300 (EP300), CD44 molecule (CD44), neurofibromin (NF1) and phosphatase and tensin homolog (PTEN), which are linked to a significant number of mutated hBCSGs. From our survival prediction analysis of the expression of human BC genes in 2,333 BC cases, we isolated a six-gene-pair classifier that stratifies BC patients with high confidence into prognostically distinct low-, moderate-, and high-risk subgroups. Furthermore, we proposed prognostic classifiers identifying three basal and three claudin-low tumor subgroups. Intriguingly, our hBCSGs are mostly unrelated to cell cycle/mitosis genes and are distinct from the prognostic signatures currently used for stratifying BC patients. Our findings illustrate the strength and validity of integrating functional mutagenesis screens in mice with human cancer transcriptomic data to identify highly prognostic BC subtyping biomarkers. PMID:28251929

  11. Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes.

    Science.gov (United States)

    Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

    2014-11-01

    Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and

  12. The NCAN gene: schizophrenia susceptibility and cognitive dysfunction

    Directory of Open Access Journals (Sweden)

    Wang P

    2016-11-01

    Full Text Available Peirong Wang,1 Jun Cai,2 Jianliang Ni,1 Jiangtao Zhang,1 Wei Tang,3 Chen Zhang2 1Department of Psychiatry, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 2Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 3Wenzhou Kangning Hospital, Wenzhou, Zhejiang, People’s Republic of China Background: Cognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN, is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia.Methods: In this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS.Results: There were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction.Conclusion: Our findings indicate

  13. Violence and Asthma: A Review

    Directory of Open Access Journals (Sweden)

    Takeo Fujiwara

    2008-01-01

    Full Text Available Recent research shows that exposure to community violence is, directly and indirectly, associated with asthma. This article reviews the findings on the impact of violence on asthma, and the pathways for the association of violence and asthma are suggested: 1 exposure to violence is directly associated with asthma, mainly through dysregulation of sympathetic-adrenal-medullary (SAM and hypothalamic-pituitary-adrenal (HPA axis, 2 exposure to violence is associated with the change of susceptibility of outdoor air pollution on asthma, probably through the change of an immune response, and 3 behavioral change due to exposure to violence (e.g. keeping children indoors leads to more exposure to indoor pollutants. The suggested framework may be useful to develop health policy on asthma in high-violence communities.

  14. Gene and environment interaction: Is the differential susceptibility hypothesis relevant for obesity?

    Science.gov (United States)

    Dalle Molle, Roberta; Fatemi, Hajar; Dagher, Alain; Levitan, Robert D; Silveira, Patricia P; Dubé, Laurette

    2017-02-01

    The differential susceptibility model states that a given genetic variant is associated with an increased risk of pathology in negative environments but greater than average resilience in enriched ones. While this theory was first implemented in psychiatric-genetic research, it may also help us to unravel the complex ways that genes and environments interact to influence feeding behavior and obesity. We reviewed evidence on gene vs. environment interactions that influence obesity development, aiming to support the applicability of the differential susceptibility model for this condition, and propose that various environmental "layers" relevant for human development should be considered when bearing the differential susceptibility model in mind. Mother-child relationship, socioeconomic status and individual's response are important modifiers of BMI and food intake when interacting with gene variants, "for better and for worse". While only a few studies to date have investigated obesity outcomes using this approach, we propose that the differential susceptibility hypothesis is in fact highly applicable to the study of genetic and environmental influences on feeding behavior and obesity risk.

  15. Association between CYP1B1 Gene Polymorphisms and Risk Factors and Susceptibility to Laryngeal Cancer

    OpenAIRE

    Yu, Peng-Ju; Chen, Wei-Guan; Feng, Quan-Lin; Chen, Wei; Jiang, Man-Jie; Li, Ze-Qing

    2015-01-01

    Background The aim of this study was to investigate the association between polymorphism of the cytochrome P450 1B1 (CYP1B1) gene, a metabolic enzyme gene, and the susceptibility to laryngeal cancer among the Chinese Han population. Material/Methods In a case-control study, we investigated polymorphisms in the CYP1B1 gene (rs10012, rs1056827, and rs1056836) with a real-time quantitative polymerase chain reaction (PCR) assay (TaqMan). The study was conducted with 300 Chinese Han patients with ...

  16. Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease.

    Science.gov (United States)

    Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B; Yang, Bing; White, Frank F; Wang, Nian; Jones, Jeffrey B

    2014-01-28

    Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccA(w), induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations.

  17. Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development.

    Science.gov (United States)

    Theodoropoulos, George E; Saridakis, Vasilios; Karantanos, Theodoros; Michalopoulos, Nikolaos V; Zagouri, Flora; Kontogianni, Panagiota; Lymperi, Maria; Gazouli, Maria; Zografos, George C

    2012-08-01

    Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.

  18. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants

    Directory of Open Access Journals (Sweden)

    Ming-Shun Chen

    2016-08-01

    Full Text Available The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. In this study, we investigated the genes that were expressed differentially between larvae in resistant plants and those in susceptible plants through RNA sequencing on the Illumina platform. Informative genes were 11,832, 14,861, 15,708, and 15,071 for the comparisons between larvae in resistant versus susceptible plants for 0.5, 1, 3, and 5 days, respectively, after larvae had reached the feeding site. The transcript abundance corresponding to 5401, 6902, 8457, and 5202 of the informative genes exhibited significant differences (p ≤ 0.05 in the respective paired comparisons. Overall, genes involved in nutrient metabolism, RNA and protein synthesis exhibited lower transcript abundance in larvae from resistant plants, indicating that resistant plants inhibited nutrient metabolism and protein production in larvae. Interestingly, the numbers of cytochrome P450 genes with higher transcript abundance in larvae from resistant plants were comparable to, or higher than those with lower transcript abundance, indicating that toxic chemicals from resistant plants may have played important roles in Hessian fly larval death. Our study also identified several families of genes encoding secreted salivary gland proteins (SSGPs that were expressed at early stage of 1st instar larvae and with more genes with higher transcript abundance in larvae from resistant plants. Those SSGPs are candidate effectors with important roles in plant manipulation.

  19. Mining susceptibility gene modules and disease risk genes from SNP data by combining network topological properties with support vector regression.

    Science.gov (United States)

    Hua, Lin; Zhou, Ping; Liu, Hong; Li, Lin; Yang, Zheng; Liu, Zhi-cheng

    2011-11-21

    Genome-wide association study is a powerful approach to identify disease risk loci. However, the molecular regulatory mechanisms for most complex diseases are still not well understood. Therefore, further investigating the interplay between genetic factors and biological networks is important for elucidating the molecular mechanisms of complex diseases. Here, we proposed a novel framework to identify susceptibility gene modules and disease risk genes by combining network topological properties with support vector regression from single nucleotide polymorphism (SNP) level. We assigned risk SNPs to genes using the University of California at Santa Cruz (UCSC) genome database, and then mapped these genes to protein-protein interaction (PPI) networks. The gene modules implicated by hub genes were extracted using the PPI networks and the topological property was analyzed for these gene modules. For each gene module, risk feature genes were determined by topological property analysis and support vector regression. As a result, five shared risk feature genes, CD80, EGFR, FN1, GSK3B and TRAF6 were found and proven to be associated with rheumatoid arthritis by previous reports. Our approach showed a good performance in comparison with other approaches and can be used for prioritizing candidate genes associated with complex diseases.

  20. 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.

  1. Bipolar disorder: idioms of susceptibility and disease and the role of 'genes' in illness explanations.

    Science.gov (United States)

    Baart, Ingrid; Widdershoven, Guy

    2013-11-01

    This qualitative study explores (1) how members of the Dutch Association for People with Bipolar Disorder explain the affliction of bipolar disorder; (2) the relationship between genetic, environmental and personal factors in these explanations and (3) the relationship between illness explanations, self-management and identity. A total of 40 participants took part in seven different focus group discussions. The results demonstrate that there are two different explanatory idioms, each one centred around an opposing concept, that is, susceptibility and disease. Individuals who construct explanations around the concept of 'disease' attach more importance to 'genes and chemicals' than to environmental components in the onset of the disorder, whereas individuals adhering to the central concept of 'susceptibility' tend to do this much less. Compared with individuals using the 'susceptibility' idiom, those who use a 'disease' idiom tend to observe fewer possibilities for self-management and are less inclined to construct normalcy through a quest for personal growth. Stories of suffering seem more integral to the 'disease' idiom than to the 'susceptibility' idiom. The 'disease' idiom seems less integrated in a contemporary surveillance psychiatric discourse than the 'susceptibility' idiom; however, both vocabularies can offer normative constraints.

  2. Matrix metalloproteinase gene polymorphisms and periodontitis susceptibility: a meta-analysis involving 6,162 individuals.

    Science.gov (United States)

    Weng, Hong; Yan, Yan; Jin, Ying-Hui; Meng, Xiang-Yu; Mo, Yuan-Yuan; Zeng, Xian-Tao

    2016-04-20

    We aimed to systematically investigate the potential association of matrix metalloproteinase (MMP)-9, -3, -2, and -8 gene polymorphisms with susceptibility to periodontitis using meta-analysis. A literature search in PubMed, Embase, and Web of Science was conducted to obtain relevant publications. Finally a total of 16 articles with 24 case-control studies (nine on MMP-9-1562 C/T, seven on MMP-3-1171 A5/A6, four on MMP-2-753C/T, and four on MMP-8-799 C/T) were considered in this meta-analysis. The results based on 2,724 periodontitis patients and 3,438 controls showed that MMP-9-1562C/T, MMP-3-1171 A5/A6, and MMP-8-799C/T polymorphisms were associated with periodontitis susceptibility. No significant association was found between MMP-2-753 C/T and periodontitis susceptibility. Subgroup analyses suggested that the MMP-9-1562 C/T polymorphism reduced chronic periodontitis susceptibility and MMP-3-1171 A5/A6 polymorphism increased chronic periodontitis susceptibility. In summary, current evidence demonstrated that MMP-9-753 C/T polymorphism reduced the risk of periodontitis, MMP-3-1171 5A/6A and MMP-8-799 C/T polymorphisms increased the risk of periodontitis, and MMP-2-753 C/T was not associated with risk of periodontitis.

  3. XPG Gene Polymorphisms Contribute to Colorectal Cancer Susceptibility: A Two-Stage Case-Control Study

    Science.gov (United States)

    Hua, Rui-Xi; Zhuo, Zhen-Jian; Zhu, Jinhong; Zhang, Shao-Dan; Xue, Wen-Qiong; Zhang, Jiang-Bo; Xu, Hong-Mei; Li, Xi-Zhao; Zhang, Pei-Fen; He, Jing; Jia, Wei-Hua

    2016-01-01

    Previous studies have reported that xeroderma pigmentosum group G (XPG) gene polymorphisms may modulate colorectal cancer (CRC) susceptibility. In this study, we performed a two-stage case-control study to comprehensively investigate the associations of five polymorphisms in the XPG gene with CRC risk in 1,901 cases and 1,976 controls from Southern China, including rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601 G>A. After combining data from two stages, we found that three of the studied polymorphisms (rs2094258 C>T, rs751402 C>T, and rs873601 G>A) were significantly associated with CRC susceptibility. After adjustment for age and gender, multivariate logistic regression analysis indicated that carriers of the rs2094258 T alleles had an increased CRC risk [CT vs. CC: adjusted odds ratio (OR)=1.17, 95% confidence interval (CI)=1.01-1.36; TT vs. CC: adjusted OR=1.49, 95% CI=1.18-1.89; TT vs. CT/CC: adjusted OR=1.38, 95% CI=1.10-1.72]. Likely, rs873601 A allele also conferred increased CRC susceptibility. In contrast, a protective association was identified between rs751402 C>T polymorphism and the risk of CRC. In summary, our results indicated that these three polymorphisms were found to associate with CRC susceptibility in a Southern Chinese population.

  4. From mouse to humans: discovery of the CACNG2 pain susceptibility gene.

    Science.gov (United States)

    Nissenbaum, J

    2012-10-01

    Chronic pain is a major healthcare problem affecting the daily lives of millions with enormous financial costs. The notorious variability and lack of efficient pain relief pharmaceuticals provide both genetic and therapeutic challenge. There are several genetic approaches that aim to uncover the molecular nature of pain phenotypes into their genetic components. Gene mapping using model organisms for various pain phenotypes has led to the identification of novel genes affecting susceptibility and response to pain stimuli. Translational studies have succeeded to tie those genes to human pain syndromes, thus suggesting new targets for drug discovery. In this short review, a perspective on pain genetics and the trajectory from pain phenotype to pain gene involving fine-mapping strategies, bioinformatic analysis and microarray profiling alongside human association analysis will be introduced. This integrated approach has led to identification of CACNG2 as a novel neuropathic pain gene affecting pain susceptibility both in mice and humans. It also serves as a prototype for efficient and economic discovery of pain genes. Comparisons to other methods as well as future directions of pain genetics will be discussed as well.

  5. Association of polymorphisms in non-classic MHC genes with susceptibility to autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    JieTang; ChengZhou; Zhi-JunZhang; Shu-SenZheng

    2012-01-01

    BACKGROUND: Autoimmune hepatitis is a chronic, generally progressive inflammatory disorder of the liver, of which the cause is unclear. It was demonstrated that genetic factors are involved in its pathogenesis. Previous studies showed that human leukocyte antigen in the major histocompatibility complex (MHC) is associated with susceptibility to autoimmune hepatitis. Current genome scanning studies suggest that genes outside the MHC also play a critical role in autoimmune disorders. This article focuses on our current understanding of the polymorphisms of these genes and their roles in the pathogenesis of autoimmune hepatitis. DATA  SOURCES: Studies were identified by searching MEDLINE and PubMed for articles using the keywords autoimmune hepatitis, polymorphism, CTLA-4, Fas, TNF-α, TGF-β1, TBX21 and VDR up to May 2011. Additional papers were identified by a manual search of the references from key articles. RESULTS:  According to the case-control studies on genetic polymorphisms, at least six genes (CTLA-4, Fas, TNF-α, TGF-β1, TBX21 and VDR) are involved in autoimmune hepatitis besides HLA. So far, there has been no agreement about gene susceptibility and the actual clinical significance of these genes is still controversial. CONCLUSION: Studies on gene polymorphisms outside the MHC and knowledge of genetic predispositions for autoimmune hepatitis may not only elucidate pathogenic mechanisms, but also provide new targets for therapy in the future.

  6. Investigation of Gamma-aminobutyric acid (GABA A receptors genes and migraine susceptibility

    Directory of Open Access Journals (Sweden)

    Ciccodicola Alfredo

    2008-12-01

    Full Text Available Abstract Background Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ, which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE and type θ (GABRQ genes and their involvement in migraine. Methods We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls examining a set of 3 single nucleotide polymorphisms (SNPs in the coding region (exons 3, 5 and 9 of the GABRE gene and also the I478F coding variant of the GABRQ gene. Results Our study did not show any association between the examined SNPs in our test population (P > 0.05. Conclusion Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility.

  7. Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene

    NARCIS (Netherlands)

    Himes, Blanca E.; Sheppard, Keith; Berndt, Annerose; Leme, Adriana S.; Myers, Rachel A.; Gignoux, Christopher R.; Levin, Albert M.; Gauderman, W. James; Yang, James J.; Mathias, Rasika A.; Romieu, Isabelle; Torgerson, Dara G.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Boushey, Homer; Chinchilli, Vernon M.; Israel, Elliot; Mauger, David; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A. E.; Vonk, Judith M.; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Litonjua, Augusto A.; Tantisira, Kelan G.; Raby, Benjamin A.; Bleecker, Eugene R.; Meyers, Deborah A.; London, Stephanie J.; Barnes, Kathleen C.; Gilliland, Frank D.; Williams, L. Keoki; Burchard, Esteban G.; Nicolae, Dan L.; Ober, Carole; DeMeo, Dawn L.; Silverman, Edwin K.; Paigen, Beverly; Churchill, Gary; Shapiro, Steve D.; Weiss, Scott

    2013-01-01

    Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthm

  8. The localization of type 2 diabetes susceptibility gene loci in northern Chinese Han families

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    We conducted a genome-wide scan,in which 358 well distributed fluorescent dye-labe- led microsatellite marker sets were applied in 32 Chinese Han type 2 diabetes families from Northern China to search for the susceptibility gene loci.The data collected from screening all the chromosomes of genome were genotyped by using genescan and genotyping software,then,parametric and non-parametric multipoint test,and affected sib-pair analysis as well,were used to analyze the data.We identified some susceptibility gene loci residing in chromosomes 1,12,18,20,respectively,or precisely,located around D1S214,D1S207,D1S218,D1S235,D12S336,D18S61 and D20S118.The comparison of this result with those from other regions and races reflected the complexity and heterogeneity of type 2 diabetes.

  9. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Steve P. Crampton

    2014-09-01

    Full Text Available Systemic lupus erythematosus (SLE represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.

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

    OpenAIRE

    Trubicka Joanna; Grabowska-Kłujszo Ewa; Suchy Janina; Masojć Bartłomiej; Serrano-Fernandez Pablo; Kurzawski Grzegorz; Cybulski Cezary; Górski Bohdan; Huzarski Tomasz; Byrski Tomasz; Gronwald Jacek; Złowocka Elżbieta; Kładny Józef; Banaszkiewicz Zbigniew; Wiśniowski Rafał

    2010-01-01

    Abstract Background 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. Methods We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be ...

  11. Effects of disruption of heat shock genes on susceptibility of Escherichia coli to fluoroquinolones

    Directory of Open Access Journals (Sweden)

    Morioka Mizue

    2003-08-01

    Full Text Available Abstract Background It is well known that expression of certain bacterial genes responds rapidly to such stimuli as exposure to toxic chemicals and physical agents. It is generally believed that the proteins encoded in these genes are important for successful survival of the organism under the hostile conditions. Analogously, the proteins induced in bacterial cells exposed to antibiotics are believed to affect the organisms' susceptibility to these agents. Results We demonstrated that Escherichia coli cells exposed to levofloxacin (LVFX, a fluoroquinolone (FQ, induce the syntheses of heat shock proteins and RecA. To examine whether the heat shock proteins affect the bactericidal action of FQs, we constructed E. coli strains with mutations in various heat shock genes and tested their susceptibility to FQs. Mutations in dnaK, groEL, and lon increased this susceptibility; the lon mutant exhibited the greatest effects. The increased susceptibility of the lon mutant was corroborated by experiments in which the gene encoding the cell division inhibitor, SulA, was subsequently disrupted. SulA is induced by the SOS response and degraded by the Lon protease. The findings suggest that the hypersusceptibility of the lon mutant to FQs could be due to abnormally high levels of SulA protein resulting from the depletion of Lon and the continuous induction of the SOS response in the presence of FQs. Conclusion The present results show that the bactericidal action of FQs is moderately affected by the DnaK and GroEL chaperones and strongly affected by the Lon protease. FQs have contributed successfully to the treatment of various bacterial infections, but their widespread use and often misuse, coupled with emerging resistance, have gradually compromised their utility. Our results suggest that agents capable of inhibiting the Lon protease have potential for combination therapy with FQs.

  12. SCAR Markers Assisted Selection for a Bentazon Susceptible Lethality Gene (ben) in Rice

    Institute of Scientific and Technical Information of China (English)

    XIANG; Tai-he; YANG; Jian-bo; YANG; Qian-jin; ZHU; Qi-sheng; LI; Li; HUANG; Da-nian

    2003-01-01

    In progenies resulting from crosses involving rice cultivar Norin 8m susceptible to bentazon as the donor of ben gene, SCARs tightly linked to ben were utilized for selection of ben. The homozygous and heterozygous genotypes with ben could be identified with the SCARs. The molecular markers offer a powerful tool for indirect selection of ben and can accelerate the introgression of ben into current rice cultivars.

  13. Gene expression profiling in the thiamethoxam resistant and susceptible B-biotype sweetpotato whitefly, Bemisia tabaci.

    Science.gov (United States)

    Xie, Wen; Yang, Xin; Wang, Shao-Ii; Wu, Qing-jun; Yang, Ni-na; Li, Ru-mei; Jiao, Xiao-guo; Pan, Hui-peng; Liu, Bai-ming; Feng, Yun-tao; Xu, Bao-yun; Zhou, Xu-guo; Zhang, You-jun

    2012-01-01

    Thiamethoxam has been used as a major insecticide to control the B-biotype sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). Due to its excessive use, a high level of resistance to thiamethoxam has developed worldwide over the past several years. To better understand the molecular mechanisms underlying this resistance in B. tabaci, gene profiles between the thiamethoxam-resistant and thiamethoxam-susceptible strains were investigated using the suppression subtractive hybridization (SSH) library approach. A total of 72 and 52 upand down-regulated genes were obtained from the forward and reverse SSH libraries, respectively. These expressed sequence tags (ESTs) belong to several functional categories based on their gene ontology annotation. Some categories such as cell communication, response to abiotic stimulus, lipid particle, and nuclear envelope were identified only in the forward library of thiamethoxam-resistant strains. In contrast, categories such as behavior, cell proliferation, nutrient reservoir activity, sequence-specific DNA binding transcription factor activity, and signal transducer activity were identified solely in the reverse library. To study the validity of the SSH method, 16 differentially expressed genes from both forward and reverse SSH libraries were selected randomly for further analyses using quantitative realtime PCR (qRT-PCR). The qRT-PCR results were fairly consistent with the SSH results; however, only 50% of the genes showed significantly different expression profiles between the thiamethoxam-resistant and thiamethoxam-susceptible whiteflies. Among these genes, a putative NAD-dependent methanol dehydrogenase was substantially over-expressed in the thiamethoxamresistant adults compared to their susceptible counterparts. The distributed profiles show that it was highly expressed during the egg stage, and was most abundant in the abdomen of adult females.

  14. CREB1 gene polymorphisms combined with environmental risk factors increase susceptibility to major depressive disorder (MDD).

    Science.gov (United States)

    Wang, Peng; Yang, Yanjie; Yang, Xiuxian; Qiu, Xiaohui; Qiao, Zhengxue; Wang, Lin; Zhu, Xiongzhao; Sui, Hong; Ma, Jingsong

    2015-01-01

    Major depressive disorder (MDD) is one of the most severe psychiatric disorders. The objective of this study was to explore the effects of CREB1 gene polymorphisms on risk of developing MDD and the joint effects of gene-environment interactions. Genotyping was performed by Taqman allelic discrimination assay among 586 patients and 586 healthy controls. A significant impact on rs6740584 genotype distribution was found for childhood trauma (P = 0.015). We did not find an association of CREB1 polymorphisms with MDD susceptibility. However, we found a significantly increased risk associated with the interactions of CREB1 polymorphisms and drinking (OR = 11.67, 95% CI = 2.52-54.18; OR = 11.52, 95% CI = 2.55-51.95 for rs11904814; OR = 4.18, 95% CI = 1.87-9.38; OR = 5.02, 95% CI = 2.27-11.14 for rs6740584; OR = 7.58, 95% CI = 2.05-27.98; OR = 7.59, 95% CI = 2.12-27.14 for rs2553206; OR = 8.37, 95% CI = 3.02-23.23; OR = 7.84, 95% CI = 2.93-20.98 for rs2551941). We also noted that CREB polymorphisms combined with family harmony and childhood trauma conferred increased susceptibility for MDD. In conclusion, polymorphisms in the CREB gene may not be independently associated with MDD risk, but they are likely to confer increased susceptibility by interacting with environmental risk factors in the Chinese population.

  15. Gene Prospector: An evidence gateway for evaluating potential susceptibility genes and interacting risk factors for human diseases

    Directory of Open Access Journals (Sweden)

    Khoury Muin J

    2008-12-01

    Full Text Available Abstract Background Millions of single nucleotide polymorphisms have been identified as a result of the human genome project and the rapid advance of high throughput genotyping technology. Genetic association studies, such as recent genome-wide association studies (GWAS, have provided a springboard for exploring the contribution of inherited genetic variation and gene/environment interactions in relation to disease. Given the capacity of such studies to produce a plethora of information that may then be described in a number of publications, selecting possible disease susceptibility genes and identifying related modifiable risk factors is a major challenge. A Web-based application for finding evidence of such relationships is key to the development of follow-up studies and evidence for translational research. We developed a Web-based application that selects and prioritizes potential disease-related genes by using a highly curated and updated literature database of genetic association studies. The application, called Gene Prospector, also provides a comprehensive set of links to additional data sources. Results We compared Gene Prospector results for the query "Parkinson" with a list of 13 leading candidate genes (Top Results from a curated, specialty database for genetic associations with Parkinson disease (PDGene. Nine of the thirteen leading candidate genes from PDGene were in the top 10th percentile of the ranked list from Gene Prospector. In fact, Gene Prospector included more published genetic association studies for the 13 leading candidate genes than PDGene did. Conclusion Gene Prospector provides an online gateway for searching for evidence about human genes in relation to diseases, other phenotypes, and risk factors, and provides links to published literature and other online data sources. Gene Prospector can be accessed via http://www.hugenavigator.net/HuGENavigator/geneProspectorStartPage.do.

  16. Interaction between γ-aminobutyric acid A receptor genes: new evidence in migraine susceptibility.

    Directory of Open Access Journals (Sweden)

    Marlene Quintas

    Full Text Available Migraine is a common neurological episodic disorder with a female-to-male prevalence 3- to 4-fold higher, suggesting a possible X-linked genetic component. Our aims were to assess the role of common variants of gamma-aminobutyric acid A receptor (GABAAR genes, located in the X-chromosome, in migraine susceptibility and the possible interaction between them. An association study with 188 unrelated cases and 286 migraine-free controls age- and ethnic matched was performed. Twenty-three tagging SNPs were selected in three genes (GABRE, GABRA3 and GABRQ. Allelic, genotypic and haplotypic frequencies were compared between cases and controls. We also focused on gene-gene interactions. The AT genotype of rs3810651 of GABRQ gene was associated with an increased risk for migraine (OR: 4.07; 95% CI: 1.71-9.73, p=0.002, while the CT genotype of rs3902802 (OR: 0.41; 95% CI: 0.21-0.78, p=0.006 and GA genotype of rs2131190 of GABRA3 gene (OR: 0.53; 95% CI: 0.32-0.88, p=0.013 seem to be protective factors. All associations were found in the female group and maintained significance after Bonferroni correction. We also found three nominal associations in the allelic analyses although there were no significant results in the haplotypic analyses. Strikingly, we found strong interactions between six SNPs encoding for different subunits of GABAAR, all significant after permutation correction. To our knowledge, we show for the first time, the putative involvement of polymorphisms in GABAAR genes in migraine susceptibility and more importantly we unraveled a role for novel gene-gene interactions opening new perspectives for the development of more effective treatments.

  17. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

    Directory of Open Access Journals (Sweden)

    Nigel P S Crawford

    2007-11-01

    Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

  18. Association of polymorphisms of the CHI3L1 gene with asthma and atopy: a populations-based study of 6514 Danish adults

    DEFF Research Database (Denmark)

    Rathcke, Camilla Noelle; Holmkvist, Johan; Husmoen, Lise Lotte N;

    2009-01-01

    and lung function in a large population-based sample of adults. METHODS/PRINCIPAL FINDINGS: Eleven single nucleotide polymorphisms (SNPs) of CHI3L1 including rs4950928 were genotyped in 6514 individuals. Asthma was defined as self-reported history of physician-diagnosed asthma. Total IgE and specific Ig......BACKGROUND: YKL-40 is a chitinase-like glycoprotein encoded by the chitinase 3-like 1 gene, CHI3L1, localized at chromosome 1q32.1. Increased levels of serum YKL-40 have been reported to be a biomarker for asthma and a reduced lung function. Interestingly, the C-allele of the -131 C-->G (rs4950928......) polymorphism of CHI3L1 has been shown to associate with bronchial hyperresponsiveness and reduced lung function suggesting that variations in CHI3L1 may influence risk of asthma. The objective of the present study was to investigate the association of common variation in the CHI3L1 locus with asthma, atopy...

  19. Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene

    DEFF Research Database (Denmark)

    hart, Leen M; Hansen, Torben; Rietveld, Ingrid;

    2005-01-01

    Previously, we have shown that a mutation in the mitochondrial DNA-encoded tRNA(Leu(UUR)) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNA(Leu(UUR)). In this study, we have examined whether variants in the leucyl tRNA synthetase...... gene (LARS2), involved in aminoacylation of tRNA(Leu(UUR)), associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations...... no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established...

  20. Experimental strategy to identify genes susceptible to oxidative stress in nigral dopaminergic neurons.

    Science.gov (United States)

    Yoo, Myung S; Kawamata, Hibiki; Kim, Dae J; Chun, Hong S; Son, Jin H

    2004-06-01

    Neuropathological evidence from both human and experimental models of Parkinson's disease (PD) firmly supports a significant role for oxidative stress (OS) in the death of dopaminergic (DA) neurons in substantia nigra. Largely unknown are the genes underlying selective susceptibility of nigral DA neuron to OS and how they effect nigral DA cell death. The major barriers to high-throughput identification of candidate genes are the paucity of nigral DA neurons as well as the dilution effect of non-DA cells both in primary cultures and brain tissues. To overcome these barriers, we have developed a DA cell line model, SN4741, appropriate for cDNA microarray analysis. Candidate genes were selected from both the microarray analysis and the molecular implication of their pathological mechanisms (i.e., decreased mitochondrial complex I activity and proteasomal dysfunction) of PD. Subsequent secondary validation tests were devised to characterize genes including clone #45 that may underlie selective vulnerability of nigral DA neuron to OS.

  1. Rice Yellow Mottle Virus stress responsive genes from susceptible and tolerant rice genotypes

    Directory of Open Access Journals (Sweden)

    Siré Christelle

    2008-03-01

    Full Text Available Abstract Background The effects of viral infection involve concomitant plant gene variations and cellular changes. A simple system is required to assess the complexity of host responses to viral infection. The genome of the Rice yellow mottle virus (RYMV is a single-stranded RNA with a simple organisation. It is the most well-known monocotyledon virus model. Several studies on its biology, structure and phylogeography have provided a suitable background for further genetic studies. 12 rice chromosome sequences are now available and provide strong support for genomic studies, particularly physical mapping and gene identification. Results The present data, obtained through the cDNA-AFLP technique, demonstrate differential responses to RYMV of two different rice cultivars, i.e. susceptible IR64 (Oryza sativa indica, and partially resistant Azucena (O. s. japonica. This RNA profiling provides a new original dataset that will enable us to gain greater insight into the RYMV/rice interaction and the specificity of the host response. Using the SIM4 subroutine, we took the intron/exon structure of the gene into account and mapped 281 RYMV stress responsive (RSR transcripts on 12 rice chromosomes corresponding to 234 RSR genes. We also mapped previously identified deregulated proteins and genes involved in partial resistance and thus constructed the first global physical map of the RYMV/rice interaction. RSR transcripts on rice chromosomes 4 and 10 were found to be not randomly distributed. Seven genes were identified in the susceptible and partially resistant cultivars, and transcripts were colocalized for these seven genes in both cultivars. During virus infection, many concomitant plant gene expression changes may be associated with host changes caused by the infection process, general stress or defence responses. We noted that some genes (e.g. ABC transporters were regulated throughout the kinetics of infection and differentiated susceptible and

  2. Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Objectives To formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation. Methods Lewontin's linkage disequilibrium (LD) measure D' was used to formulate an equation for mapping disease genes in the presence of phenocopies, locus heterogeneity, gene-gene and gene-environment interactions, incomplete penetrance, uncertain liability and threshold, incomplete initial LD, natural selection, recurrent mutation, high disease allele frequency and unknown mode of inheritance. This equation was then used to determine the distance between a marker (ε4 within the apolipoprotein E gene, APOE) and Alzheimer's disease (AD) loci using published data.Results An equation was formulated for mapping disease genes under the above conditions. If these conditions are present but ignored, then recombination fraction θ between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of θ can be obtained. AD has been found to be associated with the marker allele ε4 in Africans, Asians, and Caucasians. This suggests that the AD-ε4 allelic LD predates the divergence of peoples occurring 100·!000 years ago. With the age of AD-ε4 allelic LD so estimated, the maximal distance was calculated to be 23.2 kb (mean 5.8 kb).Conclusions (1) A method is developed for LD mapping of susceptibility genes. (2) A mutation within the APOE gene itself, among others, is responsible for the susceptibility to AD, which is supported by recent evidence from studies using transgenic mice.

  3. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

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    Zheng Lin

    Full Text Available The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2 is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445 and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445 and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605, in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605 may be involved in the susceptibility to paranoid

  4. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

    Science.gov (United States)

    Lin, Zheng; Su, Yousong; Zhang, Chengfang; Xing, Mengjuan; Ding, Wenhua; Liao, Liwei; Guan, Yangtai; Li, Zezhi; Cui, Donghong

    2013-01-01

    The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia.

  5. Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene

    Science.gov (United States)

    Himes, Blanca E.; Jiang, Xiaofeng; Hu, Ruoxi; Wu, Ann C.; Lasky-Su, Jessica A.; Klanderman, Barbara J.; Ziniti, John; Senter-Sylvia, Jody; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Meyers, Deborah A.; Bleecker, Eugene R.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Hanrahan, John P.; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A. E.; Vonk, Judith M.; Panettieri, Reynold A.; Markezich, Amy; Israel, Elliot; Carey, Vincent J.; Tantisira, Kelan G.; Litonjua, Augusto A.; Lu, Quan; Weiss, Scott T.

    2012-01-01

    Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS. PMID:22792082

  6. Antimicrobial Susceptibility of Bordetella bronchiseptica Isolates from Swine and Companion Animals and Detection of Resistance Genes.

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    Sandra Prüller

    Full Text Available Bordetella bronchiseptica causes infections of the respiratory tract in swine and other mammals and is a precursor for secondary infections with Pasteurella multocida. Treatment of B. bronchiseptica infections is conducted primarily with antimicrobial agents. Therefore it is essential to get an overview of the susceptibility status of these bacteria. The aim of this study was to comparatively analyse broth microdilution susceptibility testing according to CLSI recommendations with an incubation time of 16 to 20 hours and a longer incubation time of 24 hours, as recently proposed to obtain more homogenous MICs. Susceptibility testing against a panel of 22 antimicrobial agents and two fixed combinations was performed with 107 porcine isolates from different farms and regions in Germany and 43 isolates obtained from companion animals in Germany and other European countries. Isolates with increased MICs were investigated by PCR assays for the presence of resistance genes. For ampicillin, all 107 porcine isolates were classified as resistant, whereas only a single isolate was resistant to florfenicol. All isolates obtained from companion animals showed elevated MICs for β-lactam antibiotics and demonstrated an overall low susceptibility to cephalosporines. Extension of the incubation time resulted in 1-2 dilution steps higher MIC50 values of porcine isolates for seven antimicrobial agents tested, while isolates from companion animals exhibited twofold higher MIC50/90 values only for tetracycline and cefotaxime. For three antimicrobial agents, lower MIC50 and MIC90 values were detected for both, porcine and companion animal isolates. Among the 150 isolates tested, the resistance genes blaBOR-1 (n = 147, blaOXA-2, (n = 4, strA and strB (n = 17, sul1 (n = 10, sul2 (n = 73, dfrA7 (n = 3 and tet(A (n = 8 were detected and a plasmid localisation was identified for several of the resistance genes.

  7. Childhood Asthma Management and Environmental Triggers.

    Science.gov (United States)

    Hollenbach, Jessica P; Cloutier, Michelle M

    2015-10-01

    Asthma is the most common chronic disease among children. It cannot be prevented but can be controlled. Industrialized countries experience high lifetime asthma prevalence that has increased over recent decades. Asthma has a complex interplay of genetic and environmental triggers. Studies have revealed complex interactions of lung structure and function genes with environmental exposures such as environmental tobacco smoke and vitamin D. Home environmental strategies can reduce asthma morbidity in children but should be tailored to specific allergens. Coupled with education and severity-specific asthma therapy, tailored interventions may be the most effective strategy to manage childhood asthma.

  8. Comparison of gene activation by two TAL effectors from Xanthomonas axonopodis pv. manihotis reveals candidate host susceptibility genes in cassava.

    Science.gov (United States)

    Cohn, Megan; Morbitzer, Robert; Lahaye, Thomas; Staskawicz, Brian J

    2016-08-01

    Xanthomonas axonopodis pv. manihotis (Xam) employs transcription activator-like (TAL) effectors to promote bacterial growth and symptom formation during infection of cassava. TAL effectors are secreted via the bacterial type III secretion system into plant cells, where they are directed to the nucleus, bind DNA in plant promoters and activate the expression of downstream genes. The DNA-binding activity of TAL effectors is carried out by a central domain which contains a series of repeat variable diresidues (RVDs) that dictate the sequence of bound nucleotides. TAL14Xam668 promotes virulence in Xam strain Xam668 and has been shown to activate multiple cassava genes. In this study, we used RNA sequencing to identify the full target repertoire of TAL14Xam668 in cassava, which includes over 50 genes. A subset of highly up-regulated genes was tested for activation by TAL14CIO151 from Xam strain CIO151. Although TAL14CIO151 and TAL14Xam668 differ by only a single RVD, they display differential activation of gene targets. TAL14CIO151 complements the TAL14Xam668 mutant defect, implying that shared target genes are important for TAL14Xam668 -mediated disease susceptibility. Complementation with closely related TAL effectors is a novel approach to the narrowing down of biologically relevant susceptibility genes of TAL effectors with multiple targets. This study provides an example of how TAL effector target activation by two strains within a single species of Xanthomonas can be dramatically affected by a small change in RVD-nucleotide affinity at a single site, and reflects the parameters of RVD-nucleotide interaction determined using designer TAL effectors in transient systems.

