WorldWideScience

Sample records for strong genetic predisposition

  1. Early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition.

    Science.gov (United States)

    Husted, Janice A; Ahmed, Rashid; Chow, Eva W C; Brzustowicz, Linda M; Bassett, Anne S

    2012-05-01

    There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood trauma, covariates and familial clustering (adjusted odds ratio (95% confidence interval)=1.55 (1.01, 2.38)). The results provide further support that early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Genetic predisposition to cancer.

    Science.gov (United States)

    Turnbull, Clare; Hodgson, Shirley

    2005-01-01

    Over recent decades a number of genes causing predisposition to cancer have been identified. Some of these cause rare autosomal dominant monogenic cancer predisposition syndromes. In the majority of families, the increased incidence of cancers is due to a multifactorial aetiology with a number of lower penetrance cancer predisposition genes interacting with environmental factors. Identification of those at increased risk of cancer on account of their family history is important, as genetic testing, enhanced surveillance, prophylactic surgery and chemoprophylaxis may be indicated. In this article the issues surrounding genetic predisposition to cancer are considered by examining two common cancers: colorectal and breast cancer.

  3. Genetic Predisposition to Rosacea.

    Science.gov (United States)

    Awosika, Olabola; Oussedik, Elias

    2018-04-01

    Rosacea is a common inflammatory skin disease with a multifaceted pathophysiology, including environmental stressors and neurovascular and immune dysfunction affected by the presence of pathogens. The genetic component of this disorder is not well understood. However, a possible genetic origin in Northern European descendants, family inheritance, twin concordance, and genetic associations with autoimmune disorders attest the genetic predisposition to rosacea. Currently, one single-nucleotide polymorphism has been identified in association with rosacea and is intergenic between HLA-DRA and BTNL2. Additional associations with HLA alleles and immune-mediated disorders support the role of immune-regulating genes and innate and adaptive immunity in rosacea. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Cancer predisposition in children: genetics, phenotypes & screening

    NARCIS (Netherlands)

    Hopman, S.M.J.

    2014-01-01

    This thesis describes the genetic, phenotypic and screening aspects of tumor predisposition syndromes in childhood cancer patients. In tumor predisposition syndromes, the same constitutional molecular defects that lead to the clinical phenotype predispose the patient to develop specific cancers.

  5. Genetic predisposition to bronchopulmonary dysplasia.

    Science.gov (United States)

    Lal, Charitharth Vivek; Ambalavanan, Namasivayam

    2015-12-01

    The objective of this study is to review the candidate gene and genome-wide association studies relevant to bronchopulmonary dysplasia, and to discuss the emerging understanding of the complexities involved in genetic predisposition to bronchopulmonary dysplasia and its outcomes. Genetic factors contribute much of the variance in risk for BPD. Studies to date evaluating single or a few candidate genes have not been successful in yielding results that are replicated in GWAS, perhaps due to more stringent p-value thresholds. GWAS studies have identified only a single gene (SPOCK2) at genome-wide significance in a European White and African cohort, which was not replicated in two North American studies. Pathway gene-set analysis in a North American cohort confirmed involvement of known pathways of lung development and repair (e.g., CD44 and phosphorus oxygen lyase activity) and indicated novel molecules and pathways (e.g., adenosine deaminase and targets of miR-219) involved in genetic predisposition to BPD. The genetic basis of severe BPD is different from that of mild/moderate BPD, and the variants/pathways associated with BPD vary by race/ethnicity. A pilot study of whole exome sequencing identified hundreds of genes of interest, and indicated the overall feasibility as well as complexity of this approach. Better phenotyping of BPD by severity and pathophysiology, and careful analysis of race/ethnicity is required to gain a better understanding of the genetic basis of BPD. Future translational studies are required for the identification of potential genetic predispositions (rare variants and dysregulated pathways) by next-generation sequencing methods in individual infants (personalized genomics). Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Genetic predisposition to kidney cancer.

    Science.gov (United States)

    Schmidt, Laura S; Linehan, W Marston

    2016-10-01

    Kidney cancer is not a single disease but is made up of a number of different types of cancer classified by histology that are disparate in presentation, clinical course, and genetic basis. Studies of families with inherited renal cell carcinoma (RCC) have provided the basis for our understanding of the causative genes and altered metabolic pathways in renal cancer with different histologies. Von Hippel-Lindau disease was the first renal cancer disorder with a defined genetic basis. Over the next two decades, the genes responsible for a number of other inherited renal cancer syndromes including hereditary papillary renal carcinoma, Birt-Hogg-Dube´syndrome, hereditary leiomyomatosis and renal cell carcinoma, and succinate dehydrogenase-associated renal cancer were identified. Recently, renal cell carcinoma has been confirmed as part of the clinical phenotype in individuals from families with BAP1-associated tumor predisposition syndrome and MiTF-associated cancer syndrome. Here we summarize the clinical characteristics of and causative genes for these and other inherited RCC syndromes, the pathways that are dysregulated when the inherited genes are mutated, and recommended clinical management of patients with these inherited renal cancer syndromes. Published by Elsevier Inc.

  7. Radiosensitivity and cancer : genetic predisposition

    International Nuclear Information System (INIS)

    Lavin, M.F.

    1984-01-01

    This paper considers radiation exposure in terms of individual sensitivity to radiation and predisposition to cancer, A-T homozygotes have an increased predisposition to a number of types of cancer. Immunodeficiency is an important factor involved. Radiosensitivity, chromosomal breakage, defective DNA repair and other abnormalities may also contribute to the increased incidence of cancer

  8. Breast magnetic resonance imaging significance for breast cancer diagnostic in women with genetic predisposition and a strong family history

    Directory of Open Access Journals (Sweden)

    M. S. Karpova

    2013-01-01

    Full Text Available Screening of breast cancer with mammography recommended to women over 40 has been shown to decrease breast cancer mortality. But mam- mography has much lower accuracy in young women with BRCA1/2 mutations and women with a strong family history. Therefore new screening methods in young high-risk women are necessary to detect early-stage cancer.

  9. Genetic predisposition to heart failure.

    Science.gov (United States)

    Pasotti, Michele; Repetto, Alessandra; Tavazzi, Luigi; Arbustini, Eloisa

    2004-09-01

    This review describes the numerous and complex molecular systems that are either known players or candidates in heart failure(HF). All systems whose genetic background has been investigated to date in HF are listed and discussed. Discussion also includes functional notes and known genetic polymorphisms already investigated in HF or candidates that have not yet been investigated. Despite substantial research on HF, relatively few coordinated studies have been conducted that assign precise risk to specific genetic polymorphisms. Identification of risk associated with genetic variations and subsequent translation of genetic knowledge into clinical practice will likely progress only in cases of large coordinated studies based on identical standards. The potential result will be a more accurate definition of HF identified as an evolving complex of cardiovascular diseases.

  10. Genetic predisposition to Parkinson's disease

    DEFF Research Database (Denmark)

    Halling, Jónrit; Petersen, Maria Skaalum; Grandjean, Philippe

    2008-01-01

    OBJECTIVE: To investigate whether the genetic variants of CYP2D6 and HFE are more frequent in Parkinson's disease (PD) patients compared with controls in a population where the prevalence of these variants and PD are increased. METHODS: Blood samples were collected from 79 PD patients and 154...