  9. Exome sequencing identifies KIAA1377 and C5orf42 as susceptibility genes for monomelic amyotrophy.

    Science.gov (United States)

    Lim, Young-Min; Koh, Insong; Park, Young-Mi; Kim, Jae-Jung; Kim, Dae-Seong; Kim, Hyo-Jin; Baik, Kyu-Heum; Choi, Hye-Yeon; Yang, Gap-Seok; Also-Rallo, Eva; Tizzano, Eduardo F; Gamez, Josep; Park, Kiejung; Yoo, Han-Wook; Lee, Jong-Keuk; Kim, Kwang-Kuk

    2012-05-01

    Precise topographic localization, predominance in males mostly of Asian origin, and existence of some familial cases suggest a genetic background for monomelic amyotrophy. To identify susceptibility genes for monomelic amyotrophy, we performed whole-exome sequencing of four unrelated patients with monomelic amyotrophy and detected a total of 45 novel nonsynonymous single-nucleotide polymorphisms as unique variants to monomelic amyotrophy compared to control exomes. Genetic association analysis showed significant association with monomelic amyotrophy in the Gly668Ser variant of the KIAA1377 gene (odds ratio=4.62, P-value=0.0040) and the Pro1794Leu variant of the C5orf42 gene (odds ratio=4.63, P-value=0.0040). Moreover, the combination of two variants increased the risk of monomelic amyotrophy (P=1.4×10(-5), OR=61.69, 95% confidence interval=9.62-394.94, in case of combination of two heterozygotes). These data suggest that KIAA1377 and C5orf42 synergistically play a role as susceptibility genes for monomelic amyotrophy.

  10. Transcription factor SP4 is a susceptibility gene for bipolar disorder.

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    Xianjin Zhou

    Full Text Available The Sp4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse Sp4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders. The human SP4 gene is therefore examined for its association with both bipolar disorder and schizophrenia in European Caucasian and Chinese populations respectively. Out of ten SNPs selected from human SP4 genomic locus, four displayed significant association with bipolar disorder in European Caucasian families (rs12668354, p = 0.022; rs12673091, p = 0.0005; rs3735440, p = 0.019; rs11974306, p = 0.018. To replicate the genetic association, the same set of SNPs was examined in a Chinese bipolar case control sample. Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029, and two of them (rs12673091, rs3735440 were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012 also displayed a significant association. The SNP7 (rs12673091 was therefore significantly associated in all three samples, and shared the same susceptibility allele (A across all three samples. On the other hand, we found a gene dosage effect for mouse Sp4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in Sp4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support Sp4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of Sp4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these

  11. Whole-exome sequencing for the identification of susceptibility genes of Kashin-Beck disease.

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    Zhenxing Yang

    Full Text Available OBJECTIVE: To identify and investigate the susceptibility genes of Kashin-Beck disease (KBD in Chinese population. METHODS: Whole-exome capturing and sequencing technology was used for the detection of genetic variations in 19 individuals from six families with high incidence of KBD. A total of 44 polymorphisms from 41 genes were genotyped from a total of 144 cases and 144 controls by using MassARRAY under the standard protocol from Sequenom. Association was applied on the data by using PLINK1.07. RESULTS: In the sequencing stage, each sample showed approximately 70-fold coverage, thus covering more than 99% of the target regions. Among the single nucleotide polymorphisms (SNPs used in the transmission disequilibrium test, 108 had a p-value of <0.01, whereas 1056 had a p-value of <0.05. Kyoto Encyclopedia of Genes and Genomes(KEGG pathway analysis indicates that these SNPs focus on three major pathways: regulation of actin cytoskeleton, focal adhesion, and metabolic pathways. In the validation stage, single locus effects revealed that two of these polymorphisms (rs7745040 and rs9275295 in the human leukocyte antigen (HLA-DRB1 gene and one polymorphism (rs9473132 in CD2-associated protein (CD2AP gene have a significant statistical association with KBD. CONCLUSIONS: HLA-DRB1 and CD2AP gene were identified to be among the susceptibility genes of KBD, thus supporting the role of the autoimmune response in KBD and the possibility of shared etiology between osteoarthritis, rheumatoid arthritis, and KBD.

  12. Iron homeostasis and fire blight susceptibility in transgenic pear plants overexpressing a pea ferritin gene.

    Science.gov (United States)

    Djennane, Samia; Cesbron, Colette; Sourice, Sophie; Cournol, Raphael; Dupuis, Fabrice; Eychenne, Magali; Loridon, Karine; Chevreau, Elisabeth

    2011-05-01

    The bacterial pathogen Erwinia amylovora causes the devastating disease known as fire blight in some rosaceous plants including apple and pear. One of the pathogenicity factors affecting fire blight development is the production of a siderophore, desferrioxamine, which overcomes the limiting conditions in plant tissues and also protects bacteria against active oxygen species. In this paper we examine the effect of an iron chelator protein encoded by the pea ferritin gene on the fire blight susceptibility of pear (Pyrus communis). Transgenic pear clones expressing this gene controlled either by the constitutive promoter CaMV 35S or by the inducible promoter sgd24 promoter were produced. The transgenic clones produced were analysed by Q-RT-PCR to determine the level of expression of the pea transgene. A pathogen-inducible pattern of expression of the pea transgene was observed in sgd24-promoter transformants. Adaptation to iron deficiency in vitro was tested in some transgenic clones and different iron metabolism parameters were measured. No strong effect on iron and chlorophyll content, root reductase activity and fire blight susceptibility was detected in the transgenic lines tested. No transformants showed a significant reduction in susceptibility to fire blight in greenhouse conditions when inoculated with E. amylovora.

  13. Outbreak of vancomycin-susceptible Enterococcus faecium containing the wild-type vanA gene.

    Science.gov (United States)

    Szakacs, Tom A; Kalan, Lindsay; McConnell, Michael J; Eshaghi, Alireza; Shahinas, Dea; McGeer, Allison; Wright, Gerry D; Low, Donald E; Patel, Samir N

    2014-05-01

    Accurate detection of vancomycin-resistant enterococci (VRE) is essential in preventing transmission in health care settings. Chromogenic media are widely used for screening VRE because of fast turnaround times (TAT) and high sensitivity. We report an outbreak of Enterococcus faecium bearing vanA yet susceptible to vancomycin (vancomycin-variable Enterococcus [VVE]). Between October 2009 to March 2011, clinical and screening specimens (n=14,747) were screened for VRE using VRE-selective medium and/or PCR. VVE isolates were genotyped to determine relatedness. Plasmids from these isolates were characterized by sequencing. Overall, 52 VVE isolates were identified, comprising 15% of all VRE isolates identified. Isolates demonstrated growth on Brilliance VRE agar (Oxoid) at 24 h of incubation but did not grow on brain heart infusion agar with 6 μg/ml vancomycin (Oxoid) or bile esculin azide agar with 6 μg/ml vancomycin (Oxoid) and were susceptible to vancomycin. Genotyping of 20 randomly selected VVE isolates revealed that 15/20 were identical, while 5 were highly related. PCR of the VVE transposon confirmed the presence of vanHAXY gene cluster; however, vanS (sensor) and vanR (regulator) genes were absent. The outbreak was controlled through routine infection control measures. We report an emergence of a fit strain of E. faecium containing vanA yet susceptible to vancomycin. Whether this new strain represents VRE has yet to be determined; however, unique testing procedures are required for reliable identification of VVE.

  14. Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

    Science.gov (United States)

    Xu, Ke; Ma, Lu; Li, Yang; Wang, Fang; Zheng, Gu-Yan; Sun, Zhijun; Jiang, Feng; Chen, Yundai; Liu, Huirong; Dang, Aimin; Chen, Xi; Chun, Jerold; Tian, Xiao-Li

    2015-09-01

    Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension.

  15. Antimicrobial susceptibility and macrolide resistance genes in Streptococcus pyogenes collected in Austria and Hungary.

    Science.gov (United States)

    Gattringer, Rainer; Sauermann, Robert; Lagler, Heimo; Stich, Karin; Buxbaum, Astrid; Graninger, Wolfgang; Georgopoulos, Apostolos

    2004-09-01

    A total of 341 clinical isolates of Streptococcus pyogenes from Vienna, Austria and three Hungarian cities were tested for susceptibility to four macrolides and 12 other antibiotics. All isolates were fully susceptible to penicillin and the other beta-lactams tested. A high level of tetracycline resistance was found in Austria (26.7%) and in Hungary (30.5%). The rate of resistance to erythromycin, clarithromycin and azithromycin was 4.7% in Vienna and 3.7% in the Hungarian communities. In both countries, the MIC(90) values of erythromycin and clarithromycin were 0.12 mg/L and the MIC(90) of josamycin was 0.5mg/L. The M phenotype of resistance conferred by the mefA genes was predominant (n = 9) among the macrolide-resistant isolates (n = 14).

  16. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases.......5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry....... and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according...

  17. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus).

    Science.gov (United States)

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas.

  18. Mapping the genes for susceptibility and response to Leishmania tropica in mouse.

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    Yahya Sohrabi

    Full Text Available BACKGROUND: L. tropica can cause both cutaneous and visceral leishmaniasis in humans. Although the L. tropica-induced cutaneous disease has been long known, its potential to visceralize in humans was recognized only recently. As nothing is known about the genetics of host responses to this infection and their clinical impact, we developed an informative animal model. We described previously that the recombinant congenic strain CcS-16 carrying 12.5% genes from the resistant parental strain STS/A and 87.5% genes from the susceptible strain BALB/c is more susceptible to L. tropica than BALB/c. We used these strains to map and functionally characterize the gene-loci regulating the immune responses and pathology. METHODS: We analyzed genetics of response to L. tropica in infected F2 hybrids between BALB/c×CcS-16. CcS-16 strain carries STS-derived segments on nine chromosomes. We genotyped these segments in the F2 hybrid mice and tested their linkage with pathological changes and systemic immune responses. PRINCIPAL FINDINGS: We mapped 8 Ltr (Leishmania tropica response loci. Four loci (Ltr2, Ltr3, Ltr6 and Ltr8 exhibit independent responses to L. tropica, while Ltr1, Ltr4, Ltr5 and Ltr7 were detected only in gene-gene interactions with other Ltr loci. Ltr3 exhibits the recently discovered phenomenon of transgenerational parental effect on parasite numbers in spleen. The most precise mapping (4.07 Mb was achieved for Ltr1 (chr.2, which controls parasite numbers in lymph nodes. Five Ltr loci co-localize with loci controlling susceptibility to L. major, three are likely L. tropica specific. Individual Ltr loci affect different subsets of responses, exhibit organ specific effects and a separate control of parasite load and organ pathology. CONCLUSION: We present the first identification of genetic loci controlling susceptibility to L. tropica. The different combinations of alleles controlling various symptoms of the disease likely co-determine different

  19. Differences in candidate gene association between European ancestry and African American asthmatic children.

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    Tesfaye M Baye

    Full Text Available BACKGROUND: Candidate gene case-control studies have identified several single nucleotide polymorphisms (SNPs that are associated with asthma susceptibility. Most of these studies have been restricted to evaluations of specific SNPs within a single gene and within populations from European ancestry. Recently, there is increasing interest in understanding racial differences in genetic risk associated with childhood asthma. Our aim was to compare association patterns of asthma candidate genes between children of European and African ancestry. METHODOLOGY/PRINCIPAL FINDINGS: Using a custom-designed Illumina SNP array, we genotyped 1,485 children within the Greater Cincinnati Pediatric Clinic Repository and Cincinnati Genomic Control Cohort for 259 SNPs in 28 genes and evaluated their associations with asthma. We identified 14 SNPs located in 6 genes that were significantly associated (p-values <0.05 with childhood asthma in African Americans. Among Caucasians, 13 SNPs in 5 genes were associated with childhood asthma. Two SNPs in IL4 were associated with asthma in both races (p-values <0.05. Gene-gene interaction studies identified race specific sets of genes that best discriminate between asthmatic children and non-allergic controls. CONCLUSIONS/SIGNIFICANCE: We identified IL4 as having a role in asthma susceptibility in both African American and Caucasian children. However, while IL4 SNPs were associated with asthma in asthmatic children with European and African ancestry, the relative contributions of the most replicated asthma-associated SNPs varied by ancestry. These data provides valuable insights into the pathways that may predispose to asthma in individuals with European vs. African ancestry.

  20. Reference genes for real-time qPCR in leukocytes from asthmatic patients before and after anti-asthma treatment.

    Science.gov (United States)

    Kozmus, Carina E P; Potočnik, Uroš

    2015-10-01

    The aim of this study was to develop a set of reference genes whose expression is stable and suitable for normalization of target gene expression measured in asthma patients during anti-asthmatic treatment. Real-time qPCR was used to determine expression of 7 candidate reference genes (18S rRNA, ACTB, B2M, GAPDH, POLR2A, RPL13A and RPL32) and 7 target genes in leukocytes from asthma patients before and after treatment with inhaled corticosteroids and leukotriene receptor antagonist. Variance of Cq values was analyzed and stability ranking was determined with geNorm. We further investigated how the different normalization strategies affected the consistency of conclusions if the specific investigated target gene is down-regulated or up-regulated after anti-asthmatic therapy. The top-ranking reference genes determined by geNorm, when samples before and after therapy were analyzed (ACTB, B2M and GAPDH) were different from those (POLR2A and B2M) when only samples before treatment were analyzed. Using only a single reference gene for normalization of 7 target gene expression compared to our strategy, there would be as low as 19% of consistency in conclusions. We suggest the use of the geometric mean of ACTB, B2M and GAPDH for normalization of qPCR data of target genes in pharmacogenomics studies in asthma patients before and after anti-asthmatic therapy, however if gene expression is measured only before anti-asthmatic treatment, we recommend the use of the geometric mean of POLR2A and B2M.

  1. A Review of Whole-Exome Sequencing Efforts Toward Hereditary Breast Cancer Susceptibility Gene Discovery.

    Science.gov (United States)

    Chandler, Madison R; Bilgili, Erin P; Merner, Nancy D

    2016-09-01

    Inherited genetic risk factors contribute toward breast cancer (BC) onset. BC risk variants can be divided into three categories of penetrance (high, moderate, and low) that reflect the probability of developing the disease. Traditional BC susceptibility gene discovery approaches that searched for high- and moderate-risk variants in familial BC cases have had limited success; to date, these risk variants explain only ∼30% of familial BC cases. Next-generation sequencing technologies can be used to search for novel high and moderate BC risk variants, and this manuscript reviews 12 familial BC whole-exome sequencing efforts. Study design, filtering strategies, and segregation and validation analyses are discussed. Overall, only a modest number of novel BC risk genes were identified, and 90% and 97% of the exome-sequenced families and cases, respectively, had no BC risk variants reported. It is important to learn from these studies and consider alternate strategies in order to make further advances. The discovery of new BC susceptibility genes is critical for improved risk assessment and to provide insight toward disease mechanisms for the development of more effective therapies.

  2. Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Amir Houshang Mohammad Alizadeh; Mehrdad Hajilooi; Mitra Ranjbar; Farahnaz Fallahian; Seyed Mohsen Mousavi

    2006-01-01

    AIM: To assess the three polymorphism regions within cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene, a C/T base exchange in the promoter region-318 (CTLA-4 -318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), a T/C substitution in 1172 (CTLA-4 -1172T/C) in patients with chronic hepatitis B.METHODS: Fifty-one patients with chronic hepatitis B virus infection and 150 healthy subjects were recruited sequentially as they presented to the hepatic clinic. Classification of chronic hepatitis B virus (HBV)-infected patients was as asymptomatic carrier state (26 patients) and chronic hepatitis B (25 patients). Genomic DNA was isolated from anti-coagulated peripheral blood Buffy coat using Miller's salting-out method. The presence of the CTLA-4 gene polymorphisms was determined using polymerase chain reaction amplification refractory mutation system (ARMS).RESULTS: We observed a significant association between -318 genotypes frequency (T+C-, T+C+, T-C+) and susceptibility to chronic hepatitis B (P=0.012,OR=0.49, 95%CI: 0.206-1.162). However, we did not observe a significant association for +49 genotype frequency (T+C+, T+C- T-C+) and -1172 genotype frequency (C+T+, T+C- C+T-) and state of disease.CONCLUSION: Our results suggest that CTLA-4 gene polymorphisms may partially be involved in the susceptibility to chronic hepatitis B.

  3. Association between the APC gene D1822V variant and the genetic susceptibility of colorectal cancer.

    Science.gov (United States)

    Feng, Maohui; Fang, Xiping; Yang, Qian; Ouyang, Gang; Chen, Daping; Ma, Xiang; Li, Huachi; Xie, Wei

    2014-07-01

    Adenomatous polyposis coli (APC) gene polymorphisms are believed to contribute to tumor susceptibility. However, the association between genetic variants (A/T) in the APC gene D1822V polymorphism and colorectal cancer (CRC) susceptibility remains unknown. To determine this association, a case-control study was performed. The genotype of the APC gene D1822V variants was analyzed by DNA sequencing in blood samples collected from 196 patients with CRC and 279 healthy subjects. There were no significant associations between the case and control groups in the distribution of AT [odds ratio (OR), 0.604; 95% confidence interval (CI), 0.355-1.029) and TT genotypes (OR, 0.438; 95% CI, 0.045-4.247) relative to the AA genotype. The ratio of the T allele was significantly lower (P=0.047) in the case group compared with the control group (OR, 0.611; 95% CI, 0.374-0.997), indicating that the T allele conferred a protective effect in CRC. The frequency of the AT genotype among the subjects diagnosed at >45 years of age was lower than those diagnosed at a younger age (P<0.05). The present study demonstrates that the T allele of the D1822V polymorphism may exert a protective effect against CRC, however, these findings require further validation in a larger sample size.

  4. Vitamin D receptor (VDR) gene polymorphisms and susceptibility to systemic lupus erythematosus clinical manifestations.

    Science.gov (United States)

    de Azevêdo Silva, J; Monteiro Fernandes, K; Trés Pancotto, J A; Sotero Fragoso, T; Donadi, E A; Crovella, S; Sandrin-Garcia, P

    2013-10-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical manifestations and target tissue damage. Currently, several genes have been associated with SLE susceptibility, including vitamin D receptor (VDR), which is a mediator of immune responses through the action of vitamin D. Polymorphisms in the VDR gene can impair the vitamin D (D3) function role, and since SLE patients show deficient D3 blood levels, it leads to a possible connection to the disease's onset. In our study we searched for an association between VDR polymorphisms and risk of developing SLE, as well as the disease's clinical manifestations. We enrolled 158 SLE patients and 190 Southeast Brazilian healthy controls, genotyped for five Tag single nucleotide polymorphisms (SNPs), covering most of the VDR gene region. We found an association between VDR SNPs and SLE for the following clinical manifestations: rs11168268 and cutaneous alterations (p=0.036), rs3890733 (p=0.003) rs3890733 and arthritis (p=0.001), rs2248098 and immunological alterations (p=0.040), rs4760648 and antibody anti-dsDNA (p=0.036). No association was reported between VDR polymorphisms and SLE susceptibility.

  5. Cold sore susceptibility gene-1 genotypes affect the expression of herpes labialis in unrelated human subjects.

    Science.gov (United States)

    Kriesel, John D; Bhatia, Amiteshwar; Thomas, Alun

    2014-01-01

    Our group has recently described a gene on human chromosome 21, the Cold Sore Susceptibility Gene-1 (CSSG-1, also known as C21orf91), which may confer susceptibility to frequent cold sores in humans. We present here a genotype-phenotype analysis of CSSG-1 in a new, unrelated human population. Seven hundred fifty-eight human subjects were enrolled in a case/control Cold Sore Study. CSSG-1 genotyping, herpes simplex virus 1 (HSV1) serotyping, demographic and phenotypic data was available from 622 analyzed subjects. Six major alleles (H1-H6) were tested for associations with each of the self-reported phenotypes. The statistical analysis was adjusted for age, sex and ethnicity. Genotype-phenotype associations were analyzed from 388 HSV1-seropositive subjects. There were significant CSSG-1 haplotype effects on annual cold sore outbreaks (P=0.006), lifetime cold sores (P=0.012) and perceived cold sore severity (P=0.012). There were relatively consistent trends toward protection from frequent and severe cold sores among those with the H3 or H5/6 haplotypes, whereas those with H1, H2, and H4 haplotypes tended to have more frequent and more severe episodes. Different alleles of the newly described gene CSSG-1 affect the expression of cold sore phenotypes in this new, unrelated human population, confirming the findings of the previous family-based study.

  6. Alu Elements as Novel Regulators of Gene Expression in Type 1 Diabetes Susceptibility Genes?

    DEFF Research Database (Denmark)

    Kaur, Simranjeet; Pociot, Flemming

    2015-01-01

    Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate...... genes to identify embedded Alu elements within these genes. We observed significant enrichment of Alu elements within the T1D genes (p-value genes harboring Alus revealed significant enrichment for immune......-mediated processes (p-value genes harboring inverted Alus (IRAlus) within their 3' untranslated regions (UTRs) that are known to regulate the expression of host mRNAs by generating double stranded RNA duplexes. Our in silico analysis predicted the formation of duplex structures...

  7. Interferon-inducible Ifi200-family genes as modifiers of lupus susceptibility.

    Science.gov (United States)

    Choubey, Divaker

    2012-09-01

    Both genetic and environmental factors contribute to the development and progression of systemic lupus erythematosus (SLE), a complex autoimmune disease. The disease exhibits a strong gender bias and develops predominantly in females. Additionally, most SLE patients exhibit increased serum levels of interferon-α (IFN-α) and the "IFN signature". Studies using the mouse models of lupus have identified several lupus susceptibility loci, including the New Zealand Black (NZB)-derived autoimmunity 2 (Nba2) interval on the chromosome 1. The interval, which is syntenic to the human chromosome 1q region, harbors the FcγR family, SLAM/CD2-family, and the IFN-inducible Ifi200-family genes (encoding for the p200-family proteins). Studies involving the B6.Nba2 congenic mice revealed that the development of antinuclear autoantibodies (ANAs) depends on the age, gender, and activation of type I IFN-signaling. Interestingly, recent studies involving the generation of Nba2 subcongenic mouse lines and generation of mice deficient for the Fcgr2b or Aim2 gene within the interval have provided evidence that epistatic interactions among the Nba2 genes contribute to increased lupus susceptibility. Given that the expression of some of the p200-family proteins is differentially regulated by sex hormones and these proteins differentially regulate cytosolic DNA-induced production of type I IFN and proinflammatory cytokines (IL-1β and IL-18), the major known contributors of SLE-associated inflammation, we discuss the recent advancements in our understanding of the role of p200-family proteins in lupus susceptibility modification. An improved understanding of the role of p200-family proteins in the development of autoimmunity is likely to identify new approaches to treat SLE patients.

  8. A Polymorphism in RNF213 Is a Susceptibility Gene for Intracranial Atherosclerosis.

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    Oh Young Bang

    Full Text Available Both intracranial atherosclerotic stenosis (ICAS and moyamoya disease (MMD are prevalent in Asians. We hypothesized that the Ring Finger protein 213 gene polymorphism (RNF213, a susceptibility locus for MMD in East Asians, is also a susceptibility gene for ICAS in patients whose diagnosis had been confirmed by conventional angiography (absence of basal collaterals and high-resolution MRI (HR-MRI, presence of plaque.We analyzed 532 consecutive patients with ischemic events in the middle cerebral artery (MCA distribution and relevant stenotic lesion on the distal internal carotid artery or proximal MCA, but no demonstrable carotid or cardiac embolism sources. Additional angiography was performed on 370 (69.5% patients and HR-MRI on 283 (53.2% patients.Based on angiographic and HR-MRI findings, 234 patients were diagnosed with ICAS and 288 with MMD. The RNF213 variant was observed in 50 (21.4% ICAS patients and in 119 (69.1% MMD patients. The variant was observed in 25.2% of patients with HR-MRI-confirmed ICAS. Similarly, 15.8% of ICAS patients in whom MMD was excluded by angiography had this variant. Among the ICAS patients, RNF213 variant carriers were younger and more likely to have a family history of MMD than non-carriers were. Multivariate testing showed that only the age of ICAS onset was independently associated with the RNF213 variant (odds ratio, 0.97; 95% CI, 0.944-0.99.RNF213 is a susceptibility gene not only for MMD but also for ICAS in East Asians. Further studies are needed on RNF213 variants in ICAS patients outside East Asian populations.

  9. LOD score exclusion analyses for candidate disease susceptibility genes using case-parents design

    Institute of Scientific and Technical Information of China (English)

    DENG Hongwen; GAO Guimin

    2006-01-01

    The focus of almost all the association studies of candidate genes is to test for their importance. We recently developed a LOD score approach that can be used to test against the importance of candidate genes for complex diseases and quantitative traits in random samples. As a complementary method to regular association analyses, our LOD score approach is powerful but still affected by the population admixture, though it is more conservative. To control the confounding effect of population heterogeneity, we develop here a LOD score exclusion analysis using case-parents design, the basic design of the transmission disequilibrium test (TDT) approach that is immune to population admixture. In the analysis, specific genetic effects and inheritance models at candidate genes can be analyzed and if a LOD score is ≤ - 2.0, the locus can be excluded from having an effect larger than that specified. Simulations show that this approach has reasonable power to exclude a candidate gene having small genetic effects if it is not a disease susceptibility locus (DSL) with sample size often employed in TDT studies. Similar to association analyses with the TDT in nuclear families, our exclusion analyses are generally not affected by population admixture. The exclusion analyses may be implemented to rule out candidate genes with no or minor genetic effects as supplemental analyses for the TDT. The utility of the approach is illustrated with an application to test the importance of vitamin D receptor (VDR) gene underlying the differential risk to osteoporosis.

  10. Virulence genes and antimicrobial susceptibility in Pasteurella multocida isolates from calves.

    Science.gov (United States)

    Katsuda, K; Hoshinoo, K; Ueno, Y; Kohmoto, M; Mikami, O

    2013-12-27

    A total of 378 isolates of Pasteurella multocida from clinically healthy and diseased calves were characterised for their susceptibility to 9 antimicrobial agents and screened by PCR for the presence of antimicrobial resistance genes and 22 genes virulence-associated, including capsule biosynthesis genes. Of the 378 isolates, 102 (27.0%) were resistant to at least one of the 9 tested antimicrobial agents. Resistance to oxytetracycline (21.7%) was the most frequently observed phenotype among the isolates. The tet(H) gene were the primary determinant detected. The resistance rates for thiamphenicol, ampicillin, kanamycin and florfenicol were 13.2%, 5.8%, 9.0% and 0.5%, respectively. Cefazolin, ceftiofur, cefquinome and enrofloxacin were effective antimicrobial agents, with no resistant isolates emerging over the course of the investigation. Most isolates were identified as capsular type A, only 6.3% belonged to capsular type D and no other capsular type was identified. Four of the virulence-associated genes (pfhA, tadD, tbpA and HAS) exhibited associations to the capsular type, and three (pfhA, tbpA and hgbB) were associated with the disease status of the animals. These virulence genes have been considered as epidemiological markers and are hypothesised to have a strong positive association with the outcome of disease in cattle.

  11. Extrinsic and intrinsic asthma: influence of classification on family history of asthma and allergic disease.

    Science.gov (United States)

    Sibbald, B

    1980-05-01

    The distributions of asthma, hay fever and eczema were examined in the first degree relatives of 516 asthmatics grouped according to atopic status, history of hay fever/eczema and history of asthma provoked by pollens, dust or animals. The prevalences of both asthma and eczema in relatives were strongly correlated with the presence of hay fever/eczema in probands and to a lesser extent with their atopic status. The prevalence of hay fever in relatives was strongly correlated with both the presence of hay fever/eczema and the degree of atopy in probands. In contrast, allergic provocation of asthma in probands did not influence the prevalences of asthma, hay fever or eczema. These findings are consistent with the hypothesis that there is an increased risk of asthma in relatives of atopic asthmatics which may arise from the enhanced susceptibility to asthma of individuals who inherit both a predisposition to asthma and a predisposition to atopy.

  12. Genetic variants of TSLP and asthma in an admixed urban population.

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    Mengling Liu

    Full Text Available BACKGROUND: Thymic stromal lymphopoietin (TSLP, an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations. OBJECTIVES: To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. METHODOLOGY AND MAIN RESULTS: Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671 showed nominally significant association with asthma (odds ratio (OR = 1.50; 95% confidence interval (95% CI: 1.09-2.05, p = 0.01 after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR = 2.00, 95% CI: 1.04-3.83, p = 0.04 but not significant in never-smokers (OR = 1.34; 95% CI: 0.93-1.94, p = 0.11. Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR = 1.58, 95% CI: 1.10-2.27, p = 0.01. Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR = 1.15, 95% CI: 1.07-1.23, p = 0.0003 and the results stratified by smoking status were also validated (ex-smokers: OR = 1.21, 95% CI: 1.08-1.34, p = 0.003; never-smokers: OR = 1

  13. Virulence Genes, Genetic Diversity, Antimicrobial Susceptibility and Phylogenetic Background of Escherichia coli Isolates

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    Abdi

    2015-08-01

    Full Text Available Background The epidemiology of Uropathogenic Escherichia coli (UPEC in urban and rural communities in Iran was never investigated prior to this study. Objectives The aims of this study were to detect the frequency of virulence genes and determine the antimicrobial susceptibility and phylogenetic background of Escherichia coli isolates collected from urban and rural communities. Materials and Methods A total of 100 E. coli isolates were collected from urine samples of patients with urinary tract infections (UTIs residing in two different locations, and confirmed by current biochemical tests. The phylogenetic groups were determined by the triplex-polymerase chain reaction (PCR method, and multiplex PCRs were used to detect eight Vf genes (fimH, iucD, irp2, hlyA, ompT, iha, iroN, and cnf1. The susceptibility profile of E. coli isolates was determined by the disk diffusion method. Results Ninety-five percent of UPEC showed at least one of the virulence genes, the most prevalent being fimH (95%, followed by irp2 (89%, iucD (69%, ompT (67%, iroN (29%, and iha (29%. The various combinations of detected genes were designated as virulence patterns. Phylogenetic groups, B2 (55% and D (22%, comprised the majority of isolated strains. Phenotypic tests showed that 92%, 74% and 71% of the isolates were resistant to ampicillin, ceftizoxime and cefixime, respectively. Conclusions These findings indicate that the UPEC isolates had eight virulence factors with high frequencies. Moreover, these results suggest a direct connection between virulence factors, gene diversity, phylogenetic background, and antimicrobial resistance in UPEC isolates.

  14. Identification of maize genes associated with host plant resistance or susceptibility to Aspergillus flavus infection and aflatoxin accumulation.

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    Rowena Y Kelley

    Full Text Available BACKGROUND: Aspergillus flavus infection and aflatoxin contamination of maize pose negative impacts in agriculture and health. Commercial maize hybrids are generally susceptible to this fungus. Significant levels of host plant resistance have been observed in certain maize inbred lines. This study was conducted to identify maize genes associated with host plant resistance or susceptibility to A. flavus infection and aflatoxin accumulation. RESULTS: Genome wide gene expression levels with or without A. flavus inoculation were compared in two resistant maize inbred lines (Mp313E and Mp04:86 in contrast to two susceptible maize inbred lines (Va35 and B73 by microarray analysis. Principal component analysis (PCA was used to find genes contributing to the larger variances associated with the resistant or susceptible maize inbred lines. The significance levels of gene expression were determined by using SAS and LIMMA programs. Fifty candidate genes were selected and further investigated by quantitative RT-PCR (qRT-PCR in a time-course study on Mp313E and Va35. Sixteen of the candidate genes were found to be highly expressed in Mp313E and fifteen in Va35. Out of the 31 highly expressed genes, eight were mapped to seven previously identified quantitative trait locus (QTL regions. A gene encoding glycine-rich RNA binding protein 2 was found to be associated with the host hypersensitivity and susceptibility in Va35. A nuclear pore complex protein YUP85-like gene was found to be involved in the host resistance in Mp313E. CONCLUSION: Maize genes associated with host plant resistance or susceptibility were identified by a combination of microarray analysis, qRT-PCR analysis, and QTL mapping methods. Our findings suggest that multiple mechanisms are involved in maize host plant defense systems in response to Aspergillus flavus infection and aflatoxin accumulation. These findings will be important in identification of DNA markers for breeding maize lines

  15. A preliminary study on the association of single nucleotide polymorphisms of interleukin 4 (IL4, IL13, IL4 receptor alpha (IL4Rα & Toll-like receptor 4 (TLR4 genes with asthma in Indian adults

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    Parisa Davoodi

    2015-01-01

    Full Text Available Background & objectives: Interleukin 4 (IL4 and IL13 genes are believed to be responsible for inflammation of the airways in asthmatics. These share a common receptor component called IL4Rα which is another potentially important candidate gene linked to asthma phenotypes. Another gene Toll-like receptor 4 (TLR4 might affect the incidence or progression of asthma through the expression of proinflammatory genes. Several single nucleotide polymorphisms (SNPs in IL4, IL13, IL4Rα and TLR4 have been reported to be linked to asthma or related phenotypes in several ethnic populations using linkage studies and association studies. However, the results have not been consistent. We investigated five SNPs (C-589T and C-33T of IL4, G+2044A of IL13, A+1902G of IL4Rα, and A+896G of TLR4 in patients with adult onset asthma to evaluate their role in manifestation and severity of asthma. Methods: Adult (>18 yr of age patients with asthma (n=100 and healthy controls (n=50 were included in the study. Genotyping was performed using sequenom MassARRAY technology. Results: The mutant alleles of the C-589T and C-33T SNPs in the promoter region of IL4 were present in 4 per cent patients with asthma but absent from the control group suggesting that the variations in IL4 may contribute to asthma occurrence. The SNPs of other genes were seen in both controls and patients. Interpretation & conclusions: The results suggest the possible association between the genetic distribution of C-589T and C-33T SNPs of IL4 with asthma in Indian adults.

  16. Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.

    Science.gov (United States)

    Kote-Jarai, Z; Amin Al Olama, A; Leongamornlert, D; Tymrakiewicz, M; Saunders, E; Guy, M; Giles, G G; Severi, G; Southey, M; Hopper, J L; Sit, K C; Harris, J M; Batra, J; Spurdle, A B; Clements, J A; Hamdy, F; Neal, D; Donovan, J; Muir, K; Pharoah, P D P; Chanock, S J; Brown, N; Benlloch, S; Castro, E; Mahmud, N; O'Brien, L; Hall, A; Sawyer, E; Wilkinson, R; Easton, D F; Eeles, R A

    2011-06-01

    Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

  17. Genetic polymorphisms in the carbonic anhydrase VI gene and dental caries susceptibility.

    Science.gov (United States)

    Li, Z-Q; Hu, X-P; Zhou, J-Y; Xie, X-D; Zhang, J-M

    2015-06-01

    We investigated the role of 7 single nucleotide polymorphisms in the carbonic anhydrase (CA) VI gene (rs2274328, rs17032907, rs11576766, rs2274333, rs10864376, rs3765964, and rs6680186) and the possible association between these polymorphisms and dental caries susceptibility in a Northwestern Chinese population. We collected samples from 164 high caries experience and 191 very low caries experience and conducted a case-control study according to the number of decayed, missing, and filled teeth index and genotyped the 7 polymorphisms using a 384-well plate format with the Sequenom MassARRAY platform. Individuals carrying the rs17032907 TT genotype were more likely to have an increased risk of dental caries compared with carriers of the C/C genotype in the co-dominant model, with an odds ratio (95% confidence interval) of 2.144 (1.096-4.195). We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918). However, we found no association between dental caries susceptibility and the rs2274328, rs11576766, rs2274333, rs10864376, rs3765964, and rs6680186 polymorphisms and other haplotypes. The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility.