  11. Genetic Predisposition to Obesity and Medicare Expenditures.

    Science.gov (United States)

    Wehby, George L; Domingue, Benjamin W; Ullrich, Fred; Wolinsky, Fredric D

    2017-12-12

    The relationship between obesity and health expenditures is not well understood. We examined the relationship between genetic predisposition to obesity measured by a polygenic risk score for body mass index (BMI) and Medicare expenditures. Biennial interview data from the Health and Retirement Survey for a nationally representative sample of older adults enrolled in fee-for-service Medicare were obtained from 1991 through 2010 and linked to Medicare claims for the same period and to Genome-Wide Association Study (GWAS) data. The study included 6,628 Medicare beneficiaries who provided 68,627 complete person-year observations during the study period. Outcomes were total and service-specific Medicare expenditures and indicators for expenditures exceeding the 75th and 90th percentiles. The BMI polygenic risk score was derived from GWAS data. Regression models were used to examine how the BMI polygenic risk score was related to health expenditures adjusting for demographic factors and GWAS-derived ancestry. Greater genetic predisposition to obesity was associated with higher Medicare expenditures. Specifically, a 1 SD increase in the BMI polygenic risk score was associated with a $805 (p genetic predisposition to obesity is associated with higher Medicare expenditures. © The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. [Update on genetic predisposition to prostate cancer].

    Science.gov (United States)

    Cussenot, Olivier; Cancel-Tassin, Géraldine

    2015-01-01

    Genetic predisposition to prostate cancer rarely corresponds to a high penetrance Mendelian pattern of inheritance. These hereditary forms are specific entities for which mutations in the BRCA2 gene, the HOXB13 gene (variant G84E) or, to a lesser extent BRCA1 gene, must be researched. In contrast, the genetic component of the majority of prostate cancer is polygenic, involving an unfavorable combination of common genetic variants, resulting from a mixture of the genetic inheritance of the father and the mother. One hundred of these genetic susceptibility variants have now been identified and validated. The main phenotypic trait associated with hereditary predisposition is the younger age at onset, which warrants special monitoring in order to stay in the window of curability at diagnosis. The psychological impact of a family history of prostate cancer or breast cancer favors the establishment of a dedicated monitoring and procedures for early diagnosis. Copyright © 2014 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  13. Genetic predisposition and implications for radioprotection

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, Christian [University Clinics, Essen, Essen (Germany)

    2000-05-01

    Treatments of cancer patients with ionizing radiation have shown in some cases severe acute radiation effects after radiation doses which are very well tolerated by most patients. Skin fibroblasts of these patients studied after in vitro irradiation also showed a high radiosensitivity frequently. It was found that these effects are based on genetic predisposition which was usually inherited from their parents. During recent years quite a number of these syndromes have been described in humans and often the responsible genes have been characterized: Ataxia telangiectasia, Bloom's syndrome, Fanconi anemia, Li Fraumeni syndrome, Nevoid basal cell carcinoma syndrome, Neurofibromatosis, Nijmegen breakage syndrome, Retinoblastoma. In most cases it was found that the regulation processes of DNA repair processes and of the cell cycle for cell proliferation are disturbed. Frequently these processes cannot be separated from each other. Quite a number of these syndromes also show genomic instability which can also be induced by radiation exposures. These Phenomena have mainly been studied by determining the rate of chromosomal aberrations many cell generations after the exposure took place. Genomic instability apparently plays an important role for the development of stochastic late effects for which multistep events are necessary. This is especially for carcinogenesis the case. In mice it has been shown that radiation-induced genomic instability can be transmitted to the next mouse generation. In mouse models and also with radiotherapy patients it has been shown that genetic predisposition not only increases radiosensitivity with respect to cell survival and chromosomal damage but also to carcinogenesis. This has been observed cf. with p53-knock out mice and with children after radiotherapy cf. treatment of retinoblastoma. In the children with a genetic predisposition for retinoblastoma secondary tumours occurred to a much higher rate than in those children with

  14. Genetic predisposition and implications for radioprotection

    International Nuclear Information System (INIS)