  18. NRAMP1 gene polymorphisms and cutaneous leishmaniasis: An evaluation on host susceptibility and treatment outcome

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    Marzieh Fattahi-Dolatabadi

    2016-01-01

    Full Text Available Background & objectives: Association between polymorphisms in the natural resistance associated macrophage protein 1 (NRAMP1 gene and susceptibility to cutaneous leishmaniasis (CL has been demonstrated worldwide; however, the reported results were inconsistent. This study aimed to determine the association of NRAMP1 variants with susceptibility to CL infection and patients′ response to treatment in Isfahan province of Iran. Methods: Peripheral blood samples were collected from 150 patients with CL and 136 healthy controls. The CL patients were treated with intralesional injection of meglumine antimoniate. The polymorphic variants at NRAMP1 (A318V and D543N were analyzed using PCR-RFLP. The chi-square test and Fisher′s exact test were used to compare frequencies of alleles and genotypes of polymorphisms between patient and healthy control populations. Results: There was a statistically significant difference in the D543N (rs17235409 polymorphism between the CL patients and healthy controls (p=0.008. However, no significant association was detected for A318V (rs201565523 polymorphism between groups (p=0.26. In addition, there was a lack of association between D543N and A318V genotypes with response to treatment (p=0.54 and p=0.31, respectively. Interpretation & conclusion: The results indicated that genetic variations of D543N (rs17235409 might be associated with susceptibility to CL infection. These data may be used for detection of sensitive individuals and prevention of CL in endemic areas.

  19. Interaction between retinoid acid receptor-related orphan receptor alpha (RORA and neuropeptide S receptor 1 (NPSR1 in asthma.

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    Nathalie Acevedo

    Full Text Available Retinoid acid receptor-related Orphan Receptor Alpha (RORA was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs in the vicinity of the asthma-associated SNP (rs11071559 and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1, has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children and the European cross-sectional PARSIFAL study (1120 children. Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36-2.93, p = 0.0003 in BAMSE; and 1.61, 1.18-2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively, and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility.

  20. Regulatory T-lymphocytes in asthma

    NARCIS (Netherlands)

    van Oosterhout, AJM; Bloksma, N

    2005-01-01

    T-helper cell type (Th)2 lymphocytes play an important role in the initiation, progression and persistence of allergic diseases, including asthma. However, little is known about immunoregulatory mechanisms that determine susceptibility to, severity of, or persistence of asthma. The concept of a dist

  1. Characterization of Toxin Genes and Antimicrobial Susceptibility of Staphylococcus aureus Isolates in Fishery Products in Iran

    Science.gov (United States)

    Arfatahery, Noushin; Davoodabadi, Abolfazl; Abedimohtasab, Taranehpeimaneh

    2016-01-01

    Staphylococcus aureus is one of the most common causes of seafood-borne diseases worldwide, which are attributable to the contamination of food by preformed enterotoxins. In this study, a total of 206 (34.3%) Staphylococcus aureus strains were obtained from 600 fish and shrimp samples and were tested for their antimicrobial susceptibility. We assessed the prevalence of the genes responsible for the staphylococcal enterotoxins (SEA, SEB) and toxic shock syndrome toxin 1 (TSST-1) genes. The results indicated that 34% of aqua food samples were contaminated with S. aureus, and 23.8% of these isolates were mec-A-positive. Sixty-four percent of the strains isolated from contaminated seafood was enterotoxigenic S. aureus, and 28.2% of SEs were MRSA-positive. The most prevalent genotype was characterized by the presence of the sea gene (45.2%), followed by the seb gene (18.5%), and the tst gene encoding TSST-1 was found in eight strains (3.9%). Of the 206 S. aureus isolates, 189 strains (84.9%) were resistant to at least one antibiotic. Given the frequent outbreaks of enterotoxigenic MRSA, it is necessary to make revisions to mandatory programmes to facilitate improved hygiene practices during fishing, aquaculture, processing, and sales to prevent the contamination of fishery products in Iran. PMID:27694813

  2. Study on relationship of apolipoprotein E gene polymorphism and genetic susceptibility of stress urinary incontinence

    Institute of Scientific and Technical Information of China (English)

    Tong Jia-li; Lang Jing-he; Zhu lan

    2010-01-01

    Objective: To explore the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility of stress urinary incontinence (SUI).Methods: ApoE genotypes were examined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) technique in 99 patients with SUI and 101 asymptomatic controls. Results: The frequency of allele e3 of ApoE was slightly lower in patients with anatomic SUI than that in controls (79.44% vs. 81.68%), while the frequency of allele e4 of ApoE was slightly higher in patients with anatomic SUI than that in controls (10.00% vs. 9.90%). No significant difference was found in frequency of allele e3 or e4 between SUI patients and controls (χ2=0.523, P=0.770).Conclusion: The gene polymorphism of ApoE is not independently involved in the development of SUI.

  3. The Role of Seizure-Related SEZ6 as a Susceptibility Gene in Febrile Seizures

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    John C. Mulley

    2011-01-01

    Full Text Available Sixty cases of febrile seizures from a Chinese cohort had previously been reported with a strong association between variants in the seizure-related (SEZ 6 gene and febrile seizures. They found a striking lack of genetic variation in their controls. We found genetic variation in SEZ6 at similar levels at the same DNA sequence positions in our 94 febrile seizure cases as in our 96 unaffected controls. Two of our febrile seizure cases carried rare variants predicted to have damaging consequences. Combined with some of the variants from the Chinese cohort, these data are compatible with a role for SEZ6 as a susceptibility gene for febrile seizures. However, the polygenic determinants underlying most cases of febrile seizures with complex inheritance remain to be determined.

  4. Relationship between Polymorphism of Nicotinic Acetylcholine Receptor Gene CHRNA3 and Susceptibility of Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    Shen Bo; Shi Meiqi; Mei Jinfeng; Hong Zhuan; Cao Guochun; Lu Jianwei; Feng Jifeng

    2013-01-01

    Objective:To investigate the relationship between polymorphism of nicotinic acetylcholine receptor gene CHRNA3 and susceptibility of lung cancer. Methods:Sixty hundred patients with lung cancer and 600 healthy people were respectively selected. TaqMan-MGB probe technique was applied to detect rs3743073 (T > G) genotypes at SNPs site on CHRNA3. The difference of genotype distribution among groups was compared, and its relationship with lung cancer was also investigated. Results:There was statistical signiifcance regarding the distributions of CHRNA3 rs3743073 (T>G) genotype and allele frequencies in patients with lung cancer and healthy people (P Conclusion:The risk of developing lung cancer in patients with rs3743073G mutant genotypes of CHRNA3 gene is increased markedly, especially in those more than 60 years old, males and smoking ones.

  5. Susceptibility Genes of Schizophrenia%精神分裂症易感基因

    Institute of Scientific and Technical Information of China (English)

    冯雅琴; 李巍

    2009-01-01

    Schizophrenia is a highly heritable polygenic disorder.With the improvement of multi-disciplinary technologies especially in the genetic and molecular biologic fields,a large number of new risk genes have been reported in recent years.Significant progress has been achieved in studying function of certain crutial susceptibility genes and their contribution to disease pathogenesis.%精神分裂症是一类遗传倾向性较高的多基因疾病.近年来,随着遗传学和分子生物学为主的多学科研究技术的快速发展,不断有新的易感基因报道;一些重要易感基因的生物学功能及其在该疾病发病机制中的作用研究也取得了一定进展.

  6. Characterization of obstructive airway disease in family members of probands with Asthma - An algorithm for the diagnosis of asthma

    NARCIS (Netherlands)

    Panhuysen, CIM; Bleecker, ER; Koeter, GH; Meyers, DA; Postma, DS

    1998-01-01

    To investigate the genetic susceptibility to asthma, we developed an algorithm to classify the phenotype of each family member enrolled in a family study on the genetics of asthma. This algorithm was applied to 92 two-and three-generation families, identified through a subject (proband) with asthma

  7. Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats.

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    Xiaoyan Lu

    Full Text Available The extent of drug-induced liver injury (DILI can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI, the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.

  8. Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene

    NARCIS (Netherlands)

    Himes, Blanca E.; Jiang, Xiaofeng; Hu, Ruoxi; Wu, Ann C.; Lasky-Su, Jessica A.; Klanderman, Barbara J.; Ziniti, John; Senter-Sylvia, Jody; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Meyers, Deborah A.; Bleecker, Eugene R.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Hanrahan, John P.; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A. E.; Vonk, Judith M.; Panettieri, Reynold A.; Markezich, Amy; Israel, Elliot; Carey, Vincent J.; Tantisira, Kelan G.; Litonjua, Augusto A.; Lu, Quan; Weiss, Scott T.

    2012-01-01

    Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting beta(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also

  9. Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour.

    Science.gov (United States)

    Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

    2015-02-01

    The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N = 366, M = 17.11 years, 74.9% male). Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour.

  10. Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

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    C. J. Carter

    2013-01-01

    Full Text Available Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (multiple sclerosis, and autism (, but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD to 33% (MS of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as to the disease itself.

  11. HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.

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    Angeline S Andrew

    Full Text Available Bladder cancer is the 4(th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62. This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63. The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25 than females (OR 1.56 95%CI 0.83-2.95, (SNP-gender interaction P = 0.048. We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003. The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

  12. Gene polymorphisms in African buffalo associated with susceptibility to bovine tuberculosis infection.

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    Nikki le Roex

    Full Text Available Bovine tuberculosis (BTB is a chronic, highly infectious disease that affects humans, cattle and numerous species of wildlife. In developing countries such as South Africa, the existence of extensive wildlife-human-livestock interfaces poses a significant risk of Mycobacterium bovis transmission between these groups, and has far-reaching ecological, economic and public health impacts. The African buffalo (Syncerus caffer, acts as a maintenance host for Mycobacterium bovis, and maintains and transmits the disease within the buffalo and to other species. In this study we aimed to investigate genetic susceptibility of buffalo for Mycobacterium bovis infection. Samples from 868 African buffalo of the Cape buffalo subspecies were used in this study. SNPs (n = 69, with predicted functional consequences in genes related to the immune system, were genotyped in this buffalo population by competitive allele-specific SNP genotyping. Case-control association testing and statistical analyses identified three SNPs associated with BTB status in buffalo. These SNPs, SNP41, SNP137 and SNP144, are located in the SLC7A13, DMBT1 and IL1α genes, respectively. SNP137 remained significantly associated after permutation testing. The three genetic polymorphisms identified are located in promising candidate genes for further exploration into genetic susceptibility to BTB in buffalo and other bovids, such as the domestic cow. These polymorphisms/genes may also hold potential for marker-assisted breeding programmes, with the aim of breeding more BTB-resistant animals and herds within both the national parks and the private sector.

  13. Interleukin-8 gene polymorphism –251T>A contributes to Alzheimer's disease susceptibility

    Science.gov (United States)

    Qin, Biyong; Li, Li; Wang, Shanshan; Wu, Jun; Huang, Yulan; Zhou, Ping; Bai, Jiao; Zheng, Yan

    2016-01-01

    Abstract Background: Published association studies have investigated the correlation between interleukin-8 (IL-8) gene polymorphism –251T>A and susceptibility to Alzheimer's disease (AD); however, the results are conflicting. Thus, we conducted the meta-analysis to reassess the effect of IL-8 gene –251T>A variant on the risk of AD. Methods: Relevant studies regarding this association were electronically searched and identified from the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and the Chinese Biomedicine Database. The odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs) were pooled to calculate the strength of this association. Results: Nine studies with a total of 1406 cases and 2152 controls were included in the meta-analysis. Overall, a significant association of IL-8 gene –251T>A polymorphism with increased risk of AD was observed in several genetic models (allele, A vs T: OR=1.32, 95%CI=1.16-1.50; homozygous, AA vs TT: OR=1.70, 95%CI=1.21–2.21; heterozygous, TA vs TT: OR=1.37, 95%CI=1.12–1.69; recessive, AA vs TA+TT: OR=1.40, 95%CI=1.12–1.75). Similarly, such association was also revealed both in Asian and European populations in the subgroup analysis by ethnicity. Conclusion: The current study suggested that IL-8 gene polymorphism –251T>A may contribute to the susceptibility to AD. PMID:27684880

  14. MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma.

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    Yin-Hung Chu

    Full Text Available BACKGROUND: Micro RNAs (miRNAs are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a (rs2910164, miRNA149 (rs2292832, miRNA196 (rs11614913, and miRNA499 (rs3746444 genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30. In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80. CONCLUSIONS: These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

  15. Programmed cell death 1 gene (PDCD1 polymorphism and pemphigus foliaceus (fogo selvagem disease susceptibility

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    Karin Braun-Prado

    2007-03-01

    Full Text Available Pemphigus foliaceus, also known as fogo selvagem, is an autoimmune disease of the epidermis characterized by superficial blisters and antibodies against desmoglein 1. It is a multifactorial disease and genetic susceptibility is oligogenic or polygenic. Considering the crucial function of the programmed cell death 1 molecule (PD-1 in the immune response, the aim of this study was to verify if variants of the PDCD1 gene influence susceptibility and resistance to pemphigus foliaceus, in a case - control disease association study. We analyzed patients (n = 154 and unaffected control individuals (n = 325 of the Brazilian population, in respect to the PD1.3(G,A PD1.5(C,T and PD1.6(A,G single nucleotide polymorphisms (SNPs and also investigated, for the first time, the exon 5 PDCD1 microsatellite (CTGn. The patient and control samples were divided into strata, according to the predominant ancestry of the individuals (African or European. The PD1.5 genotype distribution in the patients sample was almost indistinguishable from that in the control sample, in both population strata. A possible negative association between pemphigus foliaceus and allele PD1.3A was observed in the total African and European ancestry population sample (odds ratio (OR = 0.55, p = 0.066 and should be investigated in forthcoming studies. The PD1.6A allele was over-represented among the patients of predominantly European ancestry due to an increase of both the G/A and the A/A genotypes (OR = 2.12 and 1.74, respectively; p = 0.035. We conclude that polymorphisms of the PDCD1 gene may influence susceptibility to pemphigus foliaceus, at least in Brazilians of predominantly European ancestry.

  16. Construction of label-free electrochemical immunosensor on mesoporous carbon nanospheres for breast cancer susceptibility gene

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Haixia; Zhang, Yong; Wu, Dan; Ma, Hongmin; Li, Xiaojing; Li, Yan; Wang, Huan; Li, He; Du, Bin [Key Laboratory of Chemical Sensing and Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022 (China); Wei, Qin, E-mail: sdjndxwq@163.com [Key Laboratory of Chemical Sensing and Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022 (China)

    2013-04-03

    Highlights: ► The immunosensor is designed to determine breast cancer susceptibility gene. ► Mesoporous carbon nanospheres (MCN) have great adsorption capacity. ► MCN could enhance the electroactivity of toluidine blue. ► Room temperature ionic liquid should increase the electrochemical signal. -- Abstract: In this contribution, mesoporous carbon nanospheres (MCN) were used to fabricate a label-free electrochemical immunosensor for breast cancer susceptibility gene (BRCAl). The detection platform was constructed by conjugation of anti-BRCA1 on glassy carbon electrodes which were modified by mesoporous carbon nanospheres–toluidine blue nanocomposite (MCN–TB)/room temperature ionic-liquid (RTIL) composited film. TB was adsorbed onto MCN and acted as a redox probe. The electroactivity of TB was greatly enhanced in the presence of MCN. The good conductivity of MCN and BMIM·BF{sub 4} could promote the electron transfer and thus enhance the detection sensitivity. Moreover, the large surface area of MCN and the protein-binding properties of BMIM·BF{sub 4} could greatly increase the antibody loading. The specific antibody–antigen immunoreaction on the electrode surface resulted in a decrease of amperometric signal of the electrode. Under optimized conditions, the amperometric signal decreased linearly with BRCAl concentration in the range of 0.01–15 ng mL{sup −1} with a low detection limit of 3.97 pg mL{sup −1}. The immunosensor exhibits high sensitivity, good selectivity and stability.

  17. BoLA-DRB3 gene polymorphism and FMD resistance or susceptibility in Wanbei cattle.

    Science.gov (United States)

    Lei, Wei; Liang, Qinglong; Jing, Luo; Wang, Chengmin; Wu, Xiaobing; He, Hongxuan

    2012-09-01

    For the further characterization of foot-and-mouth disease virus (FMDV)-induced foot-and-mouth disease, we investigated the association between polymorphism of BoLA-DRB3 gene and FMD resistance/susceptibility of Wanbei cattle challenged with FMDV. One hundred cattle were challenged with FMDV and exon 2 of BoLA-DRB3 genes was amplified by hemi-nested polymerase chain reaction from asymptomatic animals and from animals with FMD. PCR products were characterized by the RFLP technique using restriction enzymes Hae III. The results revealed extensive polymorphisms, 6 RFLP patterns were identified. By analyzing alleles and genotypic frequencies between healthy and infection with FMD cattle, we found that allele Hae III A was associated with susceptibility to FMD in Wanbei cattle (P DRB3 and 13.70 % of nucleotide mutated, which resulted in 14.61 % of amino acid change. One PKC, one Tyr and one CAMP phosphorylation were increased; the hydrophobicity and secondary structure of proteins produced change after amino acid substitution. These results revealed that Wanbei cattle had the ability of resistance to disease by mutation which result changes of the protein structure to perform the regulation of the cell using different signaling pathways in the long process of choice evolution.

  18. Impacts of CA9 gene polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic characteristics in Taiwan.

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    Shian-Shiang Wang

    Full Text Available BACKGROUND: Carbonic anhydrase 9 (CA9 is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC and the clinicopathological status. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms (SNPs of the CA9 gene were assessed by a real-time PCR with the TaqMan assay. After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05 than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoker, people with at least one A allele of CA9 polymorphisms (rs1048638 had a 4.75-fold (95% CI = 1.204-18.746 increased risk of invasive cancer. CONCLUSION: The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan.

  19. TLR9 gene region polymorphisms and susceptibility to tuberculosis in Vietnam.

    Science.gov (United States)

    Graustein, A D; Horne, D J; Arentz, M; Bang, N D; Chau, T T H; Thwaites, G E; Caws, M; Thuong, N T T; Dunstan, S J; Hawn, T R

    2015-03-01

    Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p meningeal tuberculosis (dominant model; p = 0.0002, OR 2.36, CI 1.43-3.87) while rs352143 was associated with pulmonary tuberculosis (recessive model; p = 0.006, OR 5.3, CI 1.26-31.13). None of the SNPs were associated with mortality. This is the first demonstration of an association between a TLR9 gene region SNP and tuberculous meningitis. In addition, this extends previous findings that support associations of TLR9 SNPs with pulmonary tuberculosis.

  20. Down-regulation of promoter methylation level of CD4 gene after MDV infection in MD-susceptible chicken line

    Science.gov (United States)

    Marek’s disease virus (MDV) is an oncovirus that induces lymphoid tumors in susceptible chickens, and may affect the epigenetic stability of the CD4 gene. The purpose of this study was to find how the effect of MDV infection on DNA methylation status of the CD4 gene differed between MD-resistant (L6...

  1. Inverse gene-for-gene interactions contribute additively to tan spot susceptibility in wheat

    Science.gov (United States)

    Tan spot of wheat, caused by Pyrenophora tritici-repentis, is an important disease in almost all wheat-growing areas of the world. The disease system is known to involve at least three fungal-produced necrotrophic effectors (NEs) that interact with corresponding host sensitivity (S) genes in an inv...

  2. Multiple sclerosis susceptibility in a Brazilian sample, HLA and CIITA genes

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    Eduardo Ribeiro Paradela

    2014-06-01

    Full Text Available Introduction: The multiple sclerosis (MS is a chronic disease of the central nervous system that affects mainly young adults. This disease is characterized by the spread of demyelinating lesions in time and space. This condition may be influenced by genetic factors as heterogeneity, incomplete penetrance, polygenic inheritance and epigenetic factors, which makes this complex disease a challenge for geneticists. Objectives: The aim of this study was to investigate the association between HLA alleles from DQA1, DQB1 and DRB1 loci (6p21.3, genetic polymorphisms -168A/G (rs3087456 and +1614 G/C (rs4774 in the CIITA gene (16p13 and susceptibility to MS in a miscegenated sample from Rio de Janeiro state, RJ, Brazil. Method: DNA samples from 52 patients with relapsing remitting multiple sclerosis (MSRR [21 males (40.38% and 31 females (59.62%] and 116 healthy controls [46 males (39.65% and 70 females (60.35%] matched by race, sex and age were analyzed by techniques of PCR, SSP-PCR, electrophoresis and DNA sequencing. Results: A significant association between MS and HLA-DRB1*15:01 allele was observed [p value=.002; Odds Ratio (OR=3.2], especially in women (p=.001; OR=4.9, which remained statistically significant after Bonferroni correction. Furthermore, it was observed that the polymorphism +1614 G/C, “C/C” profile, in association with the allele DRB1*15:01 influences the increased susceptibility to MS in women (p=.029; OR=5.6. In addition, it was observed that the "G/G" profile in CIITA polymorphism +1614G/C may be associated with the resistance to MS (p=.02; OR=0.23, as well as HLA-DRB1*11:02 (p=.02, OR=0.5. The HLA-DQB1*06:02 allele also has been implicated as a possible susceptibility factor for MS (p=.02; OR=1.8, data not confirmed after Bonferronís correction. Conclusion: Together, these results reinforce the polygenic nature of MS, and proposed that the CIITA gene, which is the regulator of the expression of HLA-D, is an additive factor to

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

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    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.

  4. Relationship Between LAPTM4B Gene Polymorphism and Susceptibility of Malignant Melanoma in Chinese Patients

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    Meng Zhang

    2014-10-01

    Full Text Available Lysosomal-associated protein transmembrane 4 beta (LAPTM4B is known as an oncogene associated with many human malignant tumors. There are two alleles of the gene, LAPTM4B*1 and LAPTM4B*2. Previous studies have shown that LAPTM4B polymorphism contributes to the risk of many cancers. This case-control study was to investigate the relationship between LAPTM4B gene polymorphism and susceptibility of malignant melanoma. The genotypes of LAPTM4B were determined in 617 control subjects and 220 patients with malignant melanoma by utilizing polymerase chain reaction based on specific primers. The genotypic distribution of LAPTM4B and Hardy–Weinberg equilibrium were analyzed by χ2 test. Odds ratio and 95% confidence interval was calculated by unconditional logistic regression. The distributions of LAPTM4B genotypes were significantly different between melanoma patients (45.9% for *1/1, 46.4% for *1/2 and 7.7 for *2/2 and controls (54.5% for *1/1, 39.9% for *1/2 and 5.7 for *2/2. LAPTM4B *1/2 and LAPTM4B *2/2 had a 1.396-fold and 1.619-fold higher risk for melanoma occurrence than *1/1, and subjects with LAPTM4B*2 have a 1.308-fold higher risk than LAPTM4B*1 carriers. No association between LAPTM4B genotypes and gender, age, subtype, Clark level of invasion, Breslow thickness, ulceration, clinical stage, and C-KIT, BRAF gene mutation status was observed. LAPTM4B*2 is associated with the high risk of malignant melanoma and carrying LAPTM4B *2 may be a susceptible factor to Chinese melanoma patients.

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

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    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.

  6. Additive susceptibility to insulin-dependent diabetes conferred by HLA-DQB1 and insulin genes.

    Science.gov (United States)

    She, J X; Bui, M M; Tian, X H; Muir, A; Wakeland, E K; Zorovich, B; Zhang, L P; Liu, M C; Thomson, G; Maclaren, N K

    1994-01-01

    Several genomic polymorphisms at the insulin (INS) gene and its flanking regions were analyzed in 197 unrelated Caucasian patients affected by insulin-dependent diabetes (IDDM) and 159 ethnically matched, normal controls ascertained from the South-Eastern United States. We found that the frequency of homozygotes for the common variant at the insulin gene was significantly increased in the diabetic population (RR = 2.0, p INS gene. We determined the HLA-DQB1 genotypes by denaturing gradient gel electrophoresis (DGGE) and/or sequence-specific primers (SSP) techniques to assess the possible interactions between INS and HLA. DQB1*0302 had the strongest predisposing effect on IDDM susceptibility (RR = 9.3) and DQB1*0602 the strongest protective effect (RR = 0.02). However, a significant predisposing effect of DQB1*0201 could be demonstrated only after removal of the effects of DQB1*0302 and DQB1*0602. Analyses of the genotypes revealed that all genotypes containing 0602 were protective and that the heterozygous genotype 0201/0302 and homozygous genotype 0302/0302 confer the highest risk (RR = 20.9 and 12.9 respectively). However, heterozygous genotypes 0302/X (X excludes 0201, 0302 and 0602) have a significantly lower predisposing risk. Similarly, there is heterogeneity in risk between predisposing 0201/0201 homozygous individuals and protective 0201/X individuals. When subjects were stratified by HLA genotypes, the relative risks conferred by INS did not vary, thus suggesting that the susceptibility effects conferred by HLA and INS are additive rather than interactive.

  7. Interaction of collagen-related genes and susceptibility to betel quid-induced oral submucous fibrosis.

    Science.gov (United States)

    Chiu, Chung-Jung; Chang, Min-Lee; Chiang, Chun-Pin; Hahn, Liang-Jiunn; Hsieh, Ling-Ling; Chen, Chien-Jen

    2002-07-01

    Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity. It is a collagen-related disorder induced by betel quid chewing, a habit that is common in Taiwan. However, the cumulative exposure to betel quids varies in OSF patients. It seems that there is individual susceptibility to betel quid-induced OSF. This study compared the association of OSF and polymorphisms of six collagen-related genes, collagen 1A1 and 1A2 (COL1A1 and COL1A2), collagenase-1 (COLase), transforming growth factor beta1 (TGF-beta1), lysyl oxidase (LYOXase), and cystatin C (CST3), between patients with low and high exposure to betel quids. A total of 166 patients with OSF from a medical center and 284 betel quid chewers who were free of OSF and oral cancer, from the same hospital and five townships, were recruited. PCR-based restriction fragment length polymorphism assays were used to determine the genotypes of the six collagen-related genes situated on different chromosomes. We found that the genotypes associated with the highest OSF risk for collagen 1A1, collagen 1A2, collagenase-1, transforming growth factor beta1, lysyl oxidase, and cystatin C were CC, AA, TT, CC, AA, and AA, respectively, for the low-exposure group, and TT, BB, AA, CC, GG, and AA, respectively, for the high-exposure group. A trend was noted for an increased risk of OSF with increasing number of high-risk alleles for those with both high and low exposures for betel quid. The cell selection mechanism of oral fibroblasts is proposed to explain the effect of the modification of cumulative betel quid exposure on the risk profiles of collagen-related genes. These results imply that susceptibility to OSF could involve multigenic mechanisms modified by the betel quid-exposure dose.

  8. Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis

    DEFF Research Database (Denmark)

    Grauers, Anna; Wang, Jingwen; Einarsdottir, Elisabet;

    2015-01-01

    BACKGROUND CONTEXT: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants...... that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. PURPOSE: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study...... of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. STUDY DESIGN: This was a case control study. PATIENT SAMPLE: A total of 1,739 patients...

  9. Gene expression profile suggests that pigs (Sus scrofa are susceptible to Anaplasma phagocytophilum but control infection

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    Galindo Ruth C

    2012-08-01

    Full Text Available Abstract Background Anaplasma phagocytophilum infects a wide variety of hosts and causes granulocytic anaplasmosis in humans, horses and dogs and tick-borne fever in ruminants. Infection with A. phagocytophilum results in the modification of host gene expression and immune response. The objective of this research was to characterize gene expression in pigs (Sus scrofa naturally and experimentally infected with A. phagocytophilum trying to identify mechanisms that help to explain low infection prevalence in this species. Results For gene expression analysis in naturally infected pigs, microarray hybridization was used. The expression of differentially expressed immune response genes was analyzed by real-time RT-PCR in naturally and experimentally infected pigs. Results suggested that A. phagocytophilum infection affected cytoskeleton rearrangement and increased both innate and adaptive immune responses by up regulation of interleukin 1 receptor accessory protein-like 1 (IL1RAPL1, T-cell receptor alpha chain (TCR-alpha, thrombospondin 4 (TSP-4 and Gap junction protein alpha 1 (GJA1 genes. Higher serum levels of IL-1 beta, IL-8 and TNF-alpha in infected pigs when compared to controls supported data obtained at the mRNA level. Conclusions These results suggested that pigs are susceptible to A. phagocytophilum but control infection, particularly through activation of innate immune responses, phagocytosis and autophagy. This fact may account for the low infection prevalence detected in pigs in some regions and thus their low or no impact as a reservoir host for this pathogen. These results advanced our understanding of the molecular mechanisms at the host-pathogen interface and suggested a role for newly reported genes in the protection of pigs against A. phagocytophilum.

  10. Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes

    OpenAIRE

    Izumi, Kenichi; Mine, Keiichiro; Inoue, Yoshitaka; Teshima, Miho; Ogawa, Shuichiro; Kai, Yuji; Kurafuji, Toshinobu; Hirakawa, Kanako; Miyakawa, Daiki; Ikeda, Haruka; Inada, Akari; Hara, Manami; Yamada, Hisakata; Akashi, Koichi; Niho, Yoshiyuki

    2015-01-01

    Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 backgrou...

  11. Genetic analysis of dilated cardiomyopathy--HLA and immunoglobulin genes may confer susceptibility.

    Science.gov (United States)

    Nishi, H; Kimura, A; Fukuta, S; Kusukawa, R; Kawamura, K; Nimura, Y; Nagano, M; Yasuda, H; Kawai, C; Sugimoto, T

    1992-10-01

    To identify genetic factors in the immune system which control the susceptibility to dilated cardiomyopathy (DCM), HLA class II DNA typing was performed in 61 Japanese patients, using PCR/SSO probe analyses. The frequencies of HLA-DQB1*0503 (15% vs 5%; RR = 3.06, chi 2 = 7.19) and DQB1*0604 (21% vs 10%; RR = 2.41, chi 2 = 6.20) were significantly increased and that of HLA-DQB1*0502 (RR = 1.74) was slightly increased in the DCM patients. The frequency of DQB1*0303 (16% vs 31%; RR = 0.44, chi 2 = 5.16) was significantly decreased in the patients. The increased HLA-DQB1 alleles have a histidine residue in common at the 30th codon for the HLA-DQ beta chain. Among the genetic markers studied by Southern blot analyses, IGLV (immunoglobulin lambda light chain, pV3.3) showed a strong association with DCM, i.e. A2/A2 genotype was found in 37.7% of patients whereas it was observed in only 18.9% of the control subjects (RR = 2.6, chi 2 = 7.77). The frequency of this genotype was higher in patients under age 45 years at the time of diagnosis (45.5%, RR = 3.6, chi 2 = 10.02). These results suggest that HLA and immunoglobulin genes are closely linked to susceptibility to DCM.

  12. Converging Findings from Linkage and Association Analyses on Susceptibility Genes for Smoking and Other Addictions

    Science.gov (United States)

    Yang, Jackie (Jiekun); Li, Ming D.

    2016-01-01

    Experimental approaches to genetic studies of complex traits evolve with technological advances. How do discoveries using different approaches advance our knowledge of the genetic architecture underlying complex diseases/traits? Do most of the findings of newer techniques, such as genome-wide association study (GWAS), provide more information than older ones, e.g., genome-wide linkage study? In this review, we address these issues by developing a nicotine dependence (ND) genetic susceptibility map based on the results obtained by the approaches commonly used in recent years, namely, genome-wide linkage, candidate gene association, GWAS, and targeted sequencing. Converging and diverging results from these empirical approaches have elucidated a preliminary genetic architecture of this intractable psychiatric disorder and yielded new hypotheses on ND aetiology. The insights we obtained by putting together results from diverse approaches can be applied to other complex diseases/traits. In sum, developing a genetic susceptibility map and keeping it updated are effective ways to keep track of what we know about a disease/trait and what the next steps might be with new approaches. PMID:27166759

  13. Polymorphism of the DNA repair gene XPA and susceptibility to lung cancer

    Institute of Scientific and Technical Information of China (English)

    Jinfu Zhu; Zhibin Hu; Hongxia Ma; Xiang Huo; Lin Xu; Jiannong Zhou; Hongbing Shen; Yijiang Chen

    2005-01-01

    Objective: To study the relationship between one polymorphism in the promoter of the DNA repair gene XPA and the susceptibility to lung cancer. Methods: Genotypes were determined by the PCR-restriction fragment length polymorphism (PCR-RFLP)method in 310 histologically-confirmed lung cancer cases and 341 age and sex frequency-matched cancer-free controls. Results: The XPA A23G genotype frequencies were 27.1% (AA), 42.9% (AG), and 30.0% (GG) in case patients and 21.1% (AA), 52.8% (AG),and 26.1% (GG) in control subjects. Multivariate logistic regression analysis revealed that individuals carrying at least one 23G variant allele (AG + GG genotypes) had a significantly decreased risk for lung cancer (adjusted OR = 0.66; 95% CI = 0.44- 0.98) compared with the wild-type genotype (23AA). Stratified analysis showed that the protective effect was more evident in subjects with a family history of cancer. Conclusion: These results suggest that the XPA A23G polymorphism may have a role in lung cancer susceptibility in this study population.

  14. Differential Expression of Apoptosis Related Genes in Selected Strains of Aedes aegypti with Different Susceptibilities to Dengue Virus

    Science.gov (United States)

    Ocampo, Clara B.; Caicedo, Paola A.; Jaramillo, Gloria; Ursic Bedoya, Raul; Baron, Olga; Serrato, Idalba M.; Cooper, Dawn M.; Lowenberger, Carl

    2013-01-01

    Aedes aegypti is the principal vector of Dengue viruses worldwide. We identified field collected insects with differential susceptibility to Dengue-2 virus (DENv-2) and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. Previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. To identify potential molecular mechanisms associated with DENv susceptibility, we evaluated the differential expression of Caspase-16, Aedronc, Aedredd, Inhibitor of apoptosis (AeIAP1) and one member of the RNAi pathway, Argonaute-2 in the midguts and fat body tissues of the selected strains at specific times post blood feeding or infection with DENv-2. In the refractory strain there was significantly increased expression of caspases in midgut and fatbody tissues in the presence of DENv-2, compared to exposure to blood alone, and significantly higher caspase expression in the refractory strain compared with the susceptible strain at timepoints when DENv was establishing in these tissues. We used RNAi to knockdown gene expression; knockdown of AeIAP1 was lethal to the insects. In the refractory strain, knockdown of the pro-apoptotic gene Aedronc increased the susceptibility of refractory insects to DENv-2 from 53% to 78% suggesting a contributing role of this gene in the innate immune response of the refractory strain. PMID:23593426

  15. Differential expression of apoptosis related genes in selected strains of Aedes aegypti with different susceptibilities to dengue virus.

    Directory of Open Access Journals (Sweden)

    Clara B Ocampo

    Full Text Available Aedes aegypti is the principal vector of Dengue viruses worldwide. We identified field collected insects with differential susceptibility to Dengue-2 virus (DENv-2 and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. Previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. To identify potential molecular mechanisms associated with DENv susceptibility, we evaluated the differential expression of Caspase-16, Aedronc, Aedredd, Inhibitor of apoptosis (AeIAP1 and one member of the RNAi pathway, Argonaute-2 in the midguts and fat body tissues of the selected strains at specific times post blood feeding or infection with DENv-2. In the refractory strain there was significantly increased expression of caspases in midgut and fatbody tissues in the presence of DENv-2, compared to exposure to blood alone, and significantly higher caspase expression in the refractory strain compared with the susceptible strain at timepoints when DENv was establishing in these tissues. We used RNAi to knockdown gene expression; knockdown of AeIAP1 was lethal to the insects. In the refractory strain, knockdown of the pro-apoptotic gene Aedronc increased the susceptibility of refractory insects to DENv-2 from 53% to 78% suggesting a contributing role of this gene in the innate immune response of the refractory strain.

  16. Differential expression of apoptosis related genes in selected strains of Aedes aegypti with different susceptibilities to dengue virus.

    Science.gov (United States)

    Ocampo, Clara B; Caicedo, Paola A; Jaramillo, Gloria; Ursic Bedoya, Raul; Baron, Olga; Serrato, Idalba M; Cooper, Dawn M; Lowenberger, Carl

    2013-01-01

    Aedes aegypti is the principal vector of Dengue viruses worldwide. We identified field collected insects with differential susceptibility to Dengue-2 virus (DENv-2) and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. Previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. To identify potential molecular mechanisms associated with DENv susceptibility, we evaluated the differential expression of Caspase-16, Aedronc, Aedredd, Inhibitor of apoptosis (AeIAP1) and one member of the RNAi pathway, Argonaute-2 in the midguts and fat body tissues of the selected strains at specific times post blood feeding or infection with DENv-2. In the refractory strain there was significantly increased expression of caspases in midgut and fatbody tissues in the presence of DENv-2, compared to exposure to blood alone, and significantly higher caspase expression in the refractory strain compared with the susceptible strain at timepoints when DENv was establishing in these tissues. We used RNAi to knockdown gene expression; knockdown of AeIAP1 was lethal to the insects. In the refractory strain, knockdown of the pro-apoptotic gene Aedronc increased the susceptibility of refractory insects to DENv-2 from 53% to 78% suggesting a contributing role of this gene in the innate immune response of the refractory strain.

  17. Bioinformatics Analysis for Coding SNPs of the HLADQA1 Gene Involved in Susceptibility to Cervical Cancer

    Institute of Scientific and Technical Information of China (English)

    Yanyun Li; Jun Xing; Linsheng Zhao; Yanni Li; Yuchuan Wang; Weiming Zhang

    2006-01-01

    OBJECTIVE To analyze coding SNPs of the HLA-DQA1 gene involved in susceptibility for cervical cancer by a bioinformatics approach, and to choose some SNPs that may have an association with cervical cancer.METHODS By a SNPper tool we extracted SNPs from a public database (dbSNP), exporting them in FASTA formats suitable for subsequent use.Then we used PARSESNP as a tool for the analysis of the cSNPs.RESULTS In the cSNPs of the HLA-DQA1 gene, we find that rs9272693and rs9272703, are made up of missense mutations which convert a codon for one amino acid into a codon for a different amino acid. We chose a PSSM Difference >10 as a lower level for the scores of changes predicted to be deldterious.CONCLUSION We used a bioinformatics approach for cSNPs analysis of the HLA-DQA1 gene. This method can select the variants in a conserved region, and give a PSSM Difference score. But the results need to be verified in cervical cancer patients and a control population.

  18. Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.

    Science.gov (United States)

    Hosgood, H Dean; Cawthon, Richard; He, Xingzhou; Chanock, Stephen; Lan, Qing

    2009-11-01

    Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere-related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n=120) and population-based controls (n=110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in the telomere maintenance genes POT1, TERT, and TERF2, which we have previously reported were associated with risk of lung cancer in this study. POT1 rs10244817, TERT rs2075786, and TERF2 rs251796 were significantly associated with lung cancer (p(trend)telomere length was not significantly associated with risk of lung cancer (OR=1.58; 95% CI=0.79-3.18) when compared to the longest tertile of telomere length. When stratified by genotype, there was a suggestion of a dose-response relationship between tertiles of telomere length and risk of lung cancer among the POT1 rs10244817 common variant carriers (OR (95% CI)=1.33 (0.47-3.75), 3.30 (1.14-9.56), respectively) but not among variant genotype carriers (p(interaction)=0.05). Our findings provide evidence that telomere length and genetic variation in telomere maintenance genes may be associated with risk of lung cancer susceptibility and warrant replication in larger studies.

  19. HLA-A gene polymorphisms contribute to osteoporosis susceptibility in postmenopausal Han Chinese women.

    Science.gov (United States)

    Li, S M; Guo, H; Yang, H J; Lv, M Q; Zhou, D X

    2015-08-28

    Osteoporosis is a common disease characterized by low bone mineral density, deterioration in bone microarchitecture, and increased fracture risk and is more prevalent in postmenopausal women. HLA is a complex gene family; previous studies have shown that it plays an important role in the pathogenesis of osteoporosis among Japanese and Greek populations. Prompted by these findings, this study was designed to explore the associations between HLA-A gene polymorphisms and postmenopausal osteoporosis in the Han Chinese population. The polymerase chain reaction-sequence-based typing method was used for DNA genotyping at the HLA-A locus in 70 patients with postmenopausal osteoporosis and 73 healthy controls. We identified 17 HLA-A alleles in patients with postmenopausal osteoporosis and 20 HLA-A alleles in control subjects. Furthermore, we found that the frequency of the HLA-A* 02:07 allele was significantly higher in patients with postmenopausal osteoporosis than in control subjects (P = 0.023), and the relative risk was 4.065 (95% confidence interval = 1.109-14.893). Our study provides supportive evidence for the contribution of HLA-A gene polymorphisms to the susceptibility to postmenopausal osteoporosis and suggests that HLA-A* 02:07 is likely an important genetic risk factor for postmenopausal osteoporosis in the Han Chinese population.

  20. Stress and asthma

    Directory of Open Access Journals (Sweden)

    Shoji Nagata

    1999-01-01

    Full Text Available Three factors in recent medical research and treatment (advances in the field of psychoneuroimmunology, epidemiological evidence regarding important interaction between psychosocial factors and development of disease, and the recognition of the importance of patient education for self-management of asthma have led clinicians and researchers to reconsider the role of psychosocial stress in asthma. There are many reports suggesting that stressful life events, family problems and a behavior pattern that increases psychological conflict may influence the development or relapse of asthma and influence its clinical course. Depression is known as one of the risk factors of fatal asthmatic attack. In laboratory studies, about 20% of asthmatics were considered reactors who showed an airway change after exposure to emotional stress. Studies regarding the pathway of stress effect on allergy and asthma are reviewed and discussed from the standpoint of psychoneuroimmunology; for example, the enhancement of IgE production and increased susceptibility to respiratory infection by stress, conditioned anaphylaxis and nerve/mast cell interaction, the effect of stress on various bronchial responses and the inhibition of the immediate and late asthmatic response by anterior hypothalamic lesioning.

  1. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    Directory of Open Access Journals (Sweden)

    Ling Bai

    2016-04-01

    Full Text Available Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease.

  2. A susceptibility gene for premature ovarian failure (POF) maps to proximal Xq28.

    Science.gov (United States)

    Rossetti, Francesca; Rizzolio, Flavio; Pramparo, Tiziano; Sala, Cinzia; Bione, Silvia; Bernardi, Franca; Goegan, Mara; Zuffardi, Orsetta; Toniolo, Daniela

    2004-10-01

    Terminal deletions of the long arm of the human X chromosome have been described in women with premature ovarian failure (POF). We report here the molecular characterization of an inherited deletion in two affected women and in their mother. The two daughters presented secondary amenorrhea at 17 or 22 years respectively, while the mother was fertile. She had four children, but she eventually had premature menopause at 43 years of age. The fine molecular analysis of the deletion showed that the three women carried an identical deletion. We conclude that the phenotypic difference within the family must be attributed to genetic or environmental factors and not to the presence of different extent deletions. By comparison with other deletions in the region, we map a susceptibility gene for POF to 4.5 Mb, in the distal part of Xq.

  3. Associations between CD36 gene polymorphisms and susceptibility to coronary artery heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Y.; Ling, Z.Y.; Deng, S.B.; Du, H.A.; Yin, Y.H.; Yuan, J.; She, Q.; Chen, Y.Q. [Department of Cardiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China)

    2014-08-08

    Associations between polymorphisms of the CD36 gene and susceptibility to coronary artery heart disease (CHD) are not clear. We assessed allele frequencies and genotype distributions of CD36 gene polymorphisms in 112 CHD patients and 129 control patients using semi-quantitative polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Additionally, we detected CD36 mRNA expression by real-time quantitative PCR, and we quantified plasma levels of oxidized low-density lipoprotein (ox-LDL) using an enzyme-linked immunosorbent assay (ELISA). There were no significant differences between the two groups (P>0.05) in allele frequencies of rs1761667 or in genotype distribution and allele frequencies of rs3173798. The genotype distribution of rs1761667 significantly differed between CHD patients and controls (P=0.034), with a significantly higher frequency of the AG genotype in the CHD group compared to the control group (P=0.011). The plasma levels of ox-LDL in patients with the AG genotype were remarkably higher than those with the GG and AA genotypes (P=0.010). In a randomized sample taken from patients in the two groups, the CD36 mRNA expression of the CHD patients was higher than that of the controls. In CHD patients, the CD36 mRNA expression in AG genotype patients was remarkably higher than in those with an AA genotype (P=0.005). After adjusted logistic regression analysis, the AG genotype of rs1761667 was associated with an increased risk of CHD (OR=2.337, 95% CI=1.336-4.087, P=0.003). In conclusion, the rs1761667 polymorphism may be closely associated with developing CHD in the Chongqing Han population of China, and an AG genotype may be a genetic susceptibility factor for CHD.

  4. Introgression of ivermectin resistance genes into a susceptible Haemonchus contortus strain by multiple backcrossing.

    Science.gov (United States)

    Redman, Elizabeth; Sargison, Neil; Whitelaw, Fiona; Jackson, Frank; Morrison, Alison; Bartley, David Jon; Gilleard, John Stuart

    2012-02-01

    Anthelmintic drug resistance in livestock parasites is already widespread and in recent years there has been an increasing level of anthelmintic drug selection pressure applied to parasitic nematode populations in humans leading to concerns regarding the emergence of resistance. However, most parasitic nematodes, particularly those of humans, are difficult experimental subjects making mechanistic studies of drug resistance extremely difficult. The small ruminant parasitic nematode Haemonchus contortus is a more amenable model system to study many aspects of parasite biology and investigate the basic mechanisms and genetics of anthelmintic drug resistance. Here we report the successful introgression of ivermectin resistance genes from two independent ivermectin resistant strains, MHco4(WRS) and MHco10(CAVR), into the susceptible genome reference strain MHco3(ISE) using a backcrossing approach. A panel of microsatellite markers were used to monitor the procedure. We demonstrated that after four rounds of backcrossing, worms that were phenotypically resistant to ivermectin had a similar genetic background to the susceptible reference strain based on the bulk genotyping with 18 microsatellite loci and individual genotyping with a sub-panel of 9 microsatellite loci. In addition, a single marker, Hcms8a20, showed evidence of genetic linkage to an ivermectin resistance-conferring locus providing a starting point for more detailed studies of this genomic region to identify the causal mutation(s). This work presents a novel genetic approach to study anthelmintic resistance and provides a "proof-of-concept" of the use of forward genetics in an important model strongylid parasite of relevance to human hookworms. The resulting strains provide valuable resources for candidate gene studies, whole genome approaches and for further genetic analysis to identify ivermectin resistance loci.

  5. Introgression of ivermectin resistance genes into a susceptible Haemonchus contortus strain by multiple backcrossing.

    Directory of Open Access Journals (Sweden)

    Elizabeth Redman

    2012-02-01

    Full Text Available Anthelmintic drug resistance in livestock parasites is already widespread and in recent years there has been an increasing level of anthelmintic drug selection pressure applied to parasitic nematode populations in humans leading to concerns regarding the emergence of resistance. However, most parasitic nematodes, particularly those of humans, are difficult experimental subjects making mechanistic studies of drug resistance extremely difficult. The small ruminant parasitic nematode Haemonchus contortus is a more amenable model system to study many aspects of parasite biology and investigate the basic mechanisms and genetics of anthelmintic drug resistance. Here we report the successful introgression of ivermectin resistance genes from two independent ivermectin resistant strains, MHco4(WRS and MHco10(CAVR, into the susceptible genome reference strain MHco3(ISE using a backcrossing approach. A panel of microsatellite markers were used to monitor the procedure. We demonstrated that after four rounds of backcrossing, worms that were phenotypically resistant to ivermectin had a similar genetic background to the susceptible reference strain based on the bulk genotyping with 18 microsatellite loci and individual genotyping with a sub-panel of 9 microsatellite loci. In addition, a single marker, Hcms8a20, showed evidence of genetic linkage to an ivermectin resistance-conferring locus providing a starting point for more detailed studies of this genomic region to identify the causal mutation(s. This work presents a novel genetic approach to study anthelmintic resistance and provides a "proof-of-concept" of the use of forward genetics in an important model strongylid parasite of relevance to human hookworms. The resulting strains provide valuable resources for candidate gene studies, whole genome approaches and for further genetic analysis to identify ivermectin resistance loci.

  6. Environment and asthma in adults.

    Science.gov (United States)

    Le Moual, Nicole; Jacquemin, Bénédicte; Varraso, Raphaëlle; Dumas, Orianne; Kauffmann, Francine; Nadif, Rachel

    2013-09-01

    The present review addresses recent advances and especially challenging aspects regarding the role of environmental risk factors in adult-onset asthma, for which the causes are poorly established. In the first part of the review, we discuss aspects regarding some environmental risk factors for adult-onset asthma: air pollution, occupational exposures with a focus on an emerging risk represented by exposure to cleaning agents (both at home and in the workplace), and lifestyle and nutrition. The second part is focused on perspectives and challenges, regarding relevant topics on which research is needed to improve the understanding of the role of environmental factors in asthma. Aspects of exposure assessment, the complexity of multiple exposures, the interrelationships of the environment with behavioral characteristics and the importance of studying biological markers and gene-environment interactions to identify the role of the environment in asthma are discussed. We conclude that environmental and lifestyle exposures play an important role in asthma or related phenotypes. The changes in lifestyle and the environment in recent decades have modified the specific risk factors in asthma even for well-recognized risks such as occupational exposures. To better understand the role of the environment in asthma, the use of objective (quantitative measurement of exposures) or modern tools (bar code, GPS) and the development of multidisciplinary collaboration would be very promising. A better understanding of the complex interrelationships between socio-economic, nutritional, lifestyle and environmental conditions might help to study their joint and independent roles in asthma.

  7. Prenatal Stress, Prematurity, and Asthma.

    Science.gov (United States)

    Medsker, Brock; Forno, Erick; Simhan, Hyagriv; Celedón, Juan C

    2015-12-01

    Asthma is the most common chronic disease of childhood, affecting millions of children in the United States and worldwide. Prematurity is a risk factor for asthma, and certain ethnic or racial minorities such as Puerto Ricans and non-Hispanic blacks are disproportionately affected by both prematurity and asthma. In this review, we examine current evidence to support maternal psychosocial stress as a putative link between prematurity and asthma, while also focusing on disruption of the hypothalamic-pituitary-adrenal (HPA) axis and immune responses as potential underlying mechanisms for stress-induced "premature asthma." Prenatal stress may cause not only abnormalities in the HPA axis but also epigenetic changes in the fetal glucocorticoid receptor gene (NR3C1), leading to impaired glucocorticoid metabolism. Moreover, maternal stress can alter fetal cytokine balance, favoring TH2 (allergic) immune responses characteristic of atopic asthma: interleukin 6 (IL-6), which has been associated with premature labor, can promote TH2 responses by stimulating production of IL-4 and IL-13. Given a link among stress, prematurity, and asthma, future research should include birth cohorts aimed at confirming and better characterizing "premature asthma." If confirmed, clinical trials of prenatal maternal stress reduction would be warranted to reduce the burden of these common comorbidities. While awaiting the results of such studies, sound policies to prevent domestic and community violence (eg, from firearms) are justified, not only by public safety but also by growing evidence of detrimental effects of violence-induced stress on psychiatric and somatic health.

  8. Comparison of adhesin genes and antimicrobial susceptibilities between uropathogenic and intestinal commensal Escherichia coli strains.

    Science.gov (United States)

    Qin, Xiaohua; Hu, Fupin; Wu, Shi; Ye, Xinyu; Zhu, Demei; Zhang, Ying; Wang, Minggui

    2013-01-01

    The presence of adhesins is arguably an important determinant of pathogenicity for Uropathogenic Escherichia coli (UPEC). Antimicrobial susceptibilities were tested by agar dilution method, fifteen adhesin genes were detected by polymerase chain reaction, and multilocus sequence typing (MLST) was analyzed in 70 UPEC isolates and 41 commensal E. coli strains. Extended-spectrum β-lactamase (ESBL) was determined with confirmatory test. The prevalence of ESBL-producers in UPEC (53%, 37/70) was higher than the commensal intestinal isolates (7%, 3/41), and 97% (36/37) of the ESBL-producing UPEC harbored bla CTX-M genes. afa was present in 36% (10/28) UPEC isolates from recurrent lower urinary tract infection (UTI), and none in the acute pyelonephritis, acute uncomplicated cystitis or commensal strains (PUPEC isolates, while 5% (2/41) of the commensal strains were papG positive (P = 0.0025), and the prevalence of papG was significantly higher in acute pyelonephritis group (71%) than the other two UTI groups (PUPEC isolates than in the commensal strains. ESBL-producing UPEC showed a lower prevalence of adhesin genes compared with non-ESBL-producing strains. The MLST profiles were different between UPEC and commensal strains, with ST131 (19%, 13/70) and ST10 (20%, 8/41) being the most common MLSTs, respectively. This study demonstrated that several adhesin genes were more prevalent in UPEC isolates than in commensal E. coli, and afa may be associated with recurrent lower UTI whereas papG is more frequently associated with acute pyelonephritis.

  9. Human chondrocytes respond discordantly to the protein encoded by the osteoarthritis susceptibility gene GDF5.

    Directory of Open Access Journals (Sweden)

    Madhushika Ratnayake

    susceptibility at this gene.

  10. Genetic Variation in Osteopontin Gene Is Associated with Susceptibility to Sarcoidosis in Slovenian Population

    Directory of Open Access Journals (Sweden)

    A. Maver

    2009-01-01

    Full Text Available Sarcoidosis is a systemic inflammatory disease characterised by appearance of granulomas. Precise etiology has not been elucidated. Osteopontin (Opn is a Th1 cytokine whose levels have been found increased in granulomas and serum samples from patients with sarcoidosis. We investigated whether genetic variation in Osteopontin gene (OPN gene contributes to susceptibility to sarcoidosis. Haplotype-block structure in the OPN gene region was investigated using data from HapMap project. Three representative SNPs have been selected from each block of SNPs in linkage disequilibrium (rs11730582-C/T, rs11728697-C/T and rs4754-C/T. Genotyping was performed using TaqMan SNP Genotyping Assays on a sample of 165 patients and 284 controls. Statistical analyses of association were performed using Chi-Square test and algorithms implemented in the haplo.stats and PHASE packages. Genotyping analysis revealed a significant difference in genotype frequencies at rs4754 polymorphism in groups of patients and controls under recessive genetic model (p=0.036, OR=1.99, 95%CI=1.04-3.82, CC homozygotes being significantly over-represented in the patients group. However these results failed to reach significance after correction for multiple testing (p=0.25. The frequencies of predicted haplotypes differed between patient and control groups, frequency of TTT haplotype was found to be significantly decreased in the group of patients with sarcoidosis (p=0.014, OR=0.40, 95%CI=0.20-0.79. Our results suggest that variation in the OPN gene might be significantly associated with sarcoidosis and that the TTT haplotype in OPN may act as a protective factor in sarcoidosis.

  11. Functional characterization of the powdery mildew susceptibility gene SmMLO1 in eggplant (Solanum melongena L.).

    Science.gov (United States)

    Bracuto, Valentina; Appiano, Michela; Ricciardi, Luigi; Göl, Deniz; Visser, Richard G F; Bai, Yuling; Pavan, Stefano

    2017-01-09

    Eggplant (Solanum melongena L.) is one of the most important vegetables among the Solanaceae and can be a host to fungal species causing powdery mildew (PM) disease. Specific homologs of the plant Mildew Locus O (MLO) gene family are PM susceptibility factors, as their loss of function results in a recessive form of resistance known as mlo resistance. In a previous work, we isolated the eggplant MLO homolog SmMLO1. SmMLO1 is closely related to MLO susceptibility genes characterized in other plant species. However, it displays a peculiar non-synonymous substitution that leads to a T → M amino acid change at protein position 422, in correspondence of the MLO calmodulin-binding domain. In this study, we performed the functional characterization of SmMLO1. Transgenic overexpression of SmMLO1 in a tomato mlo mutant compromised resistance to the tomato PM pathogen Oidium neolycopersici, thus indicating that SmMLO1 is a PM susceptibility factor in eggplant. PM susceptibility was also restored by the transgenic expression of a synthetic gene, named s-SmMLO1, encoding a protein identical to SmMLO1, except for the presence of T at position 422. This indicates that the T → M polymorphism does not affect the protein role as PM susceptibility factor. Overall, the results of this work are of interest for the functional characterization of MLO proteins and the introduction of PM resistance in eggplant using reverse genetics.

  12. Genetic variations in the KIR gene family may contribute to susceptibility to ankylosing spondylitis: a meta-analysis.

    Science.gov (United States)

    Zuo, Hai-Ning; Wang, Zhi-Long; Cui, Dao-Ran; Xin, Da-Jiang

    2014-08-01

    The present meta-analysis of relevant case-control studies was conducted to investigate the possible relationships between genetic variations in the killer cell immunoglobulin-like receptor (KIR) gene clusters of the human KIR gene family and susceptibility to ankylosing spondylitis (AS). The following electronic databases were searched for relevant articles without language restrictions: the Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, the Chinese Biomedical Database (CBM) and Chinese National Knowledge Infrastructure (CNKI) databases, covering all papers published until 2013. STATA statistical software was adopted in this meta-analysis as well. We also calculated the crude odds ratios (OR) and its 95% confidence intervals (95 % CI). Seven case-control studies with 1,004 patients diagnosed with AS and 2,138 healthy cases were implicated in our meta-analysis, and 15 genes in the KIR gene family were also evaluated. The results of our meta-analysis show statistical significance between the genetic variations in the KIR2DL1, KIR2DS4, KIR2DS5 and KIR3DS1 genes and an increased susceptibility to AS (KIR2DL1: OR 7.82, 95% CI 3.87-15.81, P0.05). The current meta-analysis provides reliable evidence that genetic variations in the KIR gene family may contribute to susceptibility to AS, especially for the KIR2DL1, KIR2DS4, KIR2DS5 and KIR3DS1 genes.

  13. Exercise and Asthma

    Science.gov (United States)

    ... Español Text Size Email Print Share Exercise and Asthma Page Content Article Body Almost every child (and ... of Pediatrics about asthma and exercise. What is asthma Asthma is the most common chronic medical problem ...

  14. Asthma and Hispanic Americans

    Science.gov (United States)

    ... and Data > Minority Population Profiles > Hispanic/Latino > Asthma Asthma and Hispanic Americans In 2014, 2.1 million Hispanics reported that they currently have asthma. Puerto Rican Americans have almost twice the asthma ...

  15. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Ngoc-Han Ha

    2016-09-01

    Full Text Available Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ and low metastatic (MOLF/EiJ mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL SNPs with disease-free survival, consistent with the mouse studies.

  16. Fine mapping of the MLK-3 gene within 11q13 and its exclusion as the MEN1 susceptibility gene.

    Science.gov (United States)

    Lassam, N J; Lin, Z; Shennan, M G; Courseaux, A; Teh, B T; Gaudray, P; Larsson, C

    1997-06-01

    MLK-3 kinase is a widely expressed serine/ threonine kinase that bears multiple protein interaction domains and regulates signals mediated by the stress-responsive pathway. Thus, MLK-3 signaling affects numerous cellular processes, raising the possibility that MLK-3 might play a role in oncogenesis. In this report, we describe the fine mapping of the MLK-3 gene within the 11q13.1 chromosomal region. By integrating data from somatic cell hybrids and double color fluorescence in situ hybridization on metaphase chromosomes and DNA fibers. MLK-3 has been assigned approximately 1 Mb telomeric of PYGM, close to the D11S546 locus. Since the MEN1 susceptibility locus is also located within the 11q13.1 region, we have carried out Southern and Northern blot analyses, as well as protein truncation assays to establish whether abnormalities in MLK-3 lead to the development of this familial cancer syndrome. Our observations exclude MLK-3 as the MEN1 gene.

  17. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer

    Science.gov (United States)

    Ha, Ngoc-Han; Long, Jirong; Cai, Qiuyin; Shu, Xiao Ou

    2016-01-01

    Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies. PMID:27656887

  18. Childhood Asthma

    Science.gov (United States)

    ... Education Center Fellows-in-Training Grants & Awards Program Directors Practice Resources ASTHMA IQ Consultation and Referral Guidelines Practice Financial Survey Practice Tools Running a Practice Statements and Practice Parameters About AAAAI Advocacy Allergist / Immunologists: ...

  19. Occupational Asthma

    Science.gov (United States)

    ... Education Center Fellows-in-Training Grants & Awards Program Directors Practice Resources ASTHMA IQ Consultation and Referral Guidelines Practice Financial Survey Practice Tools Running a Practice Statements and Practice Parameters About AAAAI Advocacy Allergist / Immunologists: ...

  20. Asthma Quiz

    Science.gov (United States)

    ... Education Center Fellows-in-Training Grants & Awards Program Directors Practice Resources ASTHMA IQ Consultation and Referral Guidelines Practice Financial Survey Practice Tools Running a Practice Statements and Practice Parameters About AAAAI Advocacy Allergist / Immunologists: ...

  1. Exome sequencing identifies a novel gene, WNK1, for susceptibility to pelvic organ prolapse (POP).

    Science.gov (United States)

    Rao, Shuquan; Lang, Jinghe; Zhu, Lan; Chen, Juan

    2015-01-01

    Pelvic organ prolapse (POP) is a common gynecological disorder; however, the genetic components remain largely unidentified. Exome sequencing has been widely used to identify pathogenic gene mutations of several diseases because of its high chromosomal coverage and accuracy. In this study, we performed whole exome sequencing (WES), for the first time, on 8 peripheral blood DNA samples from representative POP cases. After filtering the sequencing data from the dbSNP database (build 138) and the 1000 Genomes Project, 2 missense variants in WNK1, c.2668G > A (p.G890R) and c.6761C> T (p.P2254L), were identified and further validated via Sanger sequencing. In validation stage, the c.2668G > A (p.G890R) variant and 8 additional variants were detected in 11 out of 161 POP patients. All these variants were absent in 231 healthy controls. Functional experiments showed that fibroblasts from the utero-sacral ligaments of POP with WNK1 mutations exhibited loose and irregular alignment compared with fibroblasts from healthy controls. In sum, our study identified a novel gene, WNK1, for POP susceptibility, expanded the causal mutation spectrums of POP, and provided evidence for the genetic diagnosis and medical management of POP in the future.

  2. Association Study Identifying a New Susceptibility Gene (AUTS2 for Schizophrenia

    Directory of Open Access Journals (Sweden)

    Bao Zhang

    2014-10-01

    Full Text Available Schizophrenia (SCZ is a severe and debilitating mental disorder, and the specific genetic factors that underlie the risk for SCZ remain elusive. The autism susceptibility candidate 2 (AUTS2 gene has been reported to be associated with autism, suicide, alcohol consumption, and heroin dependence. We hypothesized that AUTS2 might be associated with SCZ. In the present study, three polymorphisms (rs6943555, rs7459368, and rs9886351 in the AUTS2 gene were genotyped in 410 patients with SCZ and 435 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and forced PCR-RFLP methods. We detected an association between SCZ and the rs6943555 genotype distribution (odds ratio (OR = 1.363, 95% confidence interval (CI: 0.848–2.191, p = 0.001. The association remained significant after adjusting for gender, and a significant effect (p = 0.001 was observed among the females. In the present study, rs6943555 was determined to be associated with female SCZ. Our results confirm previous reports which have suggested that rs6943555 might elucidate the pathogenesis of schizophrenia and play an important role in its etiology.

  3. Enhanced disease susceptibility 1 and salicylic acid act redundantly to regulate resistance gene-mediated signaling.

    Directory of Open Access Journals (Sweden)

    Srivathsa C Venugopal

    2009-07-01

    Full Text Available Resistance (R protein-associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1, non-race-specific disease resistance 1 (NDR1, phytoalexin deficient 4 (PAD4, senescence associated gene 101 (SAG101, and EDS5, have been identified as components of resistance derived from many R proteins. Here, we show that EDS1 and SA fulfill redundant functions in defense signaling mediated by R proteins, which were thought to function independent of EDS1 and/or SA. Simultaneous mutations in EDS1 and the SA-synthesizing enzyme SID2 compromised hypersensitive response and/or resistance mediated by R proteins that contain coiled coil domains at their N-terminal ends. Furthermore, the expression of R genes and the associated defense signaling induced in response to a reduction in the level of oleic acid were also suppressed by compromising SA biosynthesis in the eds1 mutant background. The functional redundancy with SA was specific to EDS1. Results presented here redefine our understanding of the roles of EDS1 and SA in plant defense.

  4. Enhanced disease susceptibility 1 and salicylic acid act redundantly to regulate resistance gene-mediated signaling.

    Science.gov (United States)

    Venugopal, Srivathsa C; Jeong, Rae-Dong; Mandal, Mihir K; Zhu, Shifeng; Chandra-Shekara, A C; Xia, Ye; Hersh, Matthew; Stromberg, Arnold J; Navarre, DuRoy; Kachroo, Aardra; Kachroo, Pradeep

    2009-07-01

    Resistance (R) protein-associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA) and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1), non-race-specific disease resistance 1 (NDR1), phytoalexin deficient 4 (PAD4), senescence associated gene 101 (SAG101), and EDS5, have been identified as components of resistance derived from many R proteins. Here, we show that EDS1 and SA fulfill redundant functions in defense signaling mediated by R proteins, which were thought to function independent of EDS1 and/or SA. Simultaneous mutations in EDS1 and the SA-synthesizing enzyme SID2 compromised hypersensitive response and/or resistance mediated by R proteins that contain coiled coil domains at their N-terminal ends. Furthermore, the expression of R genes and the associated defense signaling induced in response to a reduction in the level of oleic acid were also suppressed by compromising SA biosynthesis in the eds1 mutant background. The functional redundancy with SA was specific to EDS1. Results presented here redefine our understanding of the roles of EDS1 and SA in plant defense.

  5. Autophagy gene polymorphism is associated with susceptibility to leprosy by affecting inflammatory cytokines.

    Science.gov (United States)

    Yang, Degang; Chen, Jia; Shi, Chao; Jing, Zhichun; Song, Ningjing

    2014-04-01

    Autophagy and inflammation closely interact with each other, and together, they play critical roles in bacterial infection. Leprosy is caused by the infection of Mycobacterium leprae (M. leprae). The objective of the study was to investigate the association between polymorphisms in IRGM, an autophagy gene, and susceptibility to leprosy, and identify possible functions of the polymorphism in the infection of M. leprae. Two polymorphisms in IRGM, rs4958842 and rs13361189, were tested in 412 leprosy cases and 432 healthy controls. Levels of inflammatory cytokines including interleukin 1 beta, IL-4, IL-6, and interferon gamma (INF-γ) were measured after the infection of M. leprae in the peripheral blood mononuclear cell (PBMC) of subjects with different genotypes of rs13361189. Data showed that prevalence of rs13361189TC and CC genotypes were significantly higher in leprosy patients than in healthy controls (odds ratio (OR) = 1.49, 95 % confidence interval (CI) 1.09-2.04, P = 0.012; OR = 2.58, 95 % CI 1.65-4.05, P autophagy gene polymorphism was associated with the increased risk of leprosy by affecting inflammatory cytokines.

  6. Bacillus cereus from blood cultures: virulence genes, antimicrobial susceptibility and risk factors for blood stream infection.

    Science.gov (United States)

    Horii, Toshinobu; Notake, Shigeyuki; Tamai, Kiyoko; Yanagisawa, Hideji

    2011-11-01

    We characterized the profiles of virulence genes and antimicrobial susceptibility of Bacillus cereus isolates from blood cultures as well as the risk factors for blood stream infections (BSIs). The diversity of virulence gene patterns was found to be wide among 15 B. cereus isolates from BSIs and also among 11 isolates from contaminated blood cultures. The MicroScan broth microdilution method yielded results corresponding with those of the agar dilution (reference) method for levofloxacin, linezolid, and vancomycin, while the Etest results were consistent with the reference results for clindamycin, gentamicin, imipenem, levofloxacin, and linezolid. Compared with the reference values, however, some isolates showed marked differences of the minimum inhibitory concentrations (MICs) for ampicillin and clindamycin when determined using the MicroScan method, or the MICs for ampicillin, meropenem, and vancomycin when determined using the Etest method. Significantly more patients were treated with antimicrobials for more than 3 days during the 3-month period before isolation in the BSI group. Prior antimicrobial therapy may be a risk factor for BSIs due to B. cereus.

  7. Association of XPC Gene Polymorphisms with Susceptibility to Prostate Cancer: Evidence from 3,936 Subjects

    Science.gov (United States)

    Zou, Yan-Feng; Tao, Jin-Hui; Ye, Qian-Ling; Pan, Hai-Feng; Pan, Fa-Ming; Su, Hong

    2013-01-01

    Aim: Polymorphisms of xeroderma pigmentosum complementation group C (XPC) are thought to have significant effects on prostate cancer (PCa) risk. The aim of our study was to evaluate the impact of XPC gene polymorphisms on PCa risk by using a meta-analysis. Methods: Data were collected from the following electronic databases: PubMed, EMBASE, Elsevier Science Direct, Cochrane Library, and CNKI, with the last report up to April 30, 2013. Odds ratios with 95% confidence intervals were used to assess the strength of the association. Results: A total of five separate case–control studies (1966 cases and 1970 controls) were included in this meta-analysis. Meta-analysis was performed for the rs2228001 and PAT+/−polymorphisms. We did not detect a significant association between rs2228001 polymorphism and PCa (p>0.05). Similar results were found in stratification analyses by ethnicity and tumor stage. We detected a significant association of PAT+/−polymorphism with PCa (p0.05). Conclusion: These analyses suggest that XPC gene PAT+/−polymorphism, but not rs2228001, likely contributes to susceptibility to PCa. PMID:24093803

  8. Identification of Variants in Breast Cancer Susceptibility Genes and Determination of Functional and Clinical Significance of Novel Mutations

    Science.gov (United States)

    2014-10-01

    likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1) MSH2 (1), and MUTYH (double...included 26 study genes plus BRCA1 and BRCA2 and were: 1) high penetrance breast cancer susceptibility genes (CDH1, PTEN, STK11, TP53 ); 2) genes known...for management, namely TP53 (4), CDKN2A (1) MSH2 (1), and MUTYH (double heterozygote). Twenty- four patients (8.6%) had deleterious or likely

  9. 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

  10. Dogs and humans share a common susceptibility gene SRBD1 for glaucoma risk.

    Directory of Open Access Journals (Sweden)

    Nobuyuki Kanemaki

    Full Text Available Glaucoma is a degenerative optic neuropathy that is associated with elevated intraocular pressure. Primary open angle glaucoma is the most common type of glaucoma in canines, and its highest incidence among dog breeds has been reported in Shiba-Inus, followed by Shih-Tzus. These breeds are known to have an abnormal iridocorneal angle and dysplastic prectinate ligament. However, the hereditary and genetic backgrounds of these dogs have not yet been clarified. In this study, we investigated the association between polymorphisms of the glaucoma candidate genes, SRBD1, ELOVL5, and ADAMTS10, and glaucoma in Shiba-Inus and Shih-Tzus. We analyzed 11 polymorphisms in these three genes using direct DNA sequencing. Three SRBD1 SNPs, rs8655283, rs22018514 and rs22018513 were significantly associated with glaucoma in Shiba-Inus, while rs22018513, a synonymous SNP in exon 4, showed the strongest association (P = 0.00039, OR = 3.03. Conditional analysis revealed that rs22018513 could account for most of the association of these SNPs with glaucoma in Shiba-Inus. In Shih-Tzus, only rs9172407 in the SRBD1 intron 1 was significantly associated with glaucoma (P = 0.0014, OR = 5.25. There were no significant associations between the ELOVL5 or ADAMTS10 polymorphisms and glaucoma in Shiba-Inus and Shih-Tzus. The results showed that SRBD1 polymorphisms play an important role in glaucoma pathology in both Shiba-Inus and Shih-Tzus. SRBD1 polymorphisms have also been associated with normal- and high-tension glaucomas in humans. Therefore, SRBD1 may be a common susceptibility gene for glaucoma in humans and dogs. We anticipate that the nucleotide sequencing data from this study can be used in genetic testing to determine for the first time, the genetic status and susceptibility of glaucoma in dogs, with high precision. Moreover, canine glaucoma resulting from SRBD1 polymorphisms could be a useful animal model to study human glaucoma.

  11. SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians.

    Science.gov (United States)

    Burfoot, R K; Jensen, C J; Field, J; Stankovich, J; Varney, M D; Johnson, L J; Butzkueven, H; Booth, D; Bahlo, M; Tait, B D; Taylor, B V; Speed, T P; Heard, R; Stewart, G J; Foote, S J; Kilpatrick, T J; Rubio, J P

    2008-01-01

    This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.

  12. O impacto da genética na asma infantil Impact of genetics in childhood asthma

    Directory of Open Access Journals (Sweden)

    Leonardo A. Pinto

    2008-08-01

    . SOURCES: Data were collected from MEDLINE. Genetic association studies were selected from the Genetic Association Database, which is an archive of human genetic association studies of complex diseases and disorders organized by the National Institutes of Health. SUMMARY OF THE FINDINGS: Considering the data from several important twin studies on asthma genetics, heritability, which measures the contribution of genetic factors to the variance of asthma, may be estimated in 0.48-0.79. A huge number of genetic association studies have been trying to identify asthma susceptibility genes. The most replicated results in the genetic association studies involve the following five regions of the human genome: 5q31-32, 6p21, 11q12-13, 16p11-12, and 20p13. Only recently a new asthma susceptibility gene (ORMDL3 has been identified by a whole genome association study, considered to be a major determinant for childhood asthma. CONCLUSIONS: Genetic contribution to asthma may be estimated ranging from 48 to 79%. Several different loci seem to influence asthma susceptibility. Genes located on chromosome 5q (ADRB2, IL13 and IL4 and the recently identified ORMDL3, on chromosome 17, seem to be determinants of childhood asthma. Diagnostics and pharmacogenetics may be the first clinical implication of extensive studies on asthma genetics.