    Streffer, Christian

    2000-01-01

    Treatments of cancer patients with ionizing radiation have shown in some cases severe acute radiation effects after radiation doses which are very well tolerated by most patients. Skin fibroblasts of these patients studied after in vitro irradiation also showed a high radiosensitivity frequently. It was found that these effects are based on genetic predisposition which was usually inherited from their parents. During recent years quite a number of these syndromes have been described in humans and often the responsible genes have been characterized: Ataxia telangiectasia, Bloom's syndrome, Fanconi anemia, Li Fraumeni syndrome, Nevoid basal cell carcinoma syndrome, Neurofibromatosis, Nijmegen breakage syndrome, Retinoblastoma. In most cases it was found that the regulation processes of DNA repair processes and of the cell cycle for cell proliferation are disturbed. Frequently these processes cannot be separated from each other. Quite a number of these syndromes also show genomic instability which can also be induced by radiation exposures. These Phenomena have mainly been studied by determining the rate of chromosomal aberrations many cell generations after the exposure took place. Genomic instability apparently plays an important role for the development of stochastic late effects for which multistep events are necessary. This is especially for carcinogenesis the case. In mice it has been shown that radiation-induced genomic instability can be transmitted to the next mouse generation. In mouse models and also with radiotherapy patients it has been shown that genetic predisposition not only increases radiosensitivity with respect to cell survival and chromosomal damage but also to carcinogenesis. This has been observed cf. with p53-knock out mice and with children after radiotherapy cf. treatment of retinoblastoma. In the children with a genetic predisposition for retinoblastoma secondary tumours occurred to a much higher rate than in those children with

  15. Genetic predisposition to breast cancer: past, present, and future.

    Science.gov (United States)

    Turnbull, Clare; Rahman, Nazneen

    2008-01-01

    In recent years, our understanding of genetic predisposition to breast cancer has advanced significantly. Three classes of predisposition factors, categorized by their associated risks of breast cancer, are currently known. BRCA1 and BRCA2 are high-penetrance breast cancer predisposition genes identified by genome-wide linkage analysis and positional cloning. Mutational screening of genes functionally related to BRCA1 and/or BRCA2 has revealed four genes, CHEK2, ATM, BRIP1, and PALB2; mutations in these genes are rare and confer an intermediate risk of breast cancer. Association studies have further identified eight common variants associated with low-penetrance breast cancer predisposition. Despite these discoveries, most of the familial risk of breast cancer remains unexplained. In this review, we describe the known genetic predisposition factors, expound on the methods by which they were identified, and consider how further technological and intellectual advances may assist in identifying the remaining genetic factors underlying breast cancer susceptibility.

  16. Genetic predisposition to leukemia and other hematologic malignancies.

    Science.gov (United States)

    Feurstein, Simone; Drazer, Michael W; Godley, Lucy A

    2016-10-01

    In this review, we provide an overview of familial myelodysplastic syndromes (MDS)/acute leukemia (AL) and bone marrow failure syndromes, as well as insights into familial myeloproliferative neoplasms (MPNs), familial multiple myeloma (MM), familial Waldenström macroglobulinemia (WM), familial lymphoma, and cancer predisposition syndromes with increased risk of MDS/AL. This field will continue to accelerate as next-generation sequencing (NGS) techniques identify novel predisposition alleles in families with a genetic predisposition to hematologic malignancies. Newly identified predisposition genes continue to inform the field of inherited leukemia and other hematologic malignancies. Current developments in clinical translation include techniques detailing the acquisition of appropriate germline material for patient work-ups, methods for genetic testing, and nuances essential for the treatment and clinical management of patients with a genetic predisposition to hematologic malignancies. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. [Type 1 diabetes: from genetic predisposition to hypothetical environmental triggers].