  13. Ankylosing spondylitis susceptibility and severity--contribution of TNF gene promoter polymorphisms at positions -238 and -308.

    Science.gov (United States)

    Sousa, Elsa; Caetano-Lopes, Joana; Pinto, Patrícia; Pimentel, Fernando; Teles, José; Canhão, Helena; Rodrigues, Ana; Resende, Catarina; Mourão, Ana Filipa; Ribeiro, Célia; Pinto, Teresa Laura; Rosa, Carlos Miranda; da Silva, José Alberto Pereira; Branco, Jaime; Ventura, Francisco; Queiroz, Mário Viana; Fonseca, João Eurico

    2009-09-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disease in which genetic factors play a central role. The efficacy of TNF blockers has reoriented research in this field in order to explain the influence of TNF in AS pathogenesis. The objective of this study was to access the influence of single nucleotide polymorphisms (SNPs) at positions -308 and -238 of the promoter region of TNF gene on AS susceptibility and prognosis. SNPs were determined by restriction fragment length polymorphisms in patients and controls. AS patients exhibited a decreased frequency of the A allele at position -238 (10%) when compared with controls (18%), suggesting that this could be a protective factor for disease susceptibility. In addition, the -308 GA/AA genotypes were associated with later disease onset in AS patients. These results suggest that TNF gene promoter polymorphisms at positions -238 and -308 could have a small influence on AS susceptibility and prognosis.

  14. Recognizing asthma mimics and asthma complications.

    Science.gov (United States)

    Amundson, Dennis; Seda, Gilbert; Daheshia, Massoud

    2011-10-01

    Asthma is a chronic inflammatory disorder of the airways characterized by airflow obstruction, bronchial hyperreactivity, and underlying inflammation. Two common reasons asthmatics fail standard therapy are incorrect diagnosis and failure to recognize underlying contributing factors. A correct diagnosis of asthma is of great importance to military practitioners since misdiagnosis or uncontrolled asthma affects an individual's operational readiness or determines whether one can receive a medical waiver to enlist in military service. This article presents four cases of patients with dyspnea that have conditions which mimic asthma or complicate asthma management: vocal cord dysfunction misdiagnosed as asthma, respiratory bronchiolitis interstitial lung disease mistaken as asthma, difficult-to-control asthma because of bronchiectasis and allergic bronchopulmonary aspergillosis, and difficult and fatal asthma. Asthma is contrasted to other respiratory disorders, and an outlined approach to asthma diagnosis and management is presented using the Global Initiative for Asthma guidelines.

  15. NCOA1 is a novel susceptibility gene for multiple myeloma in the Chinese population: A case-control study

    Science.gov (United States)

    Cheng, Guixue; Huang, Jing; Qin, Xiaosong; Liu, Yong; Wang, Qingtao; Li, Yongzhe

    2017-01-01

    Multiple myeloma (MM) is an incurable malignancy of mature B-lymphoid cells, and its pathogenesis is only partially understood. Previous studies have demonstrated that a number of Non-Hodgkin Lymphoma (NHL) associated genes also show susceptibility to MM, suggesting malignancies originating from B cells may share similar genetic susceptibility. Several recent large-scale genome-wide association studies (GWAS) have identified HLA-I, HLA-II, CXCR5, ETS1, LPP and NCOA1 genes as genetic risk factors associated with NHL, and this study aimed to investigate whether these genes polymorphisms confer susceptibility with MM in the Chinese Han population. In 827 MM cases and 709 healthy controls of Chinese Han, seven single nucleotide polymorphisms (SNPs) in the HLA–I region (rs6457327), the HLA–II region (rs2647012 and rs7755224), the CXCR5 gene (rs4938573), the ETS1 gene (rs4937362), the LPP gene (rs6444305), and the NCOA1 region (rs79480871) were genotyped using the Sequenom platform. Our study indicated that genotype and allele frequencies of rs79480871 showed strong associations with MM patients (pa = 3.5×10−4 and pa = 1.5×10−4), and the rs6457327 genotype was more readily associated with MM patients than with controls (pa = 4.9×10−3). This study was the first to reveal the correlation between NCOA1 gene polymorphisms and MM patients, indicating that NCOA1 might be a novel susceptibility gene for MM patients in the Chinese Han population. PMID:28264017

  16. Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.

    Science.gov (United States)

    Asano, Koichiro; Shiomi, Tetsuya; Hasegawa, Naoki; Nakamura, Hidetoshi; Kudo, Hiroyasu; Matsuzaki, Tatsu; Hakuno, Haruhiko; Fukunaga, Kouichi; Suzuki, Yusuke; Kanazawa, Minoru; Yamaguchi, Kazuhiro

    2002-10-01

    CysLT(1) antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT(1) antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C(4) synthase (LTC(4) S) gene in Japanese patients with moderate asthma. The frequency of LTC(4) S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects ( n= 349). A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400-800 microg/day or fluticasone 200-400 microg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes ( n= 31) [14.3 5.3% vs. 3.1 2.4% improvement of forced expiratory volume in one second (FEV(1) ), 0.01], while LTC(4) S genotype-stratified response to inhaled beta-agonist salbutamol (200 microg) was not observed (17.5 2.1% vs. 18.7 2.2% improvement of FEV(1) ). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV(1) ) was correlated with LTC(4) S genotype (P < 0.01) and pretreatment airway reversibility to salbutamol (P < 0.01), but not with sex, age, atopic status, urinary leukotriene E(4) excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC(4) S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P < 0.05). We conclude that LTC(4) S genotype is predictive of the clinical response to a cysLT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.

  17. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    NARCIS (Netherlands)

    Lawrenson, K.; Li, Q.; Kar, S.; Seo, J.H.; Tyrer, J.; Spindler, T.J.; Lee, J. van der; Chen, Y; Karst, A.; Drapkin, R.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Baker, H.; Bandera, E.V.; Bean, Y.; Beckmann, M.W.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Chenevix-Trench, G.; Chen, A; Chen, Z.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Dennis, J.; Dicks, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Durst, M.; Eccles, D.; Easton, D.T.; Edwards, R.P.; Eilber, U.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goode, E.L.; Goodman, M.T.; Grownwald, J.; Harrington, P.; Harter, P.; Hasmad, H.N.; Hein, A.; Heitz, F.; Hildebrandt, M.A.; Hillemanns, P.; Hogdall, E.; Hogdall, C.; Hosono, S.; Iversen, E.S.; Jakubowska, A.; James, P.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kjaer, S. Kruger; Kelemen, L.E.; Kellar, M.; Kelley, J.L.; Kiemeney, L.A.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; Nevanlinna, H.; McNeish, I.; Menon, U.; Modugno, F.

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associat

  18. Trends in antimicrobial susceptibility and presence of resistance genes in Staphylococcus hyicus isolated from exudative epidermitis in pigs

    DEFF Research Database (Denmark)

    Aarestrup, Frank Møller; Jensen, L. B.

    2002-01-01

    From 1996 to 2001 a total of 467 Staphylococcus hyicus isolates from exudative epidermitis (EE) in pigs in Denmark were examined for susceptibility to 13 different antimicrobial agents. The presence of selected genes encoding macrolide (erm(A), erm(B) and erm(C)), penicillin (blaZ), streptogramin...

  19. Impact of passive smoking, cooking with solid fuel exposure, and MBL/MASP-2 gene polymorphism upon susceptibility to tuberculosis

    Directory of Open Access Journals (Sweden)

    Mengshi Chen

    2014-12-01

    Conclusions: Passive smoking, cooking with solid fuel, and polymorphisms of MBL (rs7096206 and MASP-2 (rs6695096 genes were associated with susceptibility to TB in non-smokers, and there were gene–environment interactions among them. Further studies are needed to explore details of the mechanisms of association.

  20. Presence of the KPC carbapenemase gene in Enterobacteriaceae causing bacteremia, and the correlation with in vitro carbapenem susceptibility

    Science.gov (United States)

    During six months, we obtained Enterobacteriaceae isolates from patients with Gram-negative bacteremia at a 1250-bed teaching hospital in St. Louis, Missouri, and compared carbapenem susceptibility with the presence of blaKPC, a transferable carbapenemase gene. Three (1.2%) out of 243 isolates were ...

  1. HTR1A a novel type 1 diabetes susceptibility gene on chromosome 5p13-q13

    DEFF Research Database (Denmark)

    Asad, Samina; Nikamo, Pernilla; Gyllenberg, Alexandra;

    2012-01-01

    We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD≤2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D...... susceptibility genes....

  2. Simulated microgravity affects ciprofloxacin susceptibility and expression of acrAB-tolC genes in E. coli ATCC25922.

    Science.gov (United States)

    Xu, Bingxin; Li, Chenglin; Zheng, Yanhua; Si, Shaoyan; Shi, Yuhua; Huang, Yuling; Zhang, Jianzhong; Cui, Yan; Cui, Yimin

    2015-01-01

    As a representative fluoroquinolone antibacterial, ciprofloxacin is frequently used to treat infections caused by bacteria such as E. coli. It is much meaningful to explore ciprofloxacin susceptibility and investigate a possible mechanism of drug susceptibility changes in E. coli ATCC25922 exposed to the environmental stress of simulated microgravity. The subculture of E. coli lasted for 7 days under simulated microgravity conditions (SMG) and normal microgravity (NG) conditions. On the 8th day, the cultures were divided into three groups: (1) NG group (continuous NG cultures); (2) SMG group (continuous SMG cultures); (3) SMCNG group (simulated microgravity change into normal gravity cultures). Ciprofloxacin (a final concentration of 0.125 μg/ml) sensitivity and expression of acrAB-tolC genes were detected in E. coli cells. The count and percentage of viable cells in the SMG cultures bacteria exposed to ciprofloxacin were higher than that in NG cultures and reduced to the levels of NG group when they were subcultivated from SMG to NG. The expressions of efflux pump genes (acrA, acrB and tolC) were upregulated in SMG culture and downregulated to the levels of NG group when they were subcultivated from SMG to NG. Susceptibility to ciprofloxacin and expression of acrAB-tolC genes in E. coli could be reversibly affected by SMG conditions. Over expression of efflux pump genes acrAB-tolC perhaps played an important role in decreased CIP susceptibility under SMG.

  3. The Intracranial Aneurysm Susceptibility Genes HSPG2 and CSPG2 Are Not Associated With Abdominal Aortic Aneurysm

    NARCIS (Netherlands)

    Baas, Annette F.; Medic, Jelena; van 't Slot, Ruben; de Vries, Jean-Paul P. M.; van Sambeek, Marc R. H. M.; Verhoeven, Eric L. G.; Boll, Bart P.; Grobbee, Diederick E.; Wijmenga, Cisca; Blankensteijn, Jan D.; Ruigrok, Ynte M.

    2010-01-01

    Background: A genetic variant on chromosome 9p21 associates with abdominal aortic aneurysm (AAA) and intracranial aneurysm (IA), indicating that despite the differences in pathology there are shared genetic risk factors. We investigated whether the IA susceptibility genes heparan sulfate proteoglyca

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

    Science.gov (United States)

    2010-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:20701755

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

    Directory of Open Access Journals (Sweden)

    Trubicka Joanna

    2010-08-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion 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.

  6. Interleukin-10 gene polymorphisms and hepatocellular carcinoma susceptibility: A meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Yong-Gang Wei; Jia-Yin Yang; Fei Liu; Bo Li; Xi Chen; Yu Ma; Lv-Nan Yan; Tian-Fu Wen; Ming-Qing Xu; Wen-Tao Wang

    2011-01-01

    AIM: To assess the association between Interleukin- 10 (IL-10) gene IL-10-1082 (G/A), IL-10-592(C/A), IL-10-819 (T/C) polymorphisms and hepatocellular carcinoma (HCC) susceptibility. METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for IL-10 polymorphisms and HCC were calculated in a fifixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS: This meta-analysis included seven eligible studies, which included 1012 HCC cases and 2308 controls. Overall, IL-10-1082 G/A polymorphism was not associated with the risk of HCC (AA vs AG + GG, OR = 1.11, 95% CI = 0.90-1.37). When stratifying for ethnicity, the results were similar (Asian, OR = 1.12, 95% CI = 0.87-1.44; non-Asian, OR = 1.10, 95% CI = 0.75-1.60). In the overall analysis, the IL-10 polymorphism at position -592 (C/A) was identifified as a genetic risk factor for HCC among Asians; patients carrying the IL-10-592*C allele had an increased risk of HCC (OR = 1.29, 95% CI = 1.12-1.49). No association was observed between the IL-10-819 T/C polymorphism and HCC susceptibility (TT vs TC + CC, OR = 1.02, 95% CI = 0.79-1.32). CONCLUSION: This meta-analysis suggests that IL-10-592 A/C polymorphism may be associated with HCC among Asians. IL-10-1082 G/A and IL-10-819 T/C polymorphisms were not detected to be related to the risk for HCC.

  7. Polymorphisms in DNA Repair Genes and Susceptibility to Glioma in a Chinese Population

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    Jun-Hong Guan

    2013-02-01

    Full Text Available The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1, and X-ray repair cross-complementing group 1 (XRCC1 genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms in ERCC1 C118T, ERCC1 C8092A, XRCC1 A194T, XRCC1 A194T, and XRCC3 C241T, with glioma risk in a Chinese population. Five single nucleotide polymorphisms (SNPs were genotyped, using the MassARRAY IPLEX platform, in 443 glioma cases and 443 controls. Association analyses based on an χ2 test and binary logistic regression were performed to determine the odds ratio (OR and a 95% confidence interval (95% CI for each SNP. For XRCC1 Arg194Trp, the variant genotype T/T was strongly associated with a lower risk of glioma cancer when compared with the wild type C/C (OR = 2.45, 95% CI = 1.43–4.45. Individuals carrying the XRCC1 399A allele had an increased risk of glioma (OR = 1.33, 95% CI = 1.02–1.64. The XRCC3 241T/T genotype was associated with a strong increased glioma risk (OR = 3.78, 95% CI = 1.86–9.06. Further analysis of the interactions of two susceptibility-associated SNPs, XRCC1 Arg194Trp and XRCC3 Thr241Met, showed that the combination of the XRCC1 194T and XRCC3 241T alleles brought a large increase in glioma risk (OR = 2.75, 95% CI = 1.54–4.04. XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 C241T, appear to be associated with susceptibility to glioma in a Chinese population.

  8. Alterations in penicillin binding protein gene of Streptococcus pneumoniae and their correlation with susceptibility patterns.

    Science.gov (United States)

    Ohsaki, Yoshinobu; Tachibana, Mineji; Nakanishi, Kyoko; Nakao, Shoko; Saito, Kumiko; Toyoshima, Eri; Sato, Maki; Takahashi, Toru; Osanai, Shinobu; Itoh, Yoshihisa; Kikuchi, Kenjiro

    2003-08-01

    Penicillin binding protein (pbp) gene alterations of 328 clinical isolates of Streptococcus pneumoniae were examined for a correlation with their antibiotic-resistance. The frequency of penicillin G (PEN-G) resistance was determined to clarify susceptibility to several antibiotics, namely PEN-G, ampicillin, sulbactam/ampicillin, cefozopram, panipenem (PAPM), clarithromycin (CLR), azithromycin (AZM) and levofloxacin (LVX). Oligonucleotide primers for three pbp genes (pbp1a, pbp2x and pbp2b) were used to detect mutations in pbp. Of the strains, 25.9% were classified as Pen-Gs, 68.0% as Pen-Gir and 6.1% as Pen-Gr. The polymerase chain reaction product for wild-type pbp1a was found in 185 isolates, that for wild-type pbp2x was found in 66 isolates and that for wild-type pbp2b was found in 213 isolates. None of these three genes was detectable in 100 isolates while all of them were detected in 64 isolates (1aw/2xw/2bw). Of those 64 isolates with 1aw/2xw/2bw, the minimum inhibitory concentration (MIC) of PEN-G was or =4.0 mg/l included one Pen-Gs and two Pen-Gir isolates. The MICs of CLR correlated significantly with those of AZM. The MIC of CLR was > or =1 mg/l for 216 isolates, and the MIC of AZM was > or =1 mg/l for 244 of them. These data suggested that PAPM may be effective against S. pneumoniae infection, although acquisition of resistance should be considered. LVX also seemed to be effective against S. pneumoniae.

  9. Heat shock protein 70-2 gene polymorphism and susceptibility to diabetic nephropathy

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    Xin-wei LIN

    2015-01-01

    Full Text Available Objective To investigate the relationship between heat shock protein 70-2 (HSP70-2 gene polymorphism and diabetic nephropathy (DN in patients with type 2 diabetes mellitus (T2DM. Methods Following the inclusion and exclusion criteria, a total of 677 subjects were enrolled in present study. They were either hospitalized or undergoing regular health check-up in the Department of Nephrology of PLA 152nd Hospital in Pingdingshan of Henan Province. Among them 226 patients were suffering from diabetes mellitus and nephrosis (DN+ group, 221 patients with T2DM but without nephrosis (DN– group, and 230 were normal controls (NC group. Data were collected by questionnaire, physical examination and laboratory examination, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP technique was applied to detect the single nucleotide polymorphisms of HSP70-2(+1267/G. Results The G/G genotype frequency of HSP70-2 was significantly higher in DN+ group than in DN– and NC group (χ2=8.123, P<0.01; χ2=11.651, P<0.01; the G allele frequency of HSP70-2 was significantly higher in DN+ group than in DN – and NC group (χ2=9.392, P<0.01, OR=1.782; χ2=11.971, P<0.01, OR=2.153. The levels of MALB/Cr and BMI were significantly higher in G/G gene carriers than in A/A gene carriers (P<0.05. Conclusion The G/G genotype of HSP70-2(+1267 may be related to susceptibility to DN and general obesity; G allele carrier may have increased risk of T2DM with DN. DOI: 10.11855/j.issn.0577-7402.2014.11.11

  10. A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis.

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    Judith Field

    Full Text Available We conducted an association study across the human leukocyte antigen (HLA complex to identify loci associated with multiple sclerosis (MS. Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6. All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001 and were highly significant in the combined dataset (P ≤ 6 x 10(-8. The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9, replication set P = 7 x 10(-4, combined P = 2 x 10(-10. HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

  11. Association of Environmental Arsenic Exposure, Genetic Polymorphisms of Susceptible Genes, and Skin Cancers in Taiwan

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    Ling-I Hsu

    2015-01-01

    Full Text Available Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1, reactive oxygen species (ROS related metabolic genes (NQO1, EPHX1, and HO-1, and DNA repair genes (XRCC1, XPD, hOGG1, and ATM together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR and 95% confidence interval (CI using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01–8.83; OR = 2.04, 95% CI = 0.99–4.27; OR = 1.74, 95% CI = 1.00–3.02, resp.. However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated.

  12. Association of the FCN2 Gene Single Nucleotide Polymorphisms with Susceptibility to Pulmonary Tuberculosis.

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    Dan-Dan Xu

    Full Text Available Ficolin-2 (FCN2 is an innate immune pattern recognition molecule that can activate the complement pathway, opsonophagocytosis, and elimination of the pathogens. The present study aimed to investigate the association of the FCN2 gene single nucleotide polymorphisms (SNPs with susceptibility to pulmonary tuberculosis (TB. A total of seven SNPs in exon 8 (+6359 C>T and +6424 G>T and in the promoter region (-986 G>A, -602 G>A, -557 A>G, -64 A>C and -4 A>G of the FCN2 gene were genotyped using the PCR amplification and DNA sequencing methods in the healthy controls group (n = 254 and the pulmonary TB group (n = 282. The correlation between SNPs and pulmonary TB was analyzed using the logistic regression method. The results showed that there were no significant differences in the distribution of allelic frequencies of seven SNPs between the pulmonary TB group and the healthy controls group. However, the frequency of the variant homozygous genotype (P = 0.037, -557 A>G; P = 0.038, -64 A>C; P = 0.024, +6424 G>T in the TB group was significantly lower than the control group. After adjustment for age and gender, these variant homozygous genotypes were found to be recessive models in association with pulmonary TB. In addition, -64 A>C (P = 0.047 and +6424 G>T (P = 0.03 were found to be codominant models in association with pulmonary TB. There was strong linkage disequilibrium (r2 > 0.80, P A site. Therefore, -557 A>G, -64 A>C and +6424 G>T SNPs of the FCN2 gene were correlated with pulmonary TB, and may be protective factors for TB. This study provides a novel idea for the prevention and control of TB transmission from a genetics perspective.

  13. Dexamethasone increases susceptibility of Aspergillus fumigatus to hydrogen peroxide via down-regulation of Afyapl gene expression in vitro

    Institute of Scientific and Technical Information of China (English)

    XU Hui; LI Li-juan; WAN Zhe; LI Ruo-yu; LIU Wei

    2011-01-01

    Background Glucocorticoid is speculated to be able to have Aspergillus fumigatus (A.fumigatus) being more susceptible to reactive oxygen species (ROS) by inhibiting Afyap1,the transcription factor activating protein-1 (AP-1)homologue in A.fumigatus,which may provide a clue to expand the clinical use of glucocorticoid in patients with fungal infections.In this study,we used dexamethasone to determine the direct effect on oxidative killing susceptibility of A.fumigatus in vitro,as well as the expression level of Afyap1 gene and its target genes (catalase and superoxide dismutase (SOD) genes).Methods A.fumigatus spores were treated with different concentrations (0,0.02,0.2 mg/ml) of glucocorticoids and assigned to four groups (A:0.5 hour,B:2 hours,C:7 hours,D:16 hours) according to the time of treatment.The H2O2 oxidative killing assay was done,using the standard method-spot test,in each group of A.fumigatus.We measured the oxidative killing susceptibility as well as the expression level of the gene Afyap1,CATA,SOD1 and SOD2in A.fumigatus at each group.The antifungal susceptibility to itraconazole and amphotericin B in each group of A.fumigatus was also measured with M38-A2 method.Results The oxidative killing susceptibility of A.fumigatus was increased,consistent with the reduction of Afyap1,CATA,SOD1 and SOD2 gene expression level after being treated with dexamethasone for 0.5 hours.However,these observations were disappeared along with being treated for longer time.The antifungal susceptibility to itraconazole and amphotericin B in the A.fumigatus strains treated with dexamethasone indicated no change,compared with those without dexamethasone treatment.Conclusion Dexamethasone can have A.fumigatus being more susceptible to ROS when treated for shorter period (0.5 to 2 hours) via the reduction of Afyap1 gene expression as well as the down-stream enzyme-coding gene expression.

  14. Selection of ovine housekeeping genes for normalisation by real-time RT-PCR; analysis of PrP gene expression and genetic susceptibility to scrapie

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    Hurtado Ana

    2005-09-01

    Full Text Available Abstract Background Cellular prion protein expression is essential for the development of transmissible spongiform encephalopathies (TSEs, and in sheep, genetic susceptibility to scrapie has been associated to PrP gene polymorphisms. To test the hypothetical linkage between PrP gene expression and genetic susceptibility, PrP mRNA levels were measured by real-time RT-PCR in six ovine tissues of animals with different genotypes. Results Previous to the PrP gene expression analysis the stability of several housekeeping (HK genes was assessed in order to select the best ones for relative quantification. The normalisation of gene expression was carried out using a minimum of three HK genes in order to detect small expression differences more accurately than using a single control gene. The expression stability analysis of six HK genes showed a large tissue-associated variation reflecting the existence of tissue-specific factors. Thereby, a specific set of HK genes was required for an accurate normalisation of the PrP gene expression within each tissue. Statistical differences in the normalised PrP mRNA levels were found among the tissues, obtaining the highest expression level in obex, followed by ileum, lymph node, spleen, cerebellum and cerebrum. A tendency towards increased PrP mRNA levels and genetic susceptibility was observed in central nervous system. However, the results did not support the hypothesis that PrP mRNA levels vary between genotypes. Conclusion The results on PrP gene expression presented here provide valuable baseline data for future studies on scrapie pathogenesis. On the other hand, the results on stability data of several HK genes reported in this study could prove very useful in other gene expression studies carried out in these relevant ovine tissues.

  15. Aim2-deficiency stimulates the expression of interferon-inducible Ifi202, a lupus susceptibility murine gene within the Nba2 autoimmune susceptibility locus

    Science.gov (United States)

    Panchanathan, Ravichandran; Duan, Xin; Shen, Hui; Rathinam, Vijay A. K.; Erickson, Loren D.; Fitzgerald, Katherine A; Choubey, Divaker

    2010-01-01

    Murine Aim2 and p202 proteins (encoded by the Aim2 and Ifi202 genes) are members of the interferon (IFN)-inducible p200-protein family. Both proteins can sense double-stranded DNA (dsDNA) in the cytoplasm. However, upon sensing dsDNA, only the Aim2 protein through its pyrin domain (PYD) can form an inflammasome to activate caspase-1 and induce cell death. Given that the p202 protein has been predicted to inhibit the activation of caspase-1 by the Aim2 protein and that increased levels of the p202 protein in female mice of certain strains are associated with lupus susceptibility, we compared the expression of Aim2 and Ifi202 genes between Aim2-deficient and age-matched wild type mice. We found that the Aim2-deficiency in immune cells stimulated the expression of Ifi202 gene. The increased levels of the p202 protein in cells were associated with increases in the expression of IFN-β, STAT1, and IFN-inducible genes. Moreover, after knockdown of Aim2 expression in the murine macrophage cell line J774.A1, IFN-β treatment of cells robustly increased STAT1 protein levels (as compared to control cells), increased the activating phosphorylation of STAT1 on Tyr-701, and stimulated the activity of an IFN-responsive reporter. Notably, the expression of Aim2 in non lupus-prone (C57BL/6 and B6.Nba2-C) and lupus-prone B6.Nba2-ABC splenic cells and in a murine macrophage cell line that overexpressed p202 protein was found to be inversely correlated with Ifi202. Collectively, our observations demonstrate an inverse correlation between Aim2 and p202 expressions. We predict that defects in Aim2 expression within immune cells contribute to increased susceptibility to lupus. PMID:21057088

  16. Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI

    Science.gov (United States)

    Vimaleswaran, Karani S.; Tachmazidou, Ioanna; Zhao, Jing Hua; Hirschhorn, Joel N.; Dudbridge, Frank; Loos, Ruth J.F.

    2012-01-01

    Before the advent of genome-wide association studies (GWASs), hundreds of candidate genes for obesity-susceptibility had been identified through a variety of approaches. We examined whether those obesity candidate genes are enriched for associations with body mass index (BMI) compared with non-candidate genes by using data from a large-scale GWAS. A thorough literature search identified 547 candidate genes for obesity-susceptibility based on evidence from animal studies, Mendelian syndromes, linkage studies, genetic association studies and expression studies. Genomic regions were defined to include the genes ±10 kb of flanking sequence around candidate and non-candidate genes. We used summary statistics publicly available from the discovery stage of the genome-wide meta-analysis for BMI performed by the genetic investigation of anthropometric traits consortium in 123 564 individuals. Hypergeometric, rank tail-strength and gene-set enrichment analysis tests were used to test for the enrichment of association in candidate compared with non-candidate genes. The hypergeometric test of enrichment was not significant at the 5% P-value quantile (P = 0.35), but was nominally significant at the 25% quantile (P = 0.015). The rank tail-strength and gene-set enrichment tests were nominally significant for the full set of genes and borderline significant for the subset without SNPs at P < 10−7. Taken together, the observed evidence for enrichment suggests that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits. PMID:22791748

  17. Asthma in Sickle Cell Disease

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    Manisha Newaskar

    2011-01-01

    Full Text Available In recent years, evidence has increased that asthma predisposes to complications of sickle cell disease (SCD, such as pain crises, acute chest syndrome, pulmonary hypertension, and stroke, and is associated with increased mortality. An obstructive pattern of pulmonary function, along with a higher-than-expected prevalence of airway hyper-responsiveness (AHR when compared to the general population, has led some researchers to suspect that underlying hemolysis may contribute to the development of a pulmonary disease similar to asthma in patients with SCD. While the pathophysiologic mechanism in atopic asthma involves up-regulation of Th2 cytokines, mast cell– and eosinophil-driven inflammation, plus increased activity of inducible nitric oxide synthase (iNOS and arginase in airway epithelium resulting in obstructive changes and AHR, the exact mechanisms of AHR, obstructive and restrictive lung disease in SCD is unclear. It is known that SCD is associated with a proinflammatory state and an enhanced inflammatory response is seen during vaso-occlusive events (VOE. Hemolysis-driven acute-on-chronic inflammation and dysregulated arginines–nitric oxide metabolism are potential mechanisms by which pulmonary dysfunction could occur in patients with SCD. In patients with a genetic predisposition of atopic asthma, these changes are probably more severe and result in increased susceptibility to sickle cell complications. Early recognition and aggressive management of asthma based on established National Institutes of Health asthma guidelines is recommended in order to minimize morbidity and mortality.

  18. Relationship between cytokines gene polymorphism and susceptibility to hepatitis B virus intrauterine infection

    Institute of Scientific and Technical Information of China (English)

    ZHU Qi-rong; GE Yan-ling; GU Shao-qing; YU Hui; WANG Jian-she; GU Xin-huan; FEI Lin-e; DONG Zuo-quan

    2005-01-01

    Background The influences of genomic background are confirmed in more diseases. Immunologic tolerance after intrauterine infection of hepatitis B virus is considered to occur in T cells. Cytokines work effectively in eliminating virus by immune system after hepatitis B virus infection. To explore the relationship between cytokines (tumor necrosis factor-α, interferon-γ, interleukin-4 and interleukin-10), which expressed abnormal quantity in the peripheral blood to intrauterine hepatitis B virus infectious children, gene single nucleotide polymorphism (SNP) and susceptibility to hepatitis B virus intrauterine infection. Methods This is a cross sectional study of molecular clinical epidemiology. The subjects in this study were selected from outpatients of hepatitis B vaccine follow-up special clinics of our hospital in the period. According to intrant criteria, the high risk children of hepatitis B virus (HBV) intrauterine infection were divided into immune failure group (group Ⅰ); and immune effective group (group Ⅱ) and non high risk children belonged to the control group. Four gene SNP sites of TNF-α -238, IFN-γ +874, IL-4 -590 and IL-10 -1082 were determined by real-time quantitative fluorescent polymerase chain reaction (PCR). Results The significant differences of TNF-α -238 A allele frequency were found between group Ⅰ and groupⅡ (χ2=6.797,P0.05); the significant differences of IFN-γ +874 A allele frequency were found between groupⅠ and groupⅡ(χ2=7.238,P0.05); the significant differences of IL-4 -590 C/T allele frequency were not found between groupⅠand group Ⅱ(χ2=0.632,P>0.05), also groupⅠ and the control group (χ2=0.584,P>0.05), and the groupⅡ and the control group (χ2=0.004,P>0.05)respectively; The significant differences of IL-10 -1082 G allele frequency were found between groupⅡ and groupⅠ (χ2=10.359,P0.05). Conclusions This study suggested the possibility that the TNF-α -238 A allele and IFN-γ +874 A allele were

  19. Analysis of the gyrA gene of clinical Yersinia ruckeri isolates with reduced susceptibility to quinolones.

    Science.gov (United States)

    Gibello, Alicia; Porrero, M Concepción; Blanco, M Mar; Vela, Ana I; Liébana, Pilar; Moreno, Miguel A; Fernández-Garayzábal, José F; Domínguez, Lucas

    2004-01-01

    Antimicrobial susceptibility of seven clinical strains of Yersinia ruckeri representative of those isolated between 1994 and 2002 from a fish farm with endemic enteric redmouth disease was studied. All isolates displayed indistinguishable pulsed-field gel electrophoresis restriction patterns, indicating that they represented a single strain. However, considering both inhibition zone diameters (IZD) and MICs, the isolates recovered in 2001-2002 formed a separate cluster with lower levels of susceptibility to all the quinolones tested, especially nalidixic acid (NA) and oxolinic acid (OA), compared with the isolates recovered between 1994 and 1998. Analysis of the PCR product of the quinolone resistance-determining region of the gyrA gene from clinical isolates of Y. ruckeri with reduced susceptibility to OA and NA revealed a single amino acid substitution, Ser-83 to Arg-83 (Escherichia coli numbering). Identical substitution was observed in induced OA-resistant mutant strains, which displayed IZD and MICs of quinolones similar to those of the clinical isolates of Y. ruckeri with reduced susceptibility to these antimicrobial agents. These data indicate in that for Y. ruckeri, the substitution of Ser by Arg at position 83 of the gyrA gene is associated with reduced susceptibility to quinolones.

  20. Association of a PAI-1 Gene Polymorphism and Early Life Infections with Asthma Risk, Exacerbations, and Reduced Lung Function

    Science.gov (United States)

    Kim, Dong Young; Oh, Sam S.; Torgerson, Dara R.; Pino-Yanes, Maria; Hu, Donglei; Sen, Saunak; Huntsman, Scott; Eng, Celeste; Farber, Harold J.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose R.; Serebrisky, Denise; Thyne, Shannon M.; Borrell, Luisa N.; Williams, L. Keoki; DuPont, William; Seibold, Max A.; Burchard, Esteban G.; Avila, Pedro C.; Kumar, Rajesh

    2016-01-01

    Background Plasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk. Methods We included Latino children, adolescents, and young adults aged 8–21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function. Results RSV infection (OR 9.9, 95%CI 4.9–20.2) and other LRI (OR 9.1, 95%CI 7.2–11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3–50.2) and genotype-LRI (OR 11.7, 95% CI 8.8–16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted. Conclusions A genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population. PMID:27556405

  1. Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

    DEFF Research Database (Denmark)

    Saunders, Edward J; Dadaev, Tokhir; Leongamornlert, Daniel A

    2016-01-01

    BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants...... identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated...... Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using...

  2. Custom genotyping for substance addiction susceptibility genes in Jordanians of Arab descent

    Directory of Open Access Journals (Sweden)

    AL-Eitan Laith N

    2012-09-01

    Full Text Available Abstract Background Both environmental and genetic factors contribute to individual susceptibility to initiation of substance use and vulnerability to addiction. Determining genetic risk factors can make an important contribution to understanding the processes leading to addiction. In order to identify gene(s and mechanisms associated with substance addiction, a custom platform array search for a genetic association in a case/control of homogenous Jordanian Arab population was undertaken. Patients meeting the DSM-VI criteria for substance dependence (n = 220 and entering eight week treatment program at two Jordanian Drug Rehabilitation Centres were genotyped. In addition, 240 healthy controls were also genotyped. The sequenom MassARRAY system (iPLEX GOLD was used to genotype 49 single nucleotide polymorphisms (SNPs within 8 genes (DRD1, DRD2, DRD3, DRD4, DRD5, BDNF, SLC6A3 and COMT. Results This study revealed six new associations involving SNPs within DRD2 gene on chromosome 11. These six SNPs within the DRD2 were found to be most strongly associated with substance addiction in the Jordanian Arabic sample. The strongest statistical evidence for these new association signals were from rs1799732 in the C/−C promoter and rs1125394 in A/G intron 1 regions of DRD2, with the overall estimate of effects returning an odds ratio of 3.37 (χ2 (2, N = 460 = 21, p-value = 0.000026 and 1.78 (χ2 (2, N = 460 = 8, p-value = 0.001, respectively. It has been suggested that DRD2, dopamine receptor D2, plays an important role in dopamine secretion and the signal pathways of dopaminergic reward and drug addiction. Conclusion This study is the first to show a genetic link to substance addiction in a Jordanian population of Arab descent. These findings may contribute to our understanding of drug addiction mechanisms in Middle Eastern populations and how to manage or dictate therapy for individuals. Comparative analysis with different

  3. Cloning of Partial Sodium Channel Gene From Strains of Fenvalerate-Resistant and Susceptible Cotton Aphid(Aphis gossypii Glover)

    Institute of Scientific and Technical Information of China (English)

    SUN Lu-juan; GAO Xi-wu; ZHENG Bing-zong

    2003-01-01

    The strain of fenvalerate-resistant cotton aphids was selected using fenvalerate insecticide in the laboratory, the resistance factor of the strain was 199.54. Three degenerate primers were designed and used to perform PCR amplification. A cDNA encoding partial sodium channel gene was cloned from the fenvalerate-resistant and -susceptible strains. There were two nucleotide acid differences between fenvalerate-resistant strain and -susceptible strain, resulting in an amino acid mutation, Met→Leu. It is predicted that the mutation is related to the cotton aphid resistance to fenvalerate.