    Science.gov (United States)

    Phlips, J-C; Radermecker, R P

    2012-01-01

    Type 1 diabetes is an autoimmune disease that results in a progressive (complete in most cases) destruction of insulin-secreting beta cells from Langerhans islets. Even if the autoimmune process becomes to be well known, no one is yet sure what specifically prompts the autoimmune response that destroys the body's ability to produce insulin. Etiology of this complex disease combines a genetic predisposition and still (almost) unknown environmental factors that trigger autoimmuninty specifically targeting beta cells. Genetic HLA predispositions are clearly identified. However, only few people with apparent genetic predisposition to type 1 diabetes actually end up getting the disease. Moreover, the remarkable increase of type 1 diabetes prevalence observed in numerous countries can not be explained by genetics. Because genetic factors can't predict alone the development of type 1 diabetes, environmental factors must be involved such as viral infections, toxins from food, cow milk during childhood (instead of breast feeding) or vitamin D deficiency. This paper aims at describing the role of the genetic predisposition and the environmental hypothesis which can be involved in the development of type 1 diabetes. We will conclude by briefly describing clinical trials targeting either the immune response or the potentially toxic environment.

  18. Genetic Predisposition to Ischemic Stroke: A Polygenic Risk Score.

    Science.gov (United States)

    Hachiya, Tsuyoshi; Kamatani, Yoichiro; Takahashi, Atsushi; Hata, Jun; Furukawa, Ryohei; Shiwa, Yuh; Yamaji, Taiki; Hara, Megumi; Tanno, Kozo; Ohmomo, Hideki; Ono, Kanako; Takashima, Naoyuki; Matsuda, Koichi; Wakai, Kenji; Sawada, Norie; Iwasaki, Motoki; Yamagishi, Kazumasa; Ago, Tetsuro; Ninomiya, Toshiharu; Fukushima, Akimune; Hozawa, Atsushi; Minegishi, Naoko; Satoh, Mamoru; Endo, Ryujin; Sasaki, Makoto; Sakata, Kiyomi; Kobayashi, Seiichiro; Ogasawara, Kuniaki; Nakamura, Motoyuki; Hitomi, Jiro; Kita, Yoshikuni; Tanaka, Keitaro; Iso, Hiroyasu; Kitazono, Takanari; Kubo, Michiaki; Tanaka, Hideo; Tsugane, Shoichiro; Kiyohara, Yutaka; Yamamoto, Masayuki; Sobue, Kenji; Shimizu, Atsushi

    2017-02-01

    The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk. We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets). In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33-2.31) and 1.99 (95% confidence interval, 1.19-3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001). The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors. © 2016 The Authors.

  19. Genetic predisposition syndromes and their management.

    Science.gov (United States)

    Euhus, David M; Robinson, Linda

    2013-04-01

    Apart from BRCA1, BRCA2, and TP53, more than a dozen breast cancer susceptibility genes have been identified. Recognizing affected individuals depends on evaluation of cancer family history and recognition of certain phenotypic markers on physical examination. Genetic testing provides a powerful tool for individualized risk stratification. Mutation carriers have several options for managing risk, including lifestyle alterations, enhanced surveillance, chemoprevention, and prophylactic surgery. Genetic counseling and testing should be considered in the initial evaluation of patients with newly diagnosed breast cancer because this information contributes to surgical decisions, radiation therapy options, and systemic therapy choices. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Genetic predisposition and tumor radiation sensitivity

    International Nuclear Information System (INIS)

    Budach, W.

    1997-01-01

    Studies on normal tissue radiation sensitivity have demonstrated profound differences of individual sensivities. A number of genetic syndroms associated with abnormal radiation sensitivity have been discribed. Significant differences have also been detected in persons without known genetic disorders. The question arises as to whether tumors orginating from normal tissues with abnormal radiation sensitivity share this abnormal sensitivity and as to whether a general correlation between normal tissue sensitivity and tumor tissue sensitivity can be substantiated. Experimental studies on normal and tumor tissues of SCID- and C3H-mice demonstrated that the 2.7-fold enhanced radiation sensitivity of SCID normal tissues is also found in SCID tumors. Clinical investigations on cervical carcinoma and breast cancer patients revealed higher local tumor control rates in patients with more pronounced acute side effects. A weak trend towards the same relationship was found in head and neck cancer patients. Case reports on unusually severe acute radiation side effects or unexpected tumor remissions as well as few reports on radiotherapy in ataxia telangiectasia (AT) patients suggest a correlation between normal- and tumor-tissue radiation sensitivity. Studies on fibroblasts and tumor cells from the same patient support this hypothesis in soft tissue sarcoma patients, but do not so for head and neck cancer patients. Tumor cells exhibit a considerably higher variation of radiation sensitivities than normal tissue cells. Experimental and clinical data are compatible with the hypothesis that normal tissue radiation sensitivity predicts for tumor tissue sensitivity. However, in view of the larger heterogeneity of tumor cell radiation sensitivity as compared to normal tissue radiation sensitivity, the development of a clinically useful predictive test for tumor sensitivity based on normal cell sensitivity appears to be unrealistic. (orig./MG) [de