  4. Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2

    Science.gov (United States)

    Rapley, E A; Barfoot, R; Bonaïti-Pellié, C; Chompret, A; Foulkes, W; Perusinghe, N; Reeve, A; Royer-Pokora, B; Schumacher, V; Shelling, A; Skeen, J; Tourreil, S de; Weirich, A; Pritchard-Jones, K; Stratton, M R; Rahman, N

    2000-01-01

    Three loci have been implicated in familial Wilms tumour: WT1 located on chromosome 11p13, FWT1 on 17q12-q21, and FWT2 on 19q13. Two out of 19 Wilms tumour families evaluated showed strong evidence against linkage at all three loci. Both of these families contained at least three cases of Wilms tumour indicating that they were highly likely to be due to genetic susceptibility and therefore that one or more additional familial Wilms tumour susceptibility genes remain to be found. © 2000 Cancer Research Campaign PMID:10901367

  5. Searching for a Schizophrenia Susceptibility Gene in the 22q11 Region

    Institute of Scientific and Technical Information of China (English)

    LIN XIE; GUI-ZHI JU; SHU-ZHENG LIU; JIE-PING SHI; YA-QIN YU; JUN WEI

    2005-01-01

    Objective To investigate a genetic association for schizophrenia within chromosome 22q11 in a Chinese Han population. Methods The PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis was used to detect three single nucleotide polymorphisms (SNPs), rs165655 (A/G base change) and rs165815 (C/T base change) present in the ARVCF (armadillo repeat gene deletion in velocardiofacial syndrome) locus, and rs756656 (A/C base change) in the LOC128979 (expressed sequence tags, EST) locus, among 100 Chinese family trios consisting of fathers, mothers and affected offspring with schizophrenia. Genotype data were analyzed by using linkage disequilibrium (LD) methods including haplotype relative risk (HRR) analysis, transmission disequilibrium test (TDT) and haplotype transmission analysis. Results The genotype frequency distributions of three SNPs were all in Hardy-Weinberg equilibrium (P>0.05). Both the HRR and the TDT analysis showed that rs165815 was associated with schizophrenia (χ2=6.447, df=1, P=0.011 and χ2=6.313, df=1, P=0.012, respectively), whereas the other two SNPs did not show any allelic association. The haplotype transmission analysis showed a biased transmission for the rs165655-rs165815 haplotype system (χ2=17.224, df=3, P=0.0006) and for the rs756656- rs165655-rs165815 hapoltype system (χ2=20.965, df=7, P=0.0038). Conclusion Either the ARVCF gene itself or a nearby locus may confer susceptibility to schizophrenia in a Chinese Han population.

  6. DNA methyl transferase (DNMT gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia.

    Directory of Open Access Journals (Sweden)

    Koramannil Radha Saradalekshmi

    Full Text Available DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility to schizophrenia. We screened for polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B and DNMT3L in 330 schizophrenia patients and 302 healthy controls for association with Schizophrenia in south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P = .004, allele P = 0.022 and rs2228611 (genotype P = 0.004, allele P = 0.022 were found to be significantly associated at genotypic and allelic level with Schizophrenia in South Indian population. DNMT3B rs2424932 genotype (P = 0.023 and allele (P = 0.0063 increased the risk of developing schizophrenia in males but not in females. DNMT3B rs1569686 (genotype P = 0.027, allele P = 0.033 was found to be associated with early onset of schizophrenia and also with family history and early onset (genotype P = 0.009. DNMT3L rs2070565 (genotype P = 0.007, allele P = 0.0026 confers an increased risk of developing schizophrenia at an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation in Schizophrenia.

  7. Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency.

    Science.gov (United States)

    Liu, Limin; Gudas, Lorraine J

    2005-12-02

    Lecithin:retinol acyltransferase (LRAT) catalyzes the esterification of retinol (vitamin A) in the liver and in some extrahepatic tissues, including the lung. We produced an LRAT gene knock-out mouse strain and assessed whether LRAT-/- mice were more susceptible to vitamin A deficiency than wild type (WT) mice. After maintenance on a vitamin A-deficient diet for 6 weeks, the serum retinol level was 1.34 +/- 0.32 microM in WT mice versus 0.13 +/- 0.06 microM in LRAT-/- mice (p retinol levels ranged from 0.05 pmol/mg (muscle and tongue) to 17.35 +/- 2.66 pmol/mg (liver) in WT mice. In contrast, retinol was not detectable (retinol levels in serum rapidly increased in the LRAT-/- mice upon re-addition of vitamin A to the diet, indicating that serum retinol levels in LRAT-/- mice can be conveniently modulated by the quantitative manipulation of dietary retinol.

  8. Polymorphisms in DNA Repair Gene XRCC3 and Susceptibility to Breast Cancer in Saudi Females

    Directory of Open Access Journals (Sweden)

    Alaa Mohammed Ali

    2016-01-01

    Full Text Available We investigated three common polymorphisms (SNPs in the XRCC3 gene (rs861539, rs1799794, and rs1799796 in 143 Saudi females suffering from breast cancer (median age = 51.4 years and 145 age matched normal healthy controls. DNA was extracted from whole blood and genotyping was conducted using PCR-RFLP. rs1799794 showed significant association, where AA and AA+AG occurred at a significantly higher frequency in the cancer patients compared to the control group (OR: 28.1; 95% CI: 3.76–21.12; χ2: 22.82; pT and rs1799796 A>G did not show a significant difference when the results in the patients and controls were compared. However, the frequency of rs1799796 differed significantly in patients with different age of diagnosis, tumor grade, and ER and HER2 status. The wild type A allele occurred at a higher frequency in the ER− and HER2− group. Our results among Saudis suggest that some variations in XRCC3 may contribute to breast cancer susceptibility. In conclusion, the results obtained during this study suggest that rs1799794 in XRCC3 shows strong association with breast cancer development in Saudi females.

  9. CTLA4 CT60 gene polymorphism is not associated with differential susceptibility to pemphigus foliaceus

    Directory of Open Access Journals (Sweden)

    Márcia Regina Pincerati

    2010-01-01

    Full Text Available Pemphigus foliaceus is an organ-specific autoimmune disease characterized by autoantibodies against the extracellular region of desmoglein 1, a protein that mediates intercellular adhesion in desmosomes. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4 is a key negative regulator of the T cell immune response, playing an important role in T cell homeostasis and maintenance of peripheral tolerance. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases and the functional CT60 single nucleotide polymorphism (rs3087243, also named 6230G > A has been proposed to be a casual variant in several of these diseases. The aim of this study was to ascertain whether this polymorphism is associated with inter-individual variation in susceptibility to pemphigus foliaceus. The population sample in this case-control association study comprised 248 patient and 367 controls. We did not found a significant association of pemphigus foliaceus with the CT60 variants. We conclude that the CTLA4 CT60 polymorphism is not an important factor for pemphigus foliaceus pathogenesis in the population analyzed.

  10. Genes related to iron metabolism and susceptibility to Alzheimer's disease in Basque population.

    Science.gov (United States)

    Blázquez, L; De Juan, D; Ruiz-Martínez, J; Emparanza, J I; Sáenz, A; Otaegui, D; Sistiaga, A; Martínez-Lage, P; Lamet, I; Samaranch, L; Buiza, C; Etxeberria, I; Arriola, E; Cuadrado, E; Urdaneta, E; Yanguas, J; López de Munain, A

    2007-12-01

    Alzheimer's disease (AD) is the most common dementing disorder and presents with a progressive and irreversible cognitive decline of gradual onset. To date, several reports have involved iron in AD physiopathology. In this study, we have analysed TFC2 variant and HFE mutations (H63D and C282Y) in 211 AD patients and 167 controls recruited from an area of the Basque Country. Furthermore, we have studied APOE genotype as it is a well-known risk factor for AD. APOE epsilon 4 allele was associated with an increased risk of AD and an earlier age at onset, whereas no association was found between TFC2 or HFE C282Y mutation and disease susceptibility. The frequency of H63D mutation was higher in control population (29.9%) than in AD patients (18%), suggesting a protective role of this allele on AD either due to the presence of the mutation itself or through the effect of other related genes in the ancestral haplotype in which it is included.

  11. Indoor Domestic environment and asthma

    Directory of Open Access Journals (Sweden)

    Papadimitriou E.

    2010-01-01

    Full Text Available Introduction: Genesis and development of asthma are greatly affected by the indoor environmental quality. Duringrecent years, it is noted an important increase in asthma cases worldwide which is mainly caused by the effects ofpollutants in indoor environments. Purpose: In this study, there has been an effort to show the impact of indoorenvironment on asthma development. Methodology: Reviewing bibliography by information retrieval from thePubmed and TRIP Database.Conclusion: Indoor air pollution is an interdisciplinary subject. The great number ofpollutants, their variety on structure and action, the conditions under which they are developed as well as theirdifferent and disparate ways of treatment and control require knowledge from many scientific fields. By assuming newdimensions in world climate changes, increasing sensitization in allergens, using respiratory irritants, such aspesticides and compounds and chemicals of industrial origin, and at the same time the poor home indoor air qualityand the family history of asthma lead to new asthma cases worldwide. An important number of asthma cases in afamily could be avoided by implementing a better environmental policy inside our homes. Finally, by understandingbetter the link between environment and asthma as well as by explaining the involved gene action, they will bedelivered more effective prevention and treatment programs.

  12. 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

    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 presence of the allelic variants of these two genes had no statistically significant effect on tumor differentiation, lymph node invasion or tumor size. CONCLUSIONS: These results suggest that allelic variants of XRCC1 and XRCC3 are not suitable markers for susceptibility to carcinomas of the oral cavity...

  13. 肿瘤易感性与消化系统肿瘤易感基因%Tumor Susceptibility and Digestic System Tumor Susceptible Gene

    Institute of Scientific and Technical Information of China (English)

    吕有勇; 郭瑞芳

    1999-01-01

    The carcinogenesis and development is a progress of multi-gene alterations in the human gastric cancer (HGC).In order to determine the relation between the aberration of these genes and gastric cancer,we chose c-met (7q31)、hMLH1 (3p21)、E-cadherin (16q22.1) and HLA loci DQA1、DR2、DR3、DR4、DR7、DR9 and detected their changes in 32 tumor specimens of intestinal type HGC and 4 cell lines of gastric cancer by performing analysis of SSP/PCR、PCR/SSCP and MSI technigues.Our data show that none point mutation was detected in c-met gene.We examined two microsatellites loci D3S1298 and D3S1561 in hMLH1 gene and detected that 6 cases retain MSI (Microsatellite Instability) and 2 cases of LOH (Loss of Heterozygosity) at D3S1298 and 2 cases of MSI at D3S1561.We also examined E-cadherin gene at two microsatellites loci D16S3083 and D16S3095 close to the gene and detected that 5 cases retain MSI and 1 case of LOH at D16S3083 and no change at D16S3095.The point mutation incidence of HLA-DR4 loci is 9/20 (45%),higher than the other loci in HLA-Ⅱ.High frequent deletion,expression deregulation and methylation of mts1/p16 gene were detected in cell lines and solid tumors from human gastric cancer patients.   Our data showed that the point mutation of c-met gene is not the main pattern of alteration in intestinal type HGC that is consistent with the previous results.E-cadherin and hMLH1 are related to intestinal type HGC but whether they are susceptibility gene still need further study.The point mutation of the HLA-Ⅱ loci DR4 is closely related to intestinal type HGC.Methylation of mts1/p16 gene 5 CpG island might be plays an important role in the carcinogenesis in HGC.

  14. Involvement of tryptophan hydroxylase 2 gene polymorphisms in susceptibility to tic disorder in Chinese Han population

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    Zheng Ping

    2013-01-01

    Full Text Available Abstract Background Tryptophan hydroxylase-2 (TPH2 is a potential candidate gene for screening tic disorder (TD. Methods A case–control study was performed to examine the association between the TPH2 gene and TD. The Sequenom® Mass ARRAY iPLEX GOLD System was used to genotype two single nucleotide polymorphisms (SNPs of the TPH2 gene in 149 TD children and in 125 normal controls. Results For rs4565946, individuals with the TT genotype showed a significantly higher risk of TD than those with TC plus CC genotypes [odds ratio (OR =3.077, 95% confidence interval (CI: 1.273–7.437; P = 0.009], as did male TD children with the TT genotype (OR = 3.228, 95% CI: 1.153–9.040; P = 0.020. The G allele of rs4570625 was significantly more frequent in TD children with higher levels of tic symptoms (Yale Global Tic Severity Scale, YGTSS than those in controls among the male children (OR = 1.684, 95%: 1.097–2.583; P = 0.017]. TD children with severe tic symptoms had significantly higher frequencies of rs4546946 TT genotype than did normal controls in boys (OR = 3.292, 95% CI: 1.139–9.513; P = 0.022. We also found that genotype distributions of both SNPs were different between the Asian and European populations. Conclusions Our results indicated that the TT genotype of rs4565946 is a potential genetic risk factor for TD, and the allele G of rs4570625 might be associated with the severity of tic symptoms in boys. These polymorphisms might be susceptibility loci for TD in the Chinese Han population. Because of the confounding of co-existing attention deficit hyperactivity disorder (ADHD,these findings need to be confirmed by studies in much larger samples.

  15. Interleukin-16 Gene Polymorphisms Are Considerable Host Genetic Factors for Patients’ Susceptibility to Chronic Hepatitis B Infection

    Directory of Open Access Journals (Sweden)

    Sara Romani

    2014-01-01

    Full Text Available Host genetic background is known as an important factor in patients’ susceptibility to infectious diseases such as viral hepatitis. The aim of this study was to determine the effect of genetic polymorphisms of interleukin-16 (IL-16 cytokine on susceptibility of hepatitis B virus (HBV infected patients to develop chronic HBV infection. Genotyping was conducted using PCR followed by enzymatic digestion and RFLP (restriction fragment length polymorphism analysis. We genotyped three single nucleotide polymorphisms (SNPs in the Il-16 gene (rs11556218 T>G, rs4778889 T>C, and rs4072111 C>T to test for relationship between variation at these loci and patients’ susceptibility to chronic HBV infection. Allele frequency of Il-16 gene rs4072111 and rs11556218 was significantly different between chronic HBV patients and healthy blood donors. Genotype frequency of rs4778889 polymorphism of Il-16 gene was significantly different when chronic HBV patients and HBV clearance subjects were compared. Our results showed that Il-16 gene polymorphisms are considerable host genetic factors when we chase biomarkers for prognosis of HBV infected patients.

  16. Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma.

    Science.gov (United States)

    Jannot, Anne-Sophie; Meziani, Roubila; Bertrand, Guylene; Gérard, Benedicte; Descamps, Vincent; Archimbaud, Alain; Picard, Catherine; Ollivaud, Laurence; Basset-Seguin, Nicole; Kerob, Delphine; Lanternier, Guy; Lebbe, Celeste; Saiag, P; Crickx, Beatrice; Clerget-Darpoux, Françoise; Grandchamp, Bernard; Soufir, Nadem; Melan-Cohort

    2005-08-01

    The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.

  17. Association of gene variants with susceptibility to type 2diabetes among Omanis

    Institute of Scientific and Technical Information of China (English)

    Sawsan Al-Sinani; Nicolas Woodhouse; Ali Al-Mamari; Omaima Al-Shafie; Mohammed Al-Shafaee; Said Al-Yahyaee; Mohammed Hassan; Deepali Jaju; Khamis Al-Hashmi; Mohammed Al-Abri; Khalid Al-Rassadi; Syed Rizvi; Yengo Loic; Philippe Froguel; Riad Bayoumi

    2015-01-01

    AIM: To investigate the association of 10 knowncommon gene variants with susceptibility to type 2diabetes mellitus (T2D) among Omanis.METHODS: Using case-control design, a total of992 diabetic patients and 294 normoglycemic OmaniArabs were genotyped, by an allelic discriminationassay-by-design TaqMan method on fast real timepolymerase chain reaction system, for the followinggene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146),CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO(rs9939609 and rs8050136), IGF2BP2 (rs4402960),SLC30A8 (rs13266634) CAPN10 (rs3792267) andHHEX (rs1111875). T2D patients were recruited fromthe Diabetes Clinic (n = 243) and inpatients (n = 749)at Sultan Qaboos Univesity Hospital (SQUH), Muscat,Oman. Adult control participants (n = 294) werevolunteers from the community and from those visitingFamily Medicine Clinic at SQU, for regular medicalcheckup. The difficulty in recruiting Omani participantswith no family history of diabetes was the main reasonbehind the small number of control participants in thisstudy. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number ofnormoglycemic controls in this study, this sample wassufficient for detection of genes and loci for commonalleles influencing T2D with an odds ratio of ≥ 1.3reaching at least 80% power. Data was collected fromJune 2010 to February 2012.RESULTS: Using binary logistic regression analysis,four gene variants showed significant association withT2D risk: KCNJ11 (rs5219, P = 5.8 × 10-6, OR = 1.74),TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1(rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B(rs10811661, P = 0.020, OR = 1.40). The fixation indexanalysis of these four gene variants indicated significantgenetic differentiation between diabetics and controls{[KCNJ11 (rs5219), P 〈 0.001], [TCF7L2 (rs7903146),P 〈 0.001], [CDKAL1 (rs10946398), P 〈 0

  18. Association of interleukin-18 and asthma.

    Science.gov (United States)

    Xu, Ming-Hui; Yuan, Feng-Lai; Wang, Shu-Jing; Xu, Hui-Ying; Li, Cheng-Wan; Tong, Xiao

    2017-02-01

    Cytokine-mediated immunity plays a dominant role in the pathogenesis of various immune diseases, including asthma. The recent identification of the family interleukin (IL)-1-related cytokine IL-18 now contributes to our understanding of the fine-tuning of cellular immunity. IL-18 can act as a cofactor for Th2 cell development and IgE production and also plays an important role in the differentiation of Th1 cells. Recent work identified an IL-18 association with the pathogenesis of asthma, wherein increased IL-18 expression was found in the serum of patients. Furthermore, IL-18 polymorphisms with susceptibility to asthma were reported, suggesting that IL-18 may be therapeutically relevant to asthma. In this review, we discuss the role of IL-18 in the pathogenesis of asthma and its therapeutic potential based on current research.

  19. Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes.

    Science.gov (United States)

    Thier, Ricarda; Brüning, Thomas; Roos, Peter H; Rihs, Hans-Peter; Golka, Klaus; Ko, Yon; Bolt, Hermann M

    2003-06-01

    Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of

  20. Transcription profiling of immune genes during parasite infection in susceptible and resistant strains of the flour beetles (Tribolium castaneum).

    Science.gov (United States)

    Zhong, Daibin; Wang, Mei-Hui; Pai, Aditi; Yan, Guiyun

    2013-05-01

    The flour beetle, Tribolium castaneum, is an intermediate host for the tapeworm Hymenolepis diminuta and has become an important genetic model to explore immune responses to parasite infection in insect hosts. The present study examined the immune responses to tapeworm infection in resistant (TIW1) and susceptible (cSM) strains of the red flour beetle, T. castaneum, using real-time quantitative reverse transcription PCR on 29 immunity-related genes that exhibit antimicrobial properties. Thirteen of the 29 genes showed constitutive differences in expression between the two strains. Fourteen to fifteen of the 29 genes exhibited significant differences in transcription levels when beetles were challenged with tapeworm parasite in the resistant and susceptible strains. Nine genes (GNBP3, cSPH2, lysozyme4, defensin1, PGRP-SA, defensin2, coleoptericin1, attacin2 and serpin29) in cSM and 13 genes (lysozyme2, proPO1, GNBP3, cSPH2, lysozyme4, defensin1, PGRP-SA, defensin2, coleoptericin1, attacin2, proPO2/3, PGRP-LE and PGRP-SB) in TIW1 were up-regulated by infections or showed parasite infection-induced expression. Seven genes (attacin2, coleoptericin1, defensin1, defensin2, lysozyme2, PGRP-SA and PGRP-SB) were more than 10 folds higher in the resistant TIW1 strain than in the susceptible cSM strain after exposure to tapeworm parasites. This study demonstrated the effects of genetic background, the transcription profile to parasite infection, and identified the immunity-related genes that were significantly regulated by the infection of tapeworms in Tribolium beetles.

  1. Association study of candidate genes for susceptibility to schizophrenia and bipolar disorder on chromosome 22Q13

    DEFF Research Database (Denmark)

    Severinsen, Jacob; Binderup, Helle; Mors, Ole

    Chromosome 22q is suspected to harbor risk genes for schizophrenia as well as bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. In a recent study of distantly related patients from...... the Faroe Islands we have obtained evidence suggesting two regions on chromosome 22q13 to potentially harbor susceptibility genes for both schizophrenia and bipolar affective disorder. We have selected a number of candidate genes from these two regions for further analysis, including the neuro-gene WKL1...... and unrelated controls, and in a Scottish case-control sample comprising 200 schizophrenics, 200 bipolar patients and 200 controls. None of the investigated SNPs have so far showed strong evidence of association to either bipolar disorder or schizophrenia....

  2. Virulence, bacterocin genes and antibacterial susceptibility in Enterococcus faecalis strains isolated from water wells for human consumption.

    Science.gov (United States)

    Padilla, Carlos; Lobos, Olga

    2013-12-01

    The objectives of this study were to detect genes for virulence and bacteriocins in addition to studying the antimicrobial susceptibility of 78 strains of E. faecalis isolated from water wells for human consumption. The virulence and bacteriocin genes of 78 E. faecalis were amplified by PCR and visualized in agarose gels. The antimicrobial susceptibility was determined through diffusion agar tests and the MIC through microdilution. It was observed that the major percentage of virulence genes in the E. faecalis strains corresponds to aggA (93.5%). The bacteriocin gene entA (64.1%) is the most frequently detected. The studied strains exhibited different virulence and bacteriocin genes, and an important antibacterial resistance. The most common resistant phenotype (n = 14) corresponds to tetracycline and chloramphenicol and the less frequent (n = 2) to ciprofloxacin and moxifloxacin. Eight different genetic profiles were observed for virulence y bacteriocin genes. It was determined a statistical association between the bacterial resistance and some of the genetic profiles detected.

  3. Identification of genes differentially expressed during interaction of resistant and susceptible apple cultivars (Malus × domestica with Erwinia amylovora

    Directory of Open Access Journals (Sweden)

    Aldwinckle Herb S

    2010-01-01

    Full Text Available Abstract Background The necrogenic enterobacterium, Erwinia amylovora is the causal agent of the fire blight (FB disease in many Rosaceaespecies, including apple and pear. During the infection process, the bacteria induce an oxidative stress response with kinetics similar to those induced in an incompatible bacteria-plant interaction. No resistance mechanism to E. amylovora in host plants has yet been characterized, recent work has identified some molecular events which occur in resistant and/or susceptible host interaction with E. amylovora: In order to understand the mechanisms that characterize responses to FB, differentially expressed genes were identified by cDNA-AFLP analysis in resistant and susceptible apple genotypes after inoculation with E. amylovora. Results cDNA were isolated from M.26 (susceptible and G.41 (resistant apple tissues collected 2 h and 48 h after challenge with a virulent E. amylovora strain or mock (buffer inoculated. To identify differentially expressed transcripts, electrophoretic banding patterns were obtained from cDNAs. In the AFLP experiments, M.26 and G.41 showed different patterns of expression, including genes specifically induced, not induced, or repressed by E. amylovora. In total, 190 ESTs differentially expressed between M.26 and G.41 were identified using 42 pairs of AFLP primers. cDNA-AFLP analysis of global EST expression in a resistant and a susceptible apple genotype identified different major classes of genes. EST sequencing data showed that genes linked to resistance, encoding proteins involved in recognition, signaling, defense and apoptosis, were modulated by E. amylovora in its host plant. The expression time course of some of these ESTs selected via a bioinformatic analysis has been characterized. Conclusion These data are being used to develop hypotheses of resistance or susceptibility mechanisms in Malus to E. amylovora and provide an initial categorization of genes possibly involved in

  4. Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness

    Directory of Open Access Journals (Sweden)

    Helal Ahmed N

    2010-06-01

    Full Text Available Abstract Background Interleukin-8 (IL-8/CXCL-8 is a prototype of the ELR+CXC chemokines that play an important role in the promotion and progression of many human cancers including breast cancer. We have recently showed the implication of polymorphism (-251 T/A of IL-8 gene in the susceptibility and prognosis of breast carcinoma. IL-8 acts through its CXCR1 and CXCR2 receptors. CXCR2, expressed on the endothelial cells, is the receptor involved in mediating the angiogenic effects of ELR+CXC chemokines and in particular IL-8. In the current study, we investigated the susceptibility and prognostic implications of the genetic variation in CXCR2 in breast carcinoma. We also confirmed the implication of IL-8 (-251 T/A polymorphism in a larger cohort. Finally, we combined the IL-8 and CXCR2 variant alleles and analyzed their effects in breast cancer risk and prognosis. Methods We used the allele-specific polymerase chain reaction to characterize the variation of IL-8 and CXCR2 for 409 unrelated Tunisian patients with breast carcinoma and 301 healthy control subjects. To estimate the relative risks, Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for the known risk factors for breast cancer. Associations of the genetic marker with the rates of breast carcinoma-specific overall survival and disease-free survival were assessed using univariate and multivariate analyses. Results A highly significant association was found between the homozygous CXCR2 (+ 1208 TT genotype (adjusted OR = 2.89; P = 0.008 and breast carcinoma. A significantly increased risk of breast carcinoma was associated with IL-8 (-251 A allele (adjusted OR = 1.86; P = 0.001. The presence of two higher risk genotypes (the TA and TT in IL-8, and the TT in CXCR2 significantly increased the risk of developing breast carcinoma (adjusted OR = 4.15; P = 0.0004. The CXCR2 (+ 1208 T allele manifested a significant association with an

  5. Increased radiosensitivity as an indicator of genes conferring breast cancer susceptibility

    Energy Technology Data Exchange (ETDEWEB)

    Varga, D.; Kreienberg, R.; Deissler, H.; Sauer, G. [Dept. of Gynecology and Obstetrics, Univ. of Ulm Medical School (Germany); Vogel, W.; Bender, A.; Surowy, H.; Maier, C. [Dept. of Genetics, Univ. of Ulm Medical School (Germany)

    2007-12-15

    Purpose: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. Material and Methods: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. Results: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). Conclusion: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness. (orig.)

  6. Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya

    OpenAIRE

    Borrmann, Steffen; Straimer, Judith; Mwai, Leah; Abdi, Abdirahman; Rippert, Anja; Okombo, John; Muriithi, Steven; Sasi, Philip; Kortok, Moses Mosobo; LOWE, BRETT; Campino, Susana; Assefa, Samuel; Auburn, Sarah; Manske, Magnus; Maslen, Gareth

    2013-01-01

    Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin tha...

  7. Inherited Susceptibility to Breast Cancer in Healthy Women: Mutation in Breast Cancer Genes, Immune Surveillance, and Psychological Distress

    Science.gov (United States)

    2005-10-01

    hypotheses were investigated: Hypothesis 1: Women with family histories of breast cancer are more emotionally distressed than women at normal risk... emotionally distressed than women at normal risk, particularly after notification that they carry a mutation in a primary susceptibility gene. o Healthy...Valdimarsdottir HB, Montgomery GH, Bovbjerg DH. Heightened cortisol responses to daily stress in working women at familial risk for breast cancer. Biological

  8. [Severe asthma].

    Science.gov (United States)

    González, Claudio D

    2016-01-01

    The objectives of this work were to investigate the frequency of severe asthma (SA) according to WHO definition and to compare SA patients' characteristics with those of non-severe asthma (NSA); secondly, to investigate the level of control reached throughout a period of regular treatment. Between 1-1-2005 and 12-31-2014, 471 medical records from patients with bronchial asthma assisted in Buenos Aires City were analyzed. SA frequency was 40.1% (189/471), being significantly higher among patients from the public health system (47.7%, 108/226 vs. 33%, 81/245, p = 0.001). SA patients were older than NSA ones (51.3 ± 17.4 vs. 42.6 ± 17.1 years, p = 0.000), presented longer time since onset of the disease (median 30 vs. 20 years, p = 0.000), lower educational levels (secondary level or higher 41.7% vs. 58.1%, p = 0.000), lower frequency of rhinitis (47% vs. 60.6%, p = 0.004), more severe levels of airway obstruction (FEV% 50.2 ± 13.7 vs. 77.7 ± 12.4, p = 0.000), more frequent antecedents of Near Fatal Asthma (11.1% vs. 2.8%, p = 0.000), higher levels of serum IgE (median of 410 vs. 279 UI/l, p = 0.01) and higher demand of systemic steroids requirements and hospitalizations (68.7% vs. 50.7%, p = 0.000 and 37.5% vs. 15.9%, p = 0.000, respectively). A 30.6% of SA patients (58/189) reached a follow-up period of 12 months, 13 (22.5%) of whom reached the controlled asthma level. The frequency of SA found seems to be considerable. Multicenter studies to investigate the levels of control reached by SA patients with access to proper treatment are recommended.

  9. Gene expression responses to Rice tungro spherical virus in susceptible and resistant near-isogenic rice plants.

    Science.gov (United States)

    Satoh, Kouji; Kondoh, Hiroaki; De Leon, Teresa B; Macalalad, Reena Jesusa A; Cabunagan, Rogelio C; Cabauatan, Pepito Q; Mauleon, Ramil; Kikuchi, Shoshi; Choi, Il-Ryong

    2013-01-01

    Rice cultivar Taichung Native 1 (TN1) is susceptible to Rice tungro spherical virus (RTSV). TW16 is a backcross line developed between TN1 and RTSV-resistant cultivar Utri Merah. RTSV accumulation in TW16 was significantly lower than in TN1, although both TN1 and TW16 remained asymptomatic. We compared the gene expression profiles of TN1 and TW16 infected by RTSV to identify the gene expression patterns accompanying the accumulation and suppression of RTSV. About 11% and 12% of the genes in the entire genome were found differentially expressed by RTSV in TN1 and TW16, respectively. About 30% of the differentially expressed genes (DEGs) were detected commonly in both TN1 and TW16. DEGs related to development and stress response processes were significantly overrepresented in both TN1 and TW16. Evident differences in gene expression between TN1 and TW16 instigated by RTSV included (1) suppression of more genes for development-related transcription factors in TW16; (2) activation of more genes for development-related peptide hormone RALF in TN1; (3) TN1- and TW16-specific regulation of genes for jasmonate synthesis and pathway, and genes for stress-related transcription factors such as WRKY, SNAC, and AP2-EREBP; (4) activation of more genes for glutathione S-transferase in TW16; (5) activation of more heat shock protein genes in TN1; and (6) suppression of more genes for Golden2-like transcription factors involved in plastid development in TN1. The results suggest that a significant number of defense and development-related genes are still regulated in asymptomatic plants even with a very low level of RTSV, and that the TN1- and TW16-specific gene regulations might be associated with regulation of RTSV accumulation in the plants.

  10. Variants in linkage disequilibrium with the late cornified envelope gene cluster deletion are associated with susceptibility to psoriatic arthritis.

    LENUS (Irish Health Repository)

    Bowes, John

    2010-12-01

    A common deletion mapping to the psoriasis susceptibility locus 4 on chromosome 1q21, encompassing two genes of the late cornified envelope (LCE) gene cluster, has been associated with an increased risk of psoriasis vulgaris (PsV). One previous report found no association of the deletion with psoriatic arthritis (PsA), suggesting it may be a specific risk factor for PsV. Given the genetic overlap between PsA and PsV, a study was undertaken to investigate whether single nucleotide polymorphisms (SNPs) mapping to this locus are risk factors for PsA in a UK and Irish population.

  11. Association of IFN-γ and P2X7 Receptor Gene Polymorphisms in Susceptibility to Tuberculosis Among Iranian Patients.

    Science.gov (United States)

    Shamsi, Mahdi; Zolfaghari, Mohammad Reza; Farnia, Parissa

    2016-03-01

    Interferon-gamma (IFN-γ) and P2X7 receptor are crucial for host defence against mycobacterial infections. Recent studies have indicated that IFN-γ, IFN-γ receptor 1 (IFN-γR1) andP2X7 gene polymorphisms are associated with susceptibility to pulmonary tuberculosis (TB). However, the relationship between IFN-γ and P2X7 polymorphism and TB susceptibility remains inconclusive in Iranian population. For this reason, single nucleotide polymorphisms (SNPs) in IFN-γ (G+2109A), IFN-γR1 (G-611A) and P2X7 genes (at -762, 1513 position) in patients (n = 100) were assessed using PCR-RFLP. Data were analysed with SPSS version 18. For the 2109 loci of IFN-γ gene, the frequency of mutant alleles between patients and controls were not statistically significant. However, there was a significant difference between the TB patient and controls for -611 alleles of IFN-γR1 (P = 0.01). Additionally, the frequency of P2X7 gene polymorphisms (SNP-762 and 1513) between patients and controls was statistically significant. In conclusions, our study revealed a significant association of IFN-γR1 and P2X7 genes polymorphisms with risk of developing TB in Iranian population.

  12. Glutathione S-Transferase P1 (GSTP1 gene polymorphism increases age-related susceptibility to hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Kuo Wu-Hsien

    2010-03-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is one of the most frequent malignant neoplasms in the world. Genetic polymorphism has been reported to be a factor increasing the risk of HCC. Phase II enzymes such as glutathione s-transferases (GSTP1, GSTA1 play important roles in protecting cells against damage induced by carcinogens. The aim of this study was to estimate the relationship of the GSTP1 and GSTA1 gene polymorphisms to HCC risk and clinico-pathological status. Methods Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP was used to measure GSTP1 (A→G and GSTA1 (C→T gene polymorphisms in 386 healthy controls and 177 patients with HCC. Results Neither gene polymorphism was associated with the clinico-pathological status of HCC and serum expression of liver-related clinico-pathological markers. No association between the GSTA1 gene polymorphism and HCC susceptibility was found. However, in the younger group, aged ≤ 57 years, individuals with AG or GG alleles of GSTP1 had a 2.18-fold (95%CI = 1.09-4.36; p = 0.02 and 5.64-fold (95%CI = 1.02-31.18; p = 0.04 risk, respectively, of developing HCC compared to individuals with AA alleles, after adjusting for other confounders. Conclusion AG and GG alleles of GSTP1 gene polymorphisms may be considered as factors increasing the susceptibility to and risk of HCC in Taiwanese aged ≤ 57 years.

  13. Common variants of the PINK1 and PARL genes do not confer genetic susceptibility to schizophrenia in Han Chinese.

    Science.gov (United States)

    Li, Xiao; Zhang, Wen; Zhang, Chen; Yi, Zhenghui; Zhang, Deng-Feng; Gong, Wei; Tang, Jinsong; Wang, Dong; Lu, Weihong; Chen, Xiaogang; Fang, Yiru; Yao, Yong-Gang

    2015-04-01

    Schizophrenia is a prevalent psychiatric disorder with a complex etiology. Mitochondrial dysfunction has been frequently reported in schizophrenia. Phosphatase and tension homologue-induced kinase 1 (PINK1) and presenilin-associated rhomboid-like protease (PARL) are mitochondrial proteins, and genetic variants of these two genes may confer genetic susceptibility to schizophrenia by influencing mitochondrial function. In this study, we conducted a two-stage genetic association study to test this hypothesis. We genotyped 4 PINK1 and 5 PARL genetic variants and evaluated the potential association of the 9 SNPs with schizophrenia in two independent case-control cohorts of 2510 Han Chinese individuals. No positive association of common genetic variants of the PINK1 and PARL genes with schizophrenia was identified in our samples after Bonferroni correction. Re-analysis of the newly updated Psychiatric Genetics Consortium (PGC) data sets confirmed our negative result. Intriguingly, one PINK1 SNP (rs10916832), which showed a marginally significant association in only Hunan samples (P = 0.032), is associated with the expression of a schizophrenia susceptible gene KIF17 according to the expression quantitative trait locus (eQTL) analysis. Our study indicated that common genetic variants of the PINK1 and PARL genes are unlikely to be involved in schizophrenia. Further studies are essential to characterize the role of the PINK1 and PARL genes in schizophrenia.

  14. ADAM33, a new candidate for psoriasis susceptibility.

    Directory of Open Access Journals (Sweden)

    Fabienne Lesueur

    Full Text Available Psoriasis is a chronic skin disorder with multifactorial etiology. In a recent study, we reported results of a genome-wide scan on 46 French extended families presenting with plaque psoriasis. In addition to unambiguous linkage to the major susceptibility locus PSORS1 on Chromosome 6p21, we provided evidence for a susceptibility locus on Chromosome 20p13. To follow up this novel psoriasis susceptibility locus we used a family-based association test (FBAT for an association scan over the 17 Mb candidate region. A total of 85 uncorrelated SNP markers located in 65 genes of the region were initially investigated in the same set of large families used for the genome wide search, which consisted of 295 nuclear families. When positive association was obtained for a SNP, candidate genes nearby were explored more in detail using a denser set of SNPs. Thus, the gene ADAM33 was found to be significantly associated with psoriasis in this family set (The best association was on a 3-SNP haplotype P = 0.00004, based on 1,000,000 permutations. This association was independent of PSORS1. ADAM33 has been previously associated with asthma, which demonstrates that immune system diseases may be controlled by common susceptibility genes with general effects on dermal inflammation and immunity. The identification of ADAM33 as a psoriasis susceptibility gene identified by positional cloning in an outbred population should provide insights into the pathogenesis and natural history of this common disease.

  15. Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression.

    Science.gov (United States)

    Ghosh, S; Dai, C; Brown, K; Rajendiran, E; Makarenko, S; Baker, J; Ma, C; Halder, S; Montero, M; Ionescu, V A; Klegeris, A; Vallance, B A; Gibson, D L

    2011-07-01

    Individuals vary in their resistance to enteric infections. The role of the intestinal microbiota in altering susceptibility to enteric infection is relatively unknown. Previous studies have identified that C3H/HeOuJ mice suffer 100% mortality during Citrobacter rodentium-induced colitis, whereas C57BL/6 mice recover from infection. The basis for their differences in susceptibility is unclear and has been mainly attributed to differences in host genetics. This study investigated the role of the intestinal microbiota in altering susceptibility to C. rodentium-induced colitis. When the feces of C57BL/6 mice were gavaged into antibiotic treated C3H/HeOuJ mice, the C57BL/6 microflora led to a complete reversal in mortality patterns where 100% of the C3H/HeOuJ mice survived infection. This protection corresponded with reduced colonic pathology and less systemic pathogen load and was associated with increased inflammatory and redox responses with reduced epithelial cell death. C3H/HeOuJ mice are normally susceptible to infection-induced dehydration due to defective expression of colonic ion transporters such as Dra, CA IV, and CA I; expression of these genes was normalized when C3H/HeOuJ mice were colonized with the C57BL/6 microflora. Together, these data reveal that the colonic microbiota play a critical role in protecting against intestinal infection by inducing proinflammatory and prooxidant responses that control pathogen load as well as ion transporter gene expression previously shown to prevent fatal dehydration. Protection of mice from lethal colitis was associated with higher levels of bacteria from Bacteroidetes. This study reveals that the microbiota is sufficient to overcome inherent genetic susceptibility patterns in C3H/HeOuJ mice that cause mortality during C. rodentium infection.

  16. Asthma discordance in twins is linked to epigenetic modifications of T cells.

    Directory of Open Access Journals (Sweden)

    R Scott Runyon

    Full Text Available T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21 all discordant for asthma. Regulatory T cell (Treg and effector T cell (Teff subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3 and interferon gamma-γ (IFNγ loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.

  17. Rhinovirus and childhood asthma: an update

    Science.gov (United States)

    2016-01-01

    Asthma is recognized as a complex disease resulting from interactions between multiple genetic and environmental factors. Accumulating evidence suggests that respiratory viral infections in early life constitute a major environmental risk factor for the development of childhood asthma. Respiratory viral infections have also been recognized as the most common cause of asthma exacerbation. The advent of molecular diagnostics to detect respiratory viruses has provided new insights into the role of human rhinovirus (HRV) infections in the pathogenesis of asthma. However, it is still unclear whether HRV infections cause asthma or if wheezing with HRV infection is simply a predictor of childhood asthma. Recent clinical and experimental studies have identified plausible pathways by which HRV infection could cause asthma, particularly in a susceptible host, and exacerbate disease. Airway epithelial cells, the primary site of infection and replication of HRV, play a key role in these processes. Details regarding the role of genetic factors, including ORMDL3, are beginning to emerge. This review discusses recent clinical and experimental evidence for the role of HRV infection in the development and exacerbation of childhood asthma and the potential underlying mechanisms that have been proposed. PMID:27895690

  18. Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.

    Science.gov (United States)

    Koster, Roelof; Mitra, Nandita; D'Andrea, Kurt; Vardhanabhuti, Saran; Chung, Charles C; Wang, Zhaoming; Loren Erickson, R; Vaughn, David J; Litchfield, Kevin; Rahman, Nazneen; Greene, Mark H; McGlynn, Katherine A; Turnbull, Clare; Chanock, Stephen J; Nathanson, Katherine L; Kanetsky, Peter A

    2014-11-15

    Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT.

  19. Allergies, asthma, and dust

    Science.gov (United States)

    Reactive airway disease - dust; Bronchial asthma - dust; Triggers - dust ... Things that make allergies or asthma worse are called triggers. Dust is a common trigger. When your asthma or allergies become worse due to dust, you are ...

  20. Allergies, asthma, and molds

    Science.gov (United States)

    Reactive airway - mold; Bronchial asthma - mold; Triggers - mold; Allergic rhinitis - pollen ... Things that make allergies or asthma worse are called triggers. Mold is a common trigger. When your asthma or allergies become worse due to mold, you are ...

  1. Asthma: Basic Information

    Science.gov (United States)

    ... Air Pollution & Respiratory Health Learn How to Control Asthma Language: English Español (Spanish) Recommend on Facebook Tweet ... Treated? Select a Language Español (Spanish) What Is Asthma? Asthma is a disease that affects your lungs. ...

  2. Asthma in Children

    Science.gov (United States)

    ... have asthma. Nearly 9 million of them are children. Children have smaller airways than adults, which makes asthma especially serious for them. Children with asthma may experience wheezing, coughing, chest tightness, ...

  3. Asthma triggers (image)

    Science.gov (United States)

    ... things make your asthma worse. These are called asthma "triggers". Avoiding them is your first step toward feeling better. The most common asthma triggers are mold, pets, dust, grasses, pollen, cockroaches, odors ...

  4. Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study.

    Directory of Open Access Journals (Sweden)

    Shufang Xu

    Full Text Available BACKGROUND: Genetic variants make some contributions to inflammatory bowel disease (IBD, including Crohn's disease (CD and ulcerative colitis (UC. More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique. METHODS: Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC, 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family. RESULTS: From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV c.374T>C (p.I125T in exon 4 of discs large homolog 1 (DLG1, a gene has been reported to play multiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (PA (p.R278Q in exon 9 of DLG1. CONCLUSIONS: We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

  5. Differential Gene Expression Profile in the Rat Caudal Vestibular Nucleus is Associated with Individual Differences in Motion Sickness Susceptibility.

    Directory of Open Access Journals (Sweden)

    Jun-Qin Wang

    Full Text Available To identify differentially expressed genes associated with motion sickness (MS susceptibility in the rat caudal vestibular nucleus.We identified MS susceptible (MSS and insusceptible (inMSS rats by quantifying rotation-induced MS symptoms: defecation and spontaneous locomotion activity. Microarray analysis was used to screen differentially expressed genes in the caudal vestibular nucleus (CVN after rotation. Plasma stress hormones were identified by radioimmunoassay. Candidate genes were selected by bioinformatics analysis and the microarray results were verified by real-time quantitative-PCR (RT-qPCR methods. By using Elvax implantation, receptor antagonists or recombinant adenovirus targeting the candidate genes were applied to the CVN to evaluate their contribution to MS susceptibility variability. Validity of gene expression manipulation was verified by RT-qPCR and western blot analysis.A total of 304 transcripts were differentially expressed in the MSS group compared with the inMSS group. RT-qPCR analysis verified the expression pattern of candidate genes, including nicotinic cholinergic receptor (nAchR α3 subunit, 5-hydroxytryptamine receptor 4 (5-HT4R, tachykinin neurokinin-1 (NK1R, γ-aminobutyric acid A receptor (GABAAR α6 subunit, olfactory receptor 81 (Olr81 and homology 2 domain-containing transforming protein 1 (Shc1. In MSS animals, the nAchR antagonist mecamylamine significantly alleviated rotation-induced MS symptoms and the plasma β-endorphin response. The NK1R antagonist CP99994 and Olr81 knock-down were effective for the defecation response, while the 5-HT4R antagonist RS39604 and Shc1 over-expression showed no therapeutic effect. In inMSS animals, rotation-induced changes in spontaneous locomotion activity and the plasma β-endorphin level occurred in the presence of the GABAAR antagonist gabazine.Our findings suggested that the variability of the CVN gene expression profile after motion stimulation might be a putative

  6. Ocular toxoplasmosis: susceptibility in respect to the genes encoding the KIR receptors and their HLA class I ligands

    Science.gov (United States)

    Ayo, Christiane Maria; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Brandão de Mattos, Cinara de Cássia; Previato, Mariana; Barbosa, Amanda Pires; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; de Mattos, Luiz Carlos

    2016-01-01

    The objective of this study was to investigate the influence of the genes encoding the KIR receptors and their HLA ligands in the susceptibility of ocular toxoplasmosis. A total of 297 patients serologically-diagnosed with toxoplasmosis were selected and stratified according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping was performed by PCR-SSOP. Statistical analyses were conducted using the Chi-square test, and odds ratio with a 95% confidence interval was also calculated to evaluate the risk association. The activating KIR3DS1 gene was associated with increased susceptibility for ocular toxoplasmosis. The activating KIR together with their HLA ligands (KIR3DS1-Bw4-80Ile and KIR2DS1+/C2++ KIR3DS1+/Bw4-80Ile+) were associated with increased susceptibility for ocular toxoplasmosis and its clinical manifestations. KIR-HLA inhibitory pairs -KIR2DL3/2DL3-C1/C1 and KIR2DL3/2DL3-C1- were associated with decreased susceptibility for ocular toxoplasmosis and its clinical forms, while the KIR3DS1−/KIR3DL1+/Bw4-80Ile+ combination was associated as a protective factor against the development of ocular toxoplasmosis and, in particular, against recurrent manifestations. Our data demonstrate that activating and inhibitory KIR genes may influence the development of ocular toxoplasmosis. PMID:27827450

  7. Ocular toxoplasmosis: susceptibility in respect to the genes encoding the KIR receptors and their HLA class I ligands.

    Science.gov (United States)

    Ayo, Christiane Maria; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Brandão de Mattos, Cinara de Cássia; Previato, Mariana; Barbosa, Amanda Pires; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; de Mattos, Luiz Carlos

    2016-11-09

    The objective of this study was to investigate the influence of the genes encoding the KIR receptors and their HLA ligands in the susceptibility of ocular toxoplasmosis. A total of 297 patients serologically-diagnosed with toxoplasmosis were selected and stratified according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping was performed by PCR-SSOP. Statistical analyses were conducted using the Chi-square test, and odds ratio with a 95% confidence interval was also calculated to evaluate the risk association. The activating KIR3DS1 gene was associated with increased susceptibility for ocular toxoplasmosis. The activating KIR together with their HLA ligands (KIR3DS1-Bw4-80Ile and KIR2DS1(+)/C2(++) KIR3DS1(+)/Bw4-80Ile(+)) were associated with increased susceptibility for ocular toxoplasmosis and its clinical manifestations. KIR-HLA inhibitory pairs -KIR2DL3/2DL3-C1/C1 and KIR2DL3/2DL3-C1- were associated with decreased susceptibility for ocular toxoplasmosis and its clinical forms, while the KIR3DS1(-)/KIR3DL1(+)/Bw4-80Ile(+) combination was associated as a protective factor against the development of ocular toxoplasmosis and, in particular, against recurrent manifestations. Our data demonstrate that activating and inhibitory KIR genes may influence the development of ocular toxoplasmosis.

  8. Lack of association between rs1800795 (-174 G/C polymorphism in the promoter region of interleukin-6 gene and susceptibility to type 2 diabetes in Isfahan population

    Directory of Open Access Journals (Sweden)

    Reza Ghavimi

    2016-01-01

    Conclusion: These results indicated that the rs1800795 SNP is not a susceptibility gene variant for the development of T2DM in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to T2DM.

  9. Evaluation of polymorphisms in pbp4 gene and genetic diversity in penicillin-resistant, ampicillin-susceptible Enterococcus faecalis from hospitals in different states in Brazil.

    Science.gov (United States)

    Infante, Victor Hugo Pacagnelli; Conceição, Natália; de Oliveira, Adriana Gonçalves; Darini, Ana Lúcia da Costa

    2016-04-01

    The aim of the present study was to verify whether penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) occurred in Brazil prior to the beginning of the 21st century, and to verify whether ampicillin susceptibility can predict susceptibility to other β-lactams in E. faecalis with this inconsistent phenotype. The presence of polymorphisms in the pbp4 gene and genetic diversity among the isolates were investigated. Of 21 PRASEF analyzed, 5 (23.8%) and 4 (19.0%) were imipenem and piperacillin resistant simultaneously by disk diffusion and broth dilution respectively, contradicting the current internationally accepted standards of susceptibility testing. Sequencing of pbp4 gene revealed an amino acid substitution (Asp-573→Glu) in all PRASEF isolates but not in the penicillin-susceptible, ampicillin-susceptible E. faecalis. Most PRASEF (90.5%) had related pulsed-field gel electrophoresis profiles, but were different from other PRASEF described to date. Results demonstrate that penicillin-resistant, ampicillin-susceptible phenotype was already a reality in the 1990s in E. faecalis isolates in different Brazilian states, and some of these isolates were also imipenem- and piperacillin-resistant; therefore, internationally accepted susceptibility criteria cannot be applied to these isolates. According to pbp4 gene sequencing, this study suggests that a specific amino acid substitution in pbp4 gene found in all PRASEF analyzed is associated with penicillin resistance.

  10. Risk of asthma in heterozygous carriers for cystic fibrosis

    DEFF Research Database (Denmark)

    Nielsen, Anne Orholm; Qayum, Sadaf; Bouchelouche, Pierre Nourdine;

    2016-01-01

    BACKGROUND: Patients with cystic fibrosis (CF) have a higher prevalence of asthma than the background population, however, it is unclear whether heterozygous CF carriers are susceptible to asthma. Given this, a meta-analysis is necessary to determine the veracity of the association of CF...

  11. Contribution of rs11465788 in IL23R gene to Crohn’s disease susceptibility and phenotype in Chinese population

    Indian Academy of Sciences (India)

    Chen Bin; Zeng Zhirong; Wu Xiaoqin; Chen Minhu; Li Mei; Gao Xiang; Chen Baili; Hu Pinjin

    2009-08-01

    Multiple studies have shown that IL23 cytokine plays an essential role in the development of autoimmune diseases by activating IL17-producing helper T (Th17) cells. Given that the susceptibility loci in IL23R for Crohn’s disease (CD) is present in Western population and not in Asian population; we screened the IL23R gene by DNA sequencing to identify susceptibility loci in a selected CD cohort and confirmed it in all our subjects (134 CD and 131 controls). A novel nonsynonymous SNP (p.Gly149Arg, c.445G>A) and 35 single nucleotide polymorphisms (SNPs) were identified. Among them, only rs11465788 was implicated in CD susceptibility (P = 4.9 × 10-4, OR = 0.30). Genotype–phenotypic interaction analysis showed that rs11465788 is associated with nonstricturing and nonpenetrating disease behaviour in CD patients ($P = 0.015$). Our results provide the evidence that rs11465788 may influence the susceptibility and clinical features of CD in Chinese population.

  12. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies

    Indian Academy of Sciences (India)

    N. Johns; B. H. Tan; M. Macmillan; T. S. Solheim; J. A. Ross; V. E. Baracos; S. Damaraju; K. C. H. Fearon

    2014-12-01

    Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986–2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and

  13. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies.

    Science.gov (United States)

    Johns, N; Tan, B H; MacMillan, M; Solheim, T S; Ross, J A; Baracos, V E; Damaraju, S; Fearon, K C H

    2014-12-01

    Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986-2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and

  14. Association between HLA class Ⅱ gene and susceptibility or resistance to chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Ye-Gui Jiang; Yu-Ming Wang; Tong-Hua Liu; Jun Liu

    2003-01-01

    AIM: To investigate the association between the polymorphism of HLA-DRB1, -DQA1 and -DQB1 alleles and viral hepatitis B.METHODS: HLA-DRB1, -DQA1 and -DQB1 alleles in 54patients with chronic hepatitis B, 30 patients with acute hepatitis B and 106 normal control subjects were analyzed by using the polymerase chain reaction/sequence specific primer (PCR/SSP) technique.RESULTS: The allele frequency of HLA-DRB1*0301 in the chronic hepatitis B group was markedly higher than that in the normal control group (17.31% VS 5.67%), there was a significant correlation between them (χ2= 12.3068,Pc=0.0074, RR=4.15). The allele frequency of HLADQA1*0501 in the chronic hepatitis B group was significantly higher than that in the normal control group (25.96% VS 13.68%), there was a significant correlation between them (χ2=9.2002, PC=0.0157, RR=2.87). The allele frequency of HLA-DQB1*0301 in the chronic hepatitis B group was notably higher than that in the normal control group (35.58%vs 18.87%), there was a significant correlation between them (χ2=15.5938, PC=0.0075, RR=4.07). The allele frequency of HLA-DRB1*1101/1104 in the chronic hepatitis B group was obviously lower than that in the normal control group (0.96% VS 13.33%), there was a significant correlation between them (χ2=11.9206, PC=0.0145, RR=18.55). The allele frequency of HLA-DQA1*0301 in the chronic hepatitis B group was remarkably lower than that in the normal control group (14.42% VS30%), there was a significant correlation between them (χ2=8.7396, Pc=0.0167, RR=0.35).CONCLUSION: HLA-DRB1*0301, HLA-DQA1*0501 and HLA-DQB1*0301 are closely related with susceptibility to chronic hepatitis B, and HLA-DRB1*1101/1104 and HLADQA1*0301 are closely related with resistance to chronic hepatitis B. These findings suggest that host HLA class Ⅱ gene is an important factor determining the outcome of HBV infection.

  15. The application of nonsense-mediated mRNA decay inhibition to the identification of breast cancer susceptibility genes

    Directory of Open Access Journals (Sweden)

    Johnson Julie K

    2012-06-01

    Full Text Available Abstract Background Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one-third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product 1. Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI, has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs from multiple-case, non- BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes. Methods We applied GINI to a total of 24 LCLs, established from breast-cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition. Results The expression profiling identified a total of eight candidate genes from these three families. One gene, PPARGC1A, was a candidate in two separate families. We performed semi-quantitative real-time reverse transcriptase PCR of all candidate genes but only PPARGC1A showed successful validation by being stabilised in individuals with breast cancer but not in many unaffected members of the same family. Sanger sequencing of all coding and splice site regions of PPARGC1A did not reveal any protein

  16. Asthma essentials

    Directory of Open Access Journals (Sweden)

    Timothy Greene

    2013-12-01

    Full Text Available Asthma is a chronic, reversible obstructive disease that when in exacerbation can present to the emergency department in a spectrum of severity. Prompt recognition of the potentially severely ill asthmatic requires a careful history and physical exam while considering alternative diagnoses for the presenting symptoms. Early administration of salbutamol and corticosteroids is indicated in almost all patients with other medications such as ipratropium and magnesium and supportive modalities like BiPAP reserved for sicker patients. The global impact of asthma is increasing, especially amongst children. While the benign clinical presentation is most common and mortality has decreased in recent decades due to improved recognition and care, the ubiquity of the condition and frequent lack of regular outpatient management contribute to the disease claiming 250,000 lives worldwide annually. The emergency physician must be prepared to assess and appropriately manage both the young child with a mild wheeze and the adult in respiratory failure.

  17. Transcriptomic analysis of colistin-susceptible and colistin-resistant isolates identifies genes associated with colistin resistance in Acinetobacter baumannii.

    Science.gov (United States)

    Park, Y K; Lee, J-Y; Ko, K S

    2015-08-01

    The emergence of colistin-resistant Acinetobacter baumannii is concerning, as colistin is often regarded as the last option for treating multidrug-resistant (MDR) A. baumannii infections. Using mRNA sequencing, we compared whole transcriptomes of colistin-susceptible and colistin-resistant A. baumannii strains, with the aim of identifying genes involved in colistin resistance. A clinical colistin-susceptible strain (06AC-179) and a colistin-resistant strain (07AC-052) were analysed in this study. In addition, a colistin-resistant mutant (06AC-179-R1) derived from 06AC-179 was also included in this study. High throughput mRNA sequencing was performed with an Illumina HiSeq TM 2000. In total, six genes were identified as associated with colistin resistance in A. baumannii. These six genes encode PmrAB two-component regulatory enzymes, PmrC (a lipid A phosphoethanolamine transferase), a glycosyltransferase, a poly-β-1,6-N-acetylglucosamine deacetylase, and a putative membrane protein. Matrix-assisted laser desorption/ionization time of flight mass spectrometry revealed that all three colistin-resistant strains used in this study had modified lipid A structure by addition of phosphoethanolamine. As genes found in our results are all associated with either lipopolysaccharide biosynthesis or electrostatic changes in the bacterial cell membrane, lipopolysaccharide modification might be one of the principal modes of acquisition of colistin resistance in some A. baumannii strains.

  18. Antimicrobial susceptibility and antibiotic resistance gene transfer analysis of foodborne, clinical, and environmental Listeria spp. isolates including Listeria monocytogenes.

    Science.gov (United States)

    Bertsch, David; Muelli, Mirjam; Weller, Monika; Uruty, Anaïs; Lacroix, Christophe; Meile, Leo

    2014-02-01

    The aims of this study were to assess antibiotic resistance pheno- and genotypes in foodborne, clinical, and environmental Listeria isolates, as well as to elucidate the horizontal gene transfer potential of detected resistance genes. A small fraction of in total 524 Listeria spp. isolates (3.1%) displayed acquired antibiotic resistance mainly to tetracycline (n = 11), but also to clindamycin (n = 4) and trimethoprim (n = 3), which was genotypically confirmed. In two cases, a tetracycline resistance phenotype was observed together with a trimethoprim resistance phenotype, namely in a clinical L. monocytogenes strain and in a foodborne L. innocua isolate. Depending on the applied guidelines, a differing number of isolates (n = 2 or n = 20) showed values for ampicillin that are on the edge between intermediate susceptibility and resistance. Transferability of the antibiotic resistance genes from the Listeria donors, elucidated in vitro by filter matings, was demonstrated for genes located on transposons of the Tn916 family and for an unknown clindamycin resistance determinant. Transfer rates of up to 10(-5) transconjugants per donor were obtained with a L. monocytogenes recipient and up to 10(-7) with an Enterococcus faecalis recipient, respectively. Although the prevalence of acquired antibiotic resistance in Listeria isolates from this study was rather low, the transferability of these resistances enables further spread in the future. This endorses the importance of surveillance of L. monocytogenes and other Listeria spp. in terms of antibiotic susceptibility.

  19. Antimicrobial susceptibility, virulence genes, and randomly amplified polymorphic DNA analysis of Staphylococcus aureus recovered from bovine mastitis in Ningxia, China.

    Science.gov (United States)

    Wang, Dong; Zhang, Limei; Zhou, Xuezhang; He, Yulong; Yong, Changfu; Shen, Mingliang; Szenci, Otto; Han, Bo

    2016-12-01

    Staphylococcus aureusis the leading pathogen involved inbovine mastitis, but knowledgeabout antimicrobial resistance, virulence factors, and genotypes of Staphylococcus aureus resulting in bovine mastitis in Ningxia, China, is limited. Therefore, antimicrobial susceptibility, virulence gene, and randomly amplified polymorphic DNA (RAPD) analyses of Staph. aureus were carried out. A total of 327 milk samples from cows with clinical and subclinical mastitis in 4 regions of Ningxia were used for the isolation and identification of pathogens according to phenotypic and molecular characteristics. Antimicrobial susceptibility against 22 antimicrobial agents was determined by disk diffusion. The presence of 8 virulence genes in Staph. aureus isolates was tested by PCR. Genotypes of isolates were investigated based on RAPD. Results showed that 35 isolates obtained from mastitis milk samples were identified as Staph. aureus. The isolates were resistant to sulfamethoxazole (100%), penicillin G (94.3%), ampicillin (94.3%), erythromycin (68.6%), azithromycin (68.6%), clindamycin (25.7%), amoxicillin (11.4%), and tetracycline (5.7%). All of the isolates contained one or more virulence genes with average (standard deviation) of 6.6±1.6. The most prevalent virulence genes were hlb (97.1%), followed by fnbpA, hla, coa (94.3% each), nuc (85.7%), fnbpB (80%), clfA (77.1%), and tsst-1 (40%). Nine different gene patterns were found and 3 of them were the dominant gene combinations (77.1%). Staphylococcus aureus isolates (n=35) were divided into 6 genotypes by RAPD tying, the genotypes III and VI were the most prevalent genotypes. There was greatvariation in genotypes of Staph. aureus isolates, not only among different farms, but also within the same herd in Ningxia province. The study showed a high incidence of Staph. aureus with genomic variation of resistance genes, which is matter of great concern in public and animal health in Ningxia province of China.

  20. The relationship between C20orf54 gene rs3746804 position single nucleotide polymorphism and susceptibility to esophageal squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    纪爱芳

    2013-01-01

    Objective To explore the association of C20orf54 gene rs3746804 position single nucleotide polymorphism and susceptibility to esophageal squamous cell carcinoma(ESCC). Methods Purification of genomic DNA from whole blood was used the

  1. The calcitonin receptor gene is a candidate for regulation of susceptibility to herpes simplex type 1 neuronal infection leading to encephalitis in rat.

    Directory of Open Access Journals (Sweden)

    Nada Abdelmagid

    Full Text Available Herpes simplex encephalitis (HSE is a fatal infection of the central nervous system (CNS predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL, Hse1, on rat chromosome 4 (confidence interval 24.3-31 Mb; LOD score 29.5 governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.

  2. STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis.

    Science.gov (United States)

    Joshita, Satoru; Umemura, Takeji; Nakamura, Minoru; Katsuyama, Yoshihiko; Shibata, Soichiro; Kimura, Takefumi; Morita, Susumu; Komatsu, Michiharu; Matsumoto, Akihiro; Yoshizawa, Kaname; Ishibashi, Hiromi; Tanaka, Eiji; Ota, Masao

    2014-01-01

    Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC) susceptibility. Although several reports have demonstrated that the interleukin (IL) 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between IL12A, IL12RB, and signal transducer and activator of transcription 4 (STAT4) genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs) were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA) status, and anti-mitochondrial antibody (AMA) status. We detected significant associations with PBC susceptibility for several STAT4 SNPs (rs10168266; P = 9.4 × 10(-3), rs11889341; P = 1.2 × 10(-3), rs7574865; P = 4.0 × 10(-4), rs8179673; P = 2.0 × 10(-4), and rs10181656; P = 4.2 × 10(-5)). Three risk alleles (rs7574865; P = 0.040, rs8179673; P = 0.032, and rs10181656; P = 0.031) were associated with ANA status, but not with AMA positivity. Our findings confirm that STAT4 is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.

  3. DNA polymorphism at the BoLA-DRB3 gene of cattle in relation to resistance and susceptibility to leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Sulimova, G.E.; Udina, I.G.; Shaikhaev, G.O. [Vavilov Institute of General Genetics, Moscow (Russian Federation)] [and others

    1995-09-01

    Polymorphism of exon 2 of the BoLA-DRB3 gene was investigated by the PCR-RFLP method in a sample of healthy and leukemia-afflicted Black Pied cattle. Allele variety was studied and allele frequencies were determined in a total sample and in the two groups. Alleles mediating resistance (BoLA-DRB3.2{sup *}11, {sup *}23, and {sup *}28) and susceptibility to leukemia (DRB3.2{sup *}22, {sup *}24, {sup *}16, and {sup *}8) were revealed in Black Pied cattle. The dominant type of inheritance of the disease resistance was confirmed. On the basis of original and published data obtained earlier for Holstein-Friesian cattle, a conclusion was made about the universal character of the spectrum of BoLA-DRB3 alleles providing resistance and susceptibility to leukemia. 18 refs., 1 fig., 3 tabs.

  4. [DNA polymorphism of the BoLA-DRB3 gene in cattle in connection with resistance and susceptibility to leukemia].

    Science.gov (United States)

    Sulimova, G E; Udina, I G; Shaĭkhaev, G O; Zakharov, I A

    1995-09-01

    Polymorphism of exon 2 of the BoLA-DRB3 gene was investigated by the PCR-RFLP method in a sample of healthy and leukemia-afflicted Black Pied cattle. Allele variety was studied and allele frequencies were determined in a total sample and in the two groups. Alleles mediating resistance (BoLA-DRB3.2*11, *23, and *28) and susceptibility to leukemia (DRB3.2*22, *24, *16, and *8) were revealed in Black Pied cattle. The dominant type of inheritance of the disease resistance was confirmed. On the basis of original and published data obtained earlier for Holstein-Friesian cattle, a conclusion was made about the universal character of the spectrum of BoLA-DRB3 alleles providing resistance and susceptibility to leukemia.

  5. Class I (H-2Kb) gene transfection reduces susceptibility of YAC-1 lymphoma targets to natural killer cells.

    Science.gov (United States)

    Carlow, D A; Payne, U; Hozumi, N; Roder, J C; Czitrom, A A

    1990-04-01

    A "hybrid gene" (MTKb) comprised of the human metallothionein IIA promoter ligated to the genomic sequence of the major histocompatibility complex class I (H-2Kb) gene was subcloned into the expression vector pSV2neo and transfected into the natural killer (NK) cell-sensitive YAC-1 lymphoma. The Kb gene product was readily detectable on the cell surface of G418-resistant transfectants using both Kb-specific monoclonal antibodies and H-2b-specific cytolytic T cells. Unlike control pSV2neo transfectants, MTKb-pSV2neo transfectants were relatively resistant to lysis by NK cells from H-2a, H-2b, H-2k or H-2 (a x b)F1 haplotype mice. These data strongly suggest that the effects of MHC expression on susceptibility to NK cells can be mediated by a single and well-defined class I molecule, Kb.

  6. The Control Level of Bronchial Asthma in Dependence of Genotype by BCL1 Polymorphism of Glucocorticoids Receptor Gene and Body Mass Index

    Directory of Open Access Journals (Sweden)

    Vladyslava V. Kmyta

    2014-09-01

    Full Text Available The frequency of allelic genotypes by BclI polymorphism glucocorticoids receptor gene (GR had been studied in dependence of the control level of bronchial asthma (BA and body mass index (BMI, and also- connection between those indicators. 188 patient with BA and 95 almost healthy humans were investigated. Determination of single nucleotide BclI polymorphism GR gene performed by the method of polymerase chain reaction with following analyze of the length of restriction fragments. Our studies demonstrated connection between BA control, BclI polymorphism GR gene and BMI. Proved, that distribution C/C, C/G and G/G genotypes by BclI polymorphism in patients with BA showed reliable difference between patients with different BMI and connection G/G genotype with obesity. The reliable difference in distributing of genotype in dependence of BA control level has been proved: with controlled BA reliably often met C/C genotype, without control – G/G genotype. Therefore, proved, that frequency G/G genotype by BclI polymorphism GR gene in patients with BA with obesity and absence of control for the flowing of disease is reliably higher, that confirmed the role of this genotype, likewise, in obesity occurrence, so in absence of the control of disease.

  7. Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

    DEFF Research Database (Denmark)

    Kamiyama, Masumi; Kobayashi, Masaaki; Araki, Shin-ichi

    2007-01-01

    Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UTR...... in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07-3.42). These results suggest that the NCALD gene is a likely candidate...... for conferring susceptibility to diabetic nephropathy....

  8. Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans

    OpenAIRE

    Walsh, Kyle M.; Christopher I Amos; Wenzlaff, Angela S.; Gorlov, Ivan P; Sison, Jennette D.; Wu, Xifeng; Spitz, Margaret R; Hansen, Helen M.; Lu, Emily Y.; Wei, Chongjuan; Zhang, Huifeng; Chen, Wei; Lloyd, Stacy M.; Frazier, Marsha L.; Paige M Bracci

    2012-01-01

    Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-America...

  9. Occupational Medicine Model and Asthma Military Recruitment.

    Science.gov (United States)

    Brooks, Stuart M

    2015-11-01

    Medical evidence hints that asymptomatic recruits with a history of childhood asthma, quiescent since their 13th birthday, are still at risk for adverse changes in their clinical status following unfavorable environmental exposures during military deployment or combat. Asthmatic persons, claiming none or few symptoms, may still manifest airflow obstruction and display biomarkers of airway inflammation even when they are relatively asymptomatic and experience few if any respiratory complaints. The occupational medicine model offers a credible foundation for acknowledging the importance of personal susceptibility in the pathogenesis of military-associated asthma. It is appropriate to re-explore the current military standard for recruits with asymptomatic childhood asthma (≥12 months) not prescribed antiasthma medications. Raising the acceptance age for these recruits may be a consideration. Unfortunately, there is no effectual screening test that recognizes such susceptible soldiers at risk for future asthma attacks. Nevertheless, there is general support for evidence-based, scientifically valid medical screening that judges fitness for military service. Screening tests comprising asthma biomarkers and genetic indices may better verify vulnerable soldiers destined to suffer future asthma reactivation.

  10. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants

    Science.gov (United States)

    The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. Hessian fly larvae manipulate susceptible plants extensively, but are unable to manipulate resistant plants and thus die in them. The mechanisms for Hessian fly l...

  11. ENHANCED DISEASE SUSCEPTIBILITY 1 and SALICYLIC ACID act redundantly to regulate resistance gene-mediated signaling

    Science.gov (United States)

    Resistance (R) protein–associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA) and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1), non–race-specific disease resistance 1 (NDR1), ...

  12. Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Gascoyne Randy D

    2009-11-01

    Full Text Available Abstract Background Translocations are hallmarks of non-Hodgkin lymphoma (NHL genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. Methods We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. Results 114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. Conclusion These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role.

  13. STUDY OF THE DELETION MUTATION OF GLUTATHIONE S TRANSFERASE M1 GENE AND ITS ROLE IN SUSCEPTIBILITY TO HEPATOCELLULAR CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objection: To investigate the glutathione S transferase M1 (GSTM1) gene inherent deletion and its relation to prevalence of hepatocellular carcinoma (HCC) in Guangxi, China. Methods: The GSTM1 gene polymorphism of 120 HCC patients and 100 healthy subjects both from the same high aflatoxin B1 (AFB1) contaminated area were detected using PCR technique with special primers. Another 40 patients from AFB1 low risk area were also tested. Results: In HCC high risk area, it was found that the frequencies of GSTM1 null genotype in HCC patients and healthy subjects were 59% and 51% respectively, with no significant difference. However, the frequency of GSTM1-null genotype in control group from AFB1 low risk area was lower than those from high risk area (P<0.01). Conclusion: Populations in this HCC endemic region show a higher rate of GSTM1-null genotype, which may be partially responsible for the susceptibility to AFB1 induced HCC. But the detoxification effect of GSTM1 alone is not sufficient to resist the genetic toxicity of AFB1, especially in those people who expose to excess AFB1. The GSTM1 gene deletion would not be suitable as an independent predictor of susceptibility to HCC.

  14. Polymorphism of CYPIA1 and GSTM1 genes associated with susceptibility of gastric cancer in Shandong Province of China

    Institute of Scientific and Technical Information of China (English)

    Hao Li; Xue-Liang Chen; Hui-Qing Li

    2005-01-01

    AIM: To explore whether polymorphisms of the CYPIA1 and GSTM1 genes are associated with susceptibility of stomach cancer.METHODS: A total of 102 stomach cancer cases and 62 healthy persons were diagnosed by pathology in 1998-2000 in the Qilu Hospital of Shandong University. Gene polymorphisms were detected by the PCR using sequence-specific primers. Data analysis of the case-control study was carried out using the unconditional logistic method.RESULTS: After adjustment for age, sex, educational levels, and occupation, the risk factors for stomach cancer were shown to be smoking, Helicobacter pylori(H pylori),and presence of the CYPIM G/G and GSTM1 O/O genotypes.Interaction was observed between the combined genotypes of either CYPIA1 G/G and GSTM1 O/O or H pylori infection,or GSTM1 O/O and H pylori infection or smoking.CONCLUSION: Polymorphisms of the CYPIA1 and GSTM1 genes, H pylori infection and smoking are related to susceptibility to stomach cancer.

  15. Identification of a haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria

    Directory of Open Access Journals (Sweden)

    Tsuchiya Naoyuki

    2009-10-01

    Full Text Available Abstract Background It has been previously demonstrated that a single nucleotide polymorphism (SNP in the IL13 promoter region, IL13 -1055T>C (rs1800925, was associated with susceptibility to severe malaria in Thais. In the present study, fine association mapping for a cytokine gene cluster including IL4, IL5, and IL13 on chromosome 5q31 was conducted using the same malaria subjects to refine the region containing a primary variant or a haplotype susceptible to severe malaria. Methods A total of 82 SNPs spanning 522 kb of the 5q31 region were analysed in 368 patients with Plasmodium falciparum malaria (203 mild malaria and 165 severe malaria patients. Results Only rs1881457 located in the promoter region of IL13, which is in linkage disequilibrium with rs1800925 (r2 = 0.73, showed a significant association with severe malaria after adjusting for multiple testing (P = 0.046 by permutation test. This SNP was in a haplotype block spanning 97 kb (from rs2069812 to rs2240032. The detected haplotype block contained the RAD50 gene and the promoter of IL13, but not the other genes. Conclusion A haplotype block in which a primary polymorphism associated with severe malaria is likely to be encoded was identified in Thai malaria patients.

  16. The Association between NOS3 Gene Polymorphisms and Hypoxic-Ischemic Encephalopathy Susceptibility and Symptoms in Chinese Han Population

    Directory of Open Access Journals (Sweden)

    Yongqin Wu

    2016-01-01

    Full Text Available Endothelial NOS (NOS3 has a potential role in the prevention of neuronal injury in hypoxic-ischemic encephalopathy (HIE. Thus, we aimed to explore the association between NOS3 gene polymorphisms and HIE susceptibility and symptoms in a Chinese Han population. Three single nucleotide polymorphisms (SNPs in the NOS3 gene, rs1800783, rs1800779, and rs2070744, were detected in 226 children with HIE and 212 healthy children in a Chinese Han population. Apgar scores and magnetic resonance image scans were used to estimate the symptoms and brain damage. The association analyses were conducted by using SNPStats and SPSS 18.0 software. The genotype and allele distributions of rs1800779 and rs1799983 displayed no significant differences between the patients and the controls, while the rs2070744 allele distribution was significantly different (corrected P=0.009. For clinical characteristics, the rs2070744 genotype distribution was significantly different in patients with different Apgar scores (≤5, TT/TC/CC = 6/7/5; 6~7, TT/TC/CC = 17/0/0; 8~9, TT/TC/CC = 6/2/0; 10, TT/TC/CC = 7/1/0; corrected P=0.006 in the 1001 to 1449 g birth weight subgroup. The haplotype test did not show any associations with the risk and clinical characteristics of HIE. The results suggest that NOS3 gene SNP rs2070744 was significantly associated with HIE susceptibility and symptom expression in Chinese Han population.

  17. Association of TCF7L2 gene polymorphisms with susceptibility to type 2 diabetes mellitus in a Chinese Hui population.

    Science.gov (United States)

    Yang, Y; Xu, J R; Wang, Y J; Liu, X M

    2015-08-21

    Diabetes is one of costly chronic diseases. Previous studies across several ethnicities have shown that polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene were strongly associated with susceptibility to type 2 diabetes (T2DM). In the present study, the association between the TCF7L2 gene and the susceptibility to T2DM in a Chinese Hui population was interrogated. Polymerase chain reaction (PCR)- restriction fragment length polymorphism analysis and allelic specific PCR were employed for examining the TCF7L2 gene rs12255372 (G>T) and rs290487 (C>T), and rs7901695 (T>C) polymorphisms, respectively, in 109 healthy individuals and 111 subjects with T2DM who were of Chinese Hui descent and lived in the Ningxia Hui Autonomous Region of China. The results showed that the genotypic frequency of rs290487 and the allelic frequency distributions of the rs7901695 and rs290487 loci were not significantly different between patients and controls in this population. However, both the genotypic and the allelic frequencies at rs12255372 exhibited statistical differences between the patients with T2DM and the unaffected cohort (P 2255372 locus in the patients was higher than that in healthy individuals (OR = 1.198, 95%CI = 1.097-1.307). These findings suggest that the TCF7L2 rs12255372 (G>T) polymorphism might be one of the most important genetic factors associated with T2DM susceptibility, and that individuals in the Chinese Hui population who carry a G allele at this locus might be at risk to develop T2DM.

  18. A meta-analysis of adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility

    Directory of Open Access Journals (Sweden)

    Xiuju Chen

    2016-01-01

    Full Text Available Several studies have investigated the correlation between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk. However, the results were not conclusive with each other. Therefore, to overcome this obstacle, we performed this meta-analysis to further explicate the adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility. Case-control or cohort studies focused on adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk were electronic searched in the databases of Medline, Pubmed, Cochrane library, Excerpta Medica database(EMBASE and China National Knowledge Infrastructure (CNKI. All the potentially relevant studies were included in this meta-analysis. The association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke was expressed by odds ratio with its confidence interval. Publication bias has been assessed by begg’s funnel plot. All the analyses have been performed by Revman 5.1 statistical software. Finally, a total of six studies with 1,345 cases and 1,421 controls were included in this meta-analysis. Our results demonstrated that there was a significant association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk (p<0.05. People with G single nucleotide of adiponectin gene have the increased risk of developing ischemic stroke compared to T single nucleotide.

  19. Association of Matrix Metalloproteinase-9 and p53 Gene Polymorphisms with Genetic Susceptibility to No-small-cell Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    ZHAO Ying-hao; MA Tong-hui; ZHENG Yong-chen; ZHANG Kun; YANG Jing-bo; YANG Long-fei; YANG Zhi-guang; SHAO Guo-guang

    2011-01-01

    Matrix metalloproteinase-9(MMP-9) and p53 genes play an essential role in the multi-step process of tumorigenesis in lung cancer. Single nucleotide polymorphisms(SNPs) of MMP-9 and p53 genes are associated with the risk and progression of many cancers. In this study, we evaluated the association of the R279Q polymo rphism of MMP-9 or the A1/A2 polymorphism of p53 gene with the risk of no-small-cell lung cancer(NSCLC) in Hah population of Northeast China. We examined the frequency of SNPs in the two kinds of genes of 50 patients with NSCLC and 50 cancer-free controls frequency-matched by age and sex. Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) technique was used to determine the genotypes. The results indicate that the 279RR genotype in MMP-9 gene and the A1/A2 genotype in p53 gene show a significantly increased risk of NSCLC. Therefore,the MMP-9 279RR and p53 A1/A2 genotypes may be used as markers for susceptibility to NSCLC in Han population of Northeast China.

  20. Head and neck squamous cell carcinoma susceptibility genes in the HLA region

    NARCIS (Netherlands)

    Reinders, Judith

    2006-01-01

    The Human Leukocyte Antigen (HLA) region on the short arm of chromosome 6 includes the classical HLA genes and in addition HLA-related and non-HLA related genes. The majority of the genes located in this region are directly or indirectly involved in the immune response. The polymorphic HLA molecules

  1. A comparison in association and linkage genome-wide scans for alcoholism susceptibility genes using single-nucleotide polymorphisms.

    Science.gov (United States)

    Chiu, Yen-Feng; Liu, Su-Yun; Tsai, Ya-Yu

    2005-12-30

    We conducted genome-wide linkage scans using both microsatellite and single-nucleotide polymorphism (SNP) markers. Regions showing the strongest evidence of linkage to alcoholism susceptibility genes were identified. Haplotype analyses using a sliding-window approach for SNPs in these regions were performed. In addition, we performed a genome-wide association scan using SNP data. SNPs in these regions with evidence of association (P alcoholism (the most significant SNP had a p-value of 0.030) as those identified from association genomic screening (the most significant SNP had a p-value of 2.0 x 10(-8)).

  2. Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

    Directory of Open Access Journals (Sweden)

    Maria José Franco Brochado

    2016-02-01

    Full Text Available Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1 is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GTn, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively, and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GTn polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66. Patients carrying the 274T allele (p = 0.04; OR = 1.49 and TT homozygosis (p = 0.02; OR = 2.46, such as the 469+14C allele (p = 0.03; OR = 1.53 of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GTn polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.

  3. Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample.

    Science.gov (United States)

    Brochado, Maria José Franco; Gatti, Maria Fernanda Chociay; Zago, Marco Antônio; Roselino, Ana Maria

    2016-02-01

    Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.

  4. Asthma and obesity

    DEFF Research Database (Denmark)

    Juel, Caroline Trunk-Black; Ali, Zarqa; Nilas, Lisbeth

    2012-01-01

    Obesity is a major health problem, and obesity is associated with a high incidence of asthma and poor asthma control. The aim of the present paper is to systematically review the current knowledge of the effect on overall asthma control of weight reduction in overweight and obese adults with asthma....

  5. Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2

    Directory of Open Access Journals (Sweden)

    Sinilnikova Olga

    2011-05-01

    Full Text Available Abstract Background The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified. Methods We implemented an assay based on high-resolution melting (HRM curve analysis and developed an analysis tool for DAE assessment. Results We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs. Conclusions Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.

  6. SnTox3 acts in effector triggered susceptibility to induce disease on wheat carrying the Snn3 gene.

    Directory of Open Access Journals (Sweden)

    Zhaohui Liu

    2009-09-01

    Full Text Available The necrotrophic fungus Stagonospora nodorum produces multiple proteinaceous host-selective toxins (HSTs which act in effector triggered susceptibility. Here, we report the molecular cloning and functional characterization of the SnTox3-encoding gene, designated SnTox3, as well as the initial characterization of the SnTox3 protein. SnTox3 is a 693 bp intron-free gene with little obvious homology to other known genes. The predicted immature SnTox3 protein is 25.8 kDa in size. A 20 amino acid signal sequence as well as a possible pro sequence are predicted. Six cysteine residues are predicted to form disulfide bonds and are shown to be important for SnTox3 activity. Using heterologous expression in Pichia pastoris and transformation into an avirulent S. nodorum isolate, we show that SnTox3 encodes the SnTox3 protein and that SnTox3 interacts with the wheat susceptibility gene Snn3. In addition, the avirulent S. nodorum isolate transformed with SnTox3 was virulent on host lines expressing the Snn3 gene. SnTox3-disrupted mutants were deficient in the production of SnTox3 and avirulent on the Snn3 differential wheat line BG220. An analysis of genetic diversity revealed that SnTox3 is present in 60.1% of a worldwide collection of 923 isolates and occurs as eleven nucleotide haplotypes resulting in four amino acid haplotypes. The cloning of SnTox3 provides a fundamental tool for the investigation of the S. nodorum-wheat interaction, as well as vital information for the general characterization of necrotroph-plant interactions.

  7. Polymorphisms in the surfactant protein a gene are associated with the susceptibility to recurrent urinary tract infection in chinese women.

    Science.gov (United States)

    Liu, Jiao; Hu, Fengqi; Liang, Wei; Wang, Guirong; Singhal, Pravin C; Ding, Guohua

    2010-05-01

    Some risk factors for susceptibility to recurrent urinary tract infection (r-UTI) are well known, but the genetic role in acquiring the disease is poorly understood. Surfactant protein A and D (SP-A and SP-D) play an important role in modulation of lung inflammatory processes. The SP-A1 and SP-A2 genes encoding SP-A and the SP-D gene are highly polymorphic, and some of polymorphisms are associated with several infective diseases, including pyelonephritis. In the present study, we investigated whether some of these polymorphisms are associated with the risk of r-UTI in Chinese population. Genomic DNA was extracted from blood samples of 32 female patients with r-UTI and 30 age-matched, unrelated healthy female subjects. Genotyping of gene polymorphisms was analyzed by PCR. Among 11 single nucleotide polymorphisms (SNPs) (five of SP-A1, four of SP-A2 and two of SP-D) observed in the enrolled subjects, Ala19Val of SP-A1 and Lys223Gln of SP-A2 were associated with susceptibility to r-UTI. The frequencies of 19Ala allele of SP-A1 gene (p = 0.038) and 223Gln allele of SP-A2 gene (p = 0.012) in the patients were significantly higher than those in healthy subjects. The serum SP-A and SP-D levels were increased and the urine SP-A and SP-D levels were decreased in r-UTI patients compared with control subjects (p UTI patients with 19Ala/Ala or 223Gln/Gln genotype were associated with high serum and low urine SP-A levels (p UTI.

  8. Mosaic-like structure of penicillin-binding protein 2 Gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime.

    Science.gov (United States)

    Ameyama, Satoshi; Onodera, Shoichi; Takahata, Masahiro; Minami, Shinzaburo; Maki, Nobuko; Endo, Katsuhisa; Goto, Hirokazu; Suzuki, Hiroo; Oishi, Yukihiko

    2002-12-01

    Neisseria gonorrhoeae strains with reduced susceptibility to cefixime (MICs, 0.25 to 0.5 micro g/ml) were isolated from male urethritis patients in Tokyo, Japan, in 2000 and 2001. The resistance to cephems including cefixime and penicillin was transferred to a susceptible recipient, N. gonorrhoeae ATCC 19424, by transformation of the penicillin-binding protein 2 gene (penA) that had been amplified by PCR from a strain with reduced susceptibility to cefixime (MIC, 0.5 micro g/ml). The sequences of penA in the strains with reduced susceptibilities to cefixime were different from those of other susceptible isolates and did not correspond to the reported N. gonorrhoeae penA gene sequences. Some regions in the transpeptidase-encoding domain in this penA gene were similar to those in the penA genes of Neisseria perflava (N. sicca), Neisseria cinerea, Neisseria flavescens, and Neisseria meningitidis. These results showed that a mosaic-like structure in the penA gene conferred reductions in the levels of susceptibility of N. gonorrhoeae to cephems and penicillin in a manner similar to that found for N. meningitidis and Streptococcus pneumoniae.

  9. Differential susceptibility in spillover between interparental conflict and maternal parenting practices: evidence for OXTR and 5-HTT genes.

    Science.gov (United States)

    Sturge-Apple, Melissa L; Cicchetti, Dante; Davies, Patrick T; Suor, Jennifer H

    2012-06-01

    Guided by the affective spillover hypothesis and the differential susceptibility to environmental influence frameworks, the present study examined how associations between interparental conflict and mothers' parenting practices were moderated by serotonin transporter (5-HTT) and oxytocin receptor (OXTR) genes. A sample of 201 mothers and their 2-year old child participated in a laboratory-based research assessment. Results supported differential susceptibility hypotheses within spillover frameworks. With respect to OXTR rs53576, mothers with the GG genotype showed greater differential maternal sensitivity across varying levels of interparental conflict. Mothers with one or two copies of the 5-HTTLPR S allele demonstrated differential susceptibility for both sensitive and harsh/punitive caregiving behaviors. Finally, analyses examined whether maternal depressive symptoms and emotional closeness to their child mediated the moderating effects. Findings suggest that maternal emotional closeness with their child indirectly linked OXTR with maternal sensitivity. The results highlight how molecular genetics may explain heterogeneity in spillover models with differential implications for specific parenting behaviors. Implications for clinicians and therapists working with maritally distressed parents are discussed.

  10. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

    Science.gov (United States)

    Grünewald, Thomas G. P.; Bernard, Virginie; Gilardi-Hebenstreit, Pascale; Raynal, Virginie; Surdez, Didier; Aynaud, Marie-Ming; Mirabeau, Olivier; Cidre-Aranaz, Florencia; Tirode, Franck; Zaidi, Sakina; Perot, Gaëlle; Jonker, Anneliene H.; Lucchesi, Carlo; Le Deley, Marie-Cécile; Oberlin, Odile; Marec-Bérard, Perrine; Véron, Amélie S.; Reynaud, Stephanie; Lapouble, Eve; Boeva, Valentina; Frio, Thomas Rio; Alonso, Javier; Bhatia, Smita; Pierron, Gaëlle; Cancel-Tassin, Geraldine; Cussenot, Olivier; Cox, David G.; Morton, Lindsay M.; Machiela, Mitchell J.; Chanock, Stephen J.; Charnay, Patrick; Delattre, Olivier

    2015-01-01

    Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs1–3. A recent genome-wide association study4 identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls revealed 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1–dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis. PMID:26214589

  11. Susceptibility genes of Graves' disease%Graves病易感基因研究进展

    Institute of Scientific and Technical Information of China (English)

    吴岚; 韩刚; 葛家璞

    2008-01-01

    Graves'disease(GD)is an organ-specific autoimmune disorder,which is commonly speculated as the result of interaction between heredity and environment.In the last years,significant progress has been made in understanding of the genetic contribution to the etiology of GD,including the human leukocyte antigen(HLA)gene,cytotoxic T lymphocyte antigen-4(CTLA-4)gene and thyroid-stimulating hormone receptor(TSHR)gene.This review focuses on immune-regulatory genes(HLA gene,CTLA-4 gene,CD40 gene,interleukin genes,vitamin D receptor gene,TAP2 gene,CBLB gene)and thyroid-specific genes(TSHR gene and thyroglobulin gene),as well as the recent advances of them.%Graves病(GD)是一种器官特异性自身免疫性疾病,目前一般认为是遗传和环境因素相互作用的结果.多年来在GD易感基因的研究上已经取得了很多进展,如人白细胞抗原(HLA)基因、细胞毒性T淋巴细胞抗原-4(CTLA-4)基因以及促甲状腺激素受体(TSHR)基因等.本文对免疫调节基因(如HLA基因、CTLA-4基因、CD40基因、白细胞介素基因、维生素D受体基因、抗原肽运载体基因、CBLB基因等)和甲状腺特异性基因(TSHR基因和甲状腺球蛋白基因)的研究现状进行综述.

  12. Meta-analysis of associations of IL1 receptor antagonist and estrogen receptor gene polymorphisms with systemic lupus erythematosus susceptibility.

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    Li Cai

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disease that affects a number of different organs and tissues. Interleukin-1 (IL1 and estrogen are considered potential elements in the pathology of SLE. Recently, the variable number of tandem repeats (VNTR polymorphism in the IL1 receptor antagonist gene (IL1-RN and PvuII (rs2234693 and XbaI (rs9340799 polymorphisms in the estrogen receptor 1 gene (ESR1 have been associated with a predisposition to SLE. However, the evidence for these associations is inconclusive. We therefore conducted a meta-analysis to validate the roles of these polymorphisms in SLE susceptibility. We searched four databases and identified a total of 17 eligible articles comprising 24 studies. The Newcastle-Ottawa quality assessment scale was used to assess the qualities of the selected studies. We assessed the strengths of the associations using odds ratios (ORs with 95% confidence intervals (95% CIs. Regarding the IL-1RN VNTR, the 2 allele significantly increased SLE susceptibility (2 vs. L: OR = 1.34, 95% CI = 1.03-1.73, P = 0.03. The ESR1 PvuII CC/CT genotype was also associated with SLE susceptibility (CC/CT vs. TT: OR = 1.25, 95% CI = 1.06-1.47, P = 0.01, and the difference was especially pronounced among Asians (CC/CT vs. TT: OR = 1.33, 95% CI = 1.04-1.69, P = 0.02. No significant association between the ESR1 XbaI polymorphism and SLE susceptibility was observed in the overall analysis. However, a marginally significant association between the GG/GA genotype was found in individuals of Asian descent (GG/GA vs. AA: OR = 1.30, 95% CI = 1.01-1.67, P = 0.04. These results indicate that the IL1-RN VNTR 2 allele, ESR1 PvuII CC/CT genotype and ESR1 XbaI GG/GA genotype may increase SLE susceptibility, especially in Asian individuals.

  13. Vitamin D Receptor Gene, Matrix Metalloproteinase 3 Polymorphisms and the Risk of Intervertebral Disc Degeneration Susceptibility: Meta-Analysis

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    Huang, Yongjing; Zhao, Shujie; Xu, Nanwei

    2016-01-01

    Several studies have evaluated the association between vitamin D receptor, matrix metalloproteinase 3 (MMP-3) polymorphisms and the risk of intervertebral disc degeneration susceptibility. The findings were inconsistent. This meta-analysis aimed to systematically assess the association between vitamin D receptor, MMP-3 polymorphisms and the risk of intervertebral disc degeneration susceptibility. A search of various databases was done covering all papers published until December 31th, 2014. Eight, 4, 3 studies were finally included that addressed the risk of intervertebral disc degeneration susceptibility and vitamin D receptor FokI (rs2228570), ApaI (rs7975232), and MMP-3 (rs731236) polymorphisms, respectively. FokI (f vs. F: summary odds ratio [OR], 1.13; 95% confidence interval [CI], 0.76–1.69; ff vs. FF: OR, 1.02; 95% CI, 0.59–1.77; ff vs. Ff/FF: OR, 1.05; 95% CI, 0.70–1.58), ApaI (a vs. A: OR, 0.73; 95% CI, 0.45–1.19; aa vs. AA: OR, 0.53; 95% CI, 0.22–1.25 p=0.14; aa vs. AA/Aa: OR, 0.69; 95% CI, 0.53–0.89) in the vitamin D receptor gene and MMP3 polymorphisms (5A vs. 6A: OR, 1.92; 95% CI, 0.77–4.80; 5A5A vs. 6A6A: OR, 2.17; 95% CI, 0.75–6.24; 5A5A vs. 5A6A/6A6A: OR, 1.58; 95% CI, 0.72–3.44) were not obviously associated with risk of intervertebral disc degeneration susceptibility. FokI, ApaI polymorphisms in the vitamin D receptor gene and MMP-3 polymorphism are not obvious risk factors for intervertebral disc degeneration susceptibility.

  14. Interferon-inducible Ifi200-family genes as modifiers of lupus susceptibility

    OpenAIRE

    2012-01-01

    Both genetic and environmental factors contribute to the development and progression of systemic lupus erythematosus (SLE), a complex autoimmune disease. The disease exhibits a strong gender bias and develops predominantly in females. Additionally, most SLE patients exhibit increased serum levels of interferon-α (IFN-α) and the “IFN signature”. Studies using the mouse models of lupus have identified several lupus susceptibility loci, including the New Zealand Black (NZB)-derived autoimmunity ...

  15. Occupational asthma in Japan

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    Dobashi, Kunio

    2012-01-01

    Research into occupational asthma (OA) in Japan has been led by the Japanese Society of Occupational and Environmental Allergy. The first report about allergic OA identified konjac asthma. After that, many kinds of OA have been reported. Cases of some types of OA, such as konjac asthma and sea squirt asthma, have been dramatically reduced by the efforts of medical personnel. Recently, with the development of new technologies, chemical antigen-induced asthma has increased in Japan. Due to adva...

  16. Evaluation of efflux pump gene expression among drug susceptible and drug resistant strains of Mycobacterium tuberculosis from Iran.

    Science.gov (United States)

    Kardan Yamchi, Jalil; Haeili, Mehri; Gizaw Feyisa, Seifu; Kazemian, Hossein; Hashemi Shahraki, Abdolrazagh; Zahednamazi, Fatemeh; Imani Fooladi, Abbas Ali; Feizabadi, Mohammad Mehdi

    2015-12-01

    Absence of mutations within the genes encoding drug targets in some phenotypically drug resistant strains of Mycobacterium tuberculosis suggests possible involvement of alternative mechanisms such as over-expression of efflux pumps. We investigated the expression level of Rv1410c, Rv2459, Rv1218c and Rv1273c efflux pumps gene by real-time quantitative reverse transcription PCR (qRT-PCR) in 31 clinical isolates of M. tuberculosis. Susceptibility to first-line drugs was performed using the proportion method. Twenty one isolates were characterized with drug resistance (DR), and among them 12 showed a significantly elevated level of expression (>4 fold) for at least one of the studied genes encoding for efflux pumps. Point mutations in the katG (codons 315 or 335) and rpoB (codons 456 and 441) genes were found in 42.85% and 66.6% of drug resistant isolates, respectively. Only one isolate showed mutation at position -15 of the inhA promoter region. Among the 7 isolates (33.33%) which had no mutation in the studied regions of drug target genes, 5 isolates showed over-expression for efflux pumps. Our results demonstrated that over-expression of efflux pumps can contribute to drug resistance in M. tuberculosis.

  17. Transcriptional analysis of rat photoreceptor cells reveals daily regulation of genes important for visual signaling and light damage susceptibility.

    Science.gov (United States)

    Kunst, Stefanie; Wolloscheck, Tanja; Hölter, Philip; Wengert, Alexander; Grether, Markus; Sticht, Carsten; Weyer, Veronika; Wolfrum, Uwe; Spessert, Rainer

    2013-03-01

    Photoreceptor cells face the challenge of adjusting their function and, possibly, their susceptibility to light damage to the marked daily changes in ambient light intensity. To achieve a better understanding of photoreceptor adaptation at the transcriptional level, this study aimed to identify genes which are under daily regulation in photoreceptor cells using microarray analysis and quantitative PCR. Included in the gene set obtained were a number of genes which up until now have not been shown to be expressed in photoreceptor cells, such as Atf3 (activating transcription factor 3) and Pde8a (phosphodiesterase 8A), and others with a known impact on phototransduction and/or photoreceptor survival, such as Grk1 (G protein-coupled receptor kinase 1) and Pgc-1α (peroxisome proliferator-activated receptor γ, coactivator 1alpha). According to their daily dynamics, the genes identified could be clustered in two groups: those with peak expression during the second part of the day which are uniformly promoted to cycle by light/dark transitions and those with peak expression during the second part of the night which are predominantly driven by a clock. Since Grk1 and Pgc-1α belong in the first group, the present results support a concept in which transcriptional regulation of genes by ambient light contributes to the functional adjustment of photoreceptor cells over the 24-h period.

  18. Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19

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    Ferrell Robert E

    2011-01-01

    Full Text Available Abstract Background Abdominal aortic aneurysm (AAA is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM database. Methods Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22 were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies. Results Several SNPs were nominally associated with AAA (p CEBPG, peptidase D (PEPD, and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non-aneurysmal tissue samples. Conclusions Association testing

  19. No association between Val158Met of the COMT gene and susceptibility to schizophrenia in the Syrian population

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    Bassam Lajin

    2011-01-01

    Full Text Available Background : The Val158Met single nucleotide polymorphism of the COMT gene has been implicated in the aetiology of schizophrenia, although results from different populations have been conflicting. Aims: The aim of the present study was to investigate possible association between schizophrenia and Val158Met in a novel Arab population from Syria. Methods and Materials: 71 unrelated schizophrenic subjects (45 men and 102 unrelated healthy controls (62 men were recruited to take part in this case- control study. The Val158Met of the COMT gene was genotyped for patients and controls, using a new optimized PCR-RFLP method. Results: the results demonstrated that there is no statistically significant difference between the two groups. Conclusion: This study does not support that Val158Met has an influence on susceptibility for schizophrenia in this population.

  20. Asma ocupacional Occupational asthma

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    P. Cebollero

    2005-01-01

    Full Text Available Asma ocupacional es aquella entidad que se desarrolla por causas o condiciones derivadas de un determinado medio laboral y no por estímulos que se encuentran fuera del trabajo. El asma ocupacional constituye hoy en día la enfermedad respiratoria ocupacional más frecuente en la mayoría de los países industrializados y se calcula que la proporción de nuevos casos de asma atribuibles a la exposición laboral se sitúa en torno al 10-15%. Puede desarrollarse tanto por un mecanismo inmunológico como no inmunológico. En su desarrollo influyen el tipo de agente al que se está expuesto, el nivel y modo de exposición y factores genéticos de susceptibilidad. En el proceso diagnóstico concurre la confirmación de que el paciente tiene asma bronquial y la confirmación de que ésta se produce por causa laboral. Como demuestra la historia natural de la enfermedad, un diagnóstico precoz y las consiguientes acciones posteriores redundan en un mejor pronóstico de la misma.Occupational asthma is an entity caused by conditions deriving from a certain work milieu and not from stimuli found outside the workplace. Nowadays, occupational asthma is the most frequent respiratory occupational disease in the majority of the industrialised countries and it is estimated that the proportion of new cases of asthma that can be attributed to exposure at work is around 10-15%. It can be developed due to an immunological mechanism or to a non-immunological mechanism. Influential in its development are the type of agent exposed to, the level and form of exposure and genetic factors of susceptibility. In the diagnostic process there is a concurrent confirmation that the patient has bronchial asthma and that this has been caused by occupational reasons. As shown by the natural history of the disease, an early diagnosis and the consequent posterior actions result in an improved prognosis.

  1. Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation.

    Science.gov (United States)

    Vijayakanthi, Nandini; Greally, John M; Rastogi, Deepa

    2016-05-01

    The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children.

  2. Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

    OpenAIRE

    Almeida, Lucas; Oliveira, Joyce; Guimarães, Luiz Henrique; Carvalho, Edgar M.; Blackwell, Jenefer M.; Castellucci, Léa

    2015-01-01

    Previous studies have demonstrated a role for wound healing genes in resolution of cutaneous lesions caused by Leishmania spp. in both mice and humans, including the gene FLI1 encoding Friend leukaemia virus integration 1. Reduction of Fli1 expression in mice has been shown to result in up-regulation of collagen type I alpha 1 (Col1a1) and alpha 2 (Col1a2) genes and, conversely, in down-regulation of the matrix metalloproteinase 1 (Mmp1) gene, suggesting that Fli1 suppression is involved in a...

  3. Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees

    Science.gov (United States)

    Steinmann, Nadja; Corona, Miguel; Neumann, Peter; Dainat, Benjamin

    2015-01-01

    The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV), one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee’s susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions. PMID:26121358

  4. Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees.

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    Nadja Steinmann

    Full Text Available The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV, one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee's susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions.

  5. Variation in the IL1B, TNF and IL6 genes and individual susceptibility to prosthetic joint infection

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    Stahelova Anna

    2012-05-01

    Full Text Available Abstract Background Prosthetic joint infection (PJI is an important failure mechanism of total joint arthroplasty (TJA. Here we examine whether the particular genetic variants can lead to increased susceptibility to PJI development. Results We conducted a genetic-association study to determine whether PJI could be associated with functional cytokine gene polymorphisms (CGP influencing on innate immunity response. A case–control design was utilized and previously published criteria for PJI were included to distinguish between cases and control subjects with/without TJA. Six single nucleotide polymorphisms (SNPs located in the genes for interleukin-1beta (SNP: IL1B-511, +3962, tumour necrosis factor alpha (TNF-308, -238 and interleukin-6 (IL6-174, nt565 were genotyped in 303 Caucasian (Czech patients with TJA (89 with PJI / 214 without PJI, and 168 unrelated healthy Czech individuals without TJA. The results showed that carriers of the less common IL1B−511*T allele were overrepresented in the group of TJA patients with PJI (69% in comparison with those that did not develop PJI (51%, p = 0.006, pcorr = 0.037 and with healthy controls (55%, p = 0.04, pcorr = N.S.. There was no significant difference in the distribution of the remaining five investigated CGPs and their haplotypes between groups. Conclusion A functional variant of the gene encoding for IL-1beta was preliminarily nominated as a genetic factor contributing to the susceptibility to PJI. Our results should be independently replicated; studies on the functional relevance of IL1B gene variants in PJI are also needed.

  6. cDNAs of aminopeptidase-like protein genes from Plodia interpunctella strains with different susceptibilities to Bacillus thuringiensis toxins.

    Science.gov (United States)

    Zhu, Y C; Kramer, K J; Oppert, B; Dowdy, A K

    2000-03-01

    Aminopeptidase N has been reported to be a Bacillus thuringiensis (Bt) Cry1A toxin-binding protein in several lepidopteran insects. cDNAs of aminopeptidase-like proteins from both Bt-susceptible RC688s and Bt-resistant HD198r strains of the Indianmeal moth, Plodia interpunctella, were cloned and sequenced. They contain 3345 and 3358 nucleotides, respectively, and each has a 3048 bp open reading frame that encodes 1016 amino acids. Putative protein sequences include 10 potential glycosylation sites and a zinc metal binding site motif of HEXXH, which is typical of the active site of zinc-dependent metallopeptidases. Sequence analysis indicated that the deduced protein sequences are most similar to an aminopeptidase from Heliothis virescens with 62% sequence identity and highly similar to three other lepidopteran aminopeptidases from Plutella xylostella, Manduca sexta, Bombyx mori with sequence identities of 51-52%. Four nucleotide differences were observed in the open reading frames that translated into two amino acid differences in the putative protein sequences. Polymerase chain reaction (PCR) confirmed an aminopeptidase gene coding difference between RC688s and HD198r strains of P. interpunctella in the PCR amplification of a specific allele (PASA) using preferential primers designed from a single base substitution. The gene mutation for Asp185-->Glu185 was also confirmed in two additional Bt-resistant P. interpunctella strains. This mutation is located within a region homologous to the conserved Cry1Aa toxin binding regions from Bombyx mori and Plutella xylostella. The aminopeptidase-like mRNA expression levels in the Bt-resistant strain were slightly higher than those in the Bt-susceptible strain. The sequences reported in this paper have been deposited in the GenBank database (accession numbers AF034483 for susceptible strain RC688s and AF034484 for resistant strain HD198r).

  7. The prion protein gene polymorphisms associated with bovine spongiform encephalopathy susceptibility differ significantly between cattle and buffalo.

    Science.gov (United States)

    Zhao, Hui; Du, Yanli; Chen, Shunmei; Qing, Lili; Wang, Xiaoyan; Huang, Jingfei; Wu, Dongdong; Zhang, Yaping

    2015-12-01

    Prion protein, encoded by the prion protein gene (PRNP), plays a crucial role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Several polymorphisms within the PRNP are known to be associated with influencing bovine spongiform encephalopathy (BSE) susceptibility in cattle, namely two insertion/deletion (indel) polymorphisms (a 23-bp indel in the putative promoter and a 12-bp indel in intron 1), the number of octapeptide repeats (octarepeats) present in coding sequence (CDS) and amino acid polymorphisms. The domestic buffaloes, Bubalus bubalis, are a ruminant involved in various aspects of agriculture. It is of interest to ask whether the PRNP polymorphisms differ between cattle and buffalo. In this study, we analyzed the previously reported polymorphisms associated with BSE susceptibility in Chinese buffalo breeds, and compared these polymorphisms in cattle with BSE, healthy cattle and buffalo by pooling data from the literature. Our analysis revealed three significant findings in buffalo: 1) extraordinarily low deletion allele frequencies of the 23- and 12-bp indel polymorphisms; 2) significantly low allelic frequencies of six octarepeats in CDS and 3) the presence of S4R, A16V, P54S, G108S, V123M, S154N and F257L substitutions in buffalo CDSs. Sequence alignments comparing the buffalo coding sequence to other species were analyzed using the McDonald-Kreitman test to reveal five groups (Bison bonasus, Bos indicus, Bos gaurus, Boselaphus tragocamelus, Syncerus caffer caffer) with significantly divergent non-synonymous substitutions from buffalo, suggesting potential divergence of buffalo PRNP and others. To the best of our knowledge this is the first study of PRNP polymorphisms associated with BSE susceptibility in Chinese buffalo. Our findings have provided evidence that buffaloes have a unique genetic background in the PRNP gene in comparison with cattle.

  8. A functional polymorphism in IFNAR1 gene is associated with susceptibility and severity of HFMD with EV71 infection.

    Science.gov (United States)

    Zou, Rongrong; Zhang, Guoliang; Li, Shaoyuan; Wang, Wenfei; Yuan, Jing; Li, Jianming; Wang, Yanrong; Lin, Yimin; Deng, Yong; Zhou, Boping; Gao, George Fu; Liu, Yingxia

    2015-01-01

    Enterovirus 71 (EV71), one of the major pathogens of Hand, foot and mouth disease (HFMD), results in millions of infections and hundreds of deaths each year in Southeast Asia. Biased infection and variable clinical manifestations of EV71 HFMD indicated that host genetic background played an important role in the occurrence and development of the disease. We identified the mRNA profiles of EV71 HFMD patients, which type I interferon (IFN) pathway related genes were down-regulated. Four single nucleotide polymorphisms (SNPs) of type I IFN receptor 1 (IFNAR1) were chosen to analyze their relationships to EV71 infection. We found that genotype GG of promoter variant rs2843710 was associated with the susceptibility and severity to EV71 HFMD. In addition, we assessed the regulatory effects of rs2843710 to IFN stimulated genes (ISGs), and found that the expressions of IFNAR1, OAS1 and MX1 were significantly lower in patients with rs2843710 genotype GG. And rs2843710 allele G showed weaker transcriptional activity compared with allele C. Our study indicated that rs2843710 of IFNAR1 was associated with the susceptibility and severity of EV71 HFMD in Chinese Han populations, acting as a functional polymorphism by regulating ISGs expression, such as OAS1 and MX1.

  9. Paternally transmitted IDDM2 influences diabetes susceptibility despite biallelic expression of the insulin gene in human pancreas.

    Science.gov (United States)

    Bui, M M; Luo, D F; She, J Y; Maclaren, N K; Muir, A; Thomson, G; She, J X

    1996-02-01

    Whereas it is well known that the insulin gene (INS) region at 11p15.5 (IDDM2) confers susceptibility to insulin-dependent diabetes mellitus (IDDM), it is still controversial whether the parental origin of IDDM2 influences IDDM susceptibility. We have analysed the Pst I + 1127 polymorphism in 123 USA multiplex families and detected linkage only in male meioses using the affected sibpair analysis (P = 0.009). Application of the transmission/disequilibrium test (TDT) found significantly increased transmission of the IDDM-associated INS allele from fathers heterozygous for INS to their diabetic offspring (P = 0.00002), but the transmission from heterozygous mothers was not significantly different from random expectation. In non-diabetic families, the transmission from parents heterozygous for INS was not significantly different from random expectation in either paternal or maternal meioses. Maternal imprinting of the INS gene in pancreatic islets was originally considered the most favorable explanation for the observed gender-related difference. However, our study has demonstrated biallelic expression of INS in pancreatic tissues from the human fetuses and thus suggests that INS is probably not imprinted in the pancreatic islets.

  10. Asthma in childhood: a complex, heterogeneous disease

    Directory of Open Access Journals (Sweden)

    Hai Lee Chung

    2011-01-01

    Full Text Available Asthma in childhood is a heterogeneous dise