  1. Genetic predisposition to bevacizumab-induced hypertension.

    Science.gov (United States)

    Frey, Melissa K; Dao, Fanny; Olvera, Narciso; Konner, Jason A; Dickler, Maura N; Levine, Douglas A

    2017-12-01

    Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests. The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1, KLKB1, and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1, KLKB1, and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR=6.45; P=0.005; 95%CI, 1.86-22.39). We concluded that genetic variation in WNK1, KLKB1, and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Retinal vein occlusion: genetic predisposition and systemic risk factors.

    Science.gov (United States)

    Giannaki, Kassiani; Politou, Marianna; Rouvas, Alexandros; Merkouri, Efrossyni; Travlou, Anthi; Theodosiadis, Panayiotis; Gialeraki, Argyri

    2013-04-01

    The role of systemic risk factors (age, smoking, diabetes, arterial hypertension) in the development of retinal vein occlusion (RVO) is well established. However, the association of RVO with genetic predisposition to thrombosis remains poorly understood. The aim of the study was to assess any possible additional effect of genetic predisposition to the already well known 'classical' risk factors of RVO in a cohort of elderly Greek patients. Fifty-one elderly patients with RVO and 51 healthy individuals matched for age and sex were evaluated for systemic risk factors (smoking, diabetes, dyslipidemia, arterial hypertension) and coagulation defects (lupus anticoagulant, natural inhibitors of coagulation). Additionally, genotyping was performed for mutations/polymorphisms involved in haemostasis such as: FV G1691A, FV G4070A, FIIG 20210A, MTHFR C677T and A1298C, PAI-1-675 4G/5G, F XIII exon 2G/T, EPCR A4600G and G4678C. We identified systemic risk factors in the majority of the patients Hypertension (P=0.001), dyslipidemia (P=0.029) and diabetes (P=0.01) are associated with RVO in the majority of the patients. The prevalence of prothrombotic risk factors was not significantly different in the patients with RVO compared to controls. Apart from systemic risk factors, genetic predisposition to thrombosis does not seem to have an important association with RVO in this group of elderly patients.

  3. Lung cancer, genetic predisposition and smoking

    DEFF Research Database (Denmark)

    Hjelmborg, Jacob; Korhonen, Tellervo; Holst, Klaus

    2017-01-01

    Background: We aimed to disentangle genetic and environmental causes in lung cancer while considering smoking status. Methods: Four Nordic twin cohorts (43 512 monozygotic (MZ) and 71 895 same sex dizygotic (DZ) twin individuals) had smoking data before cancer diagnosis. We used time......-to-event analyses accounting for censoring and competing risk of death to estimate incidence, concordance risk and heritability of liability to develop lung cancer by smoking status. Results: During a median of 28.5 years of follow-up, we recorded 1508 incident lung cancers. Of the 30 MZ and 28 DZ pairs concordant...... compared with the cumulative incidence for both MZ and DZ pairs. This ratio, the relative recurrence risk, significantly decreased by age for MZ but was constant for DZ pairs. Heritability of lung cancer was 0.41 (95% CI 0.26 to 0.56) for currently smoking and 0.37 (95% CI 0.25 to 0.49) for ever smoking...

  4. Genetic Predisposition to Dyslipidemia and Risk of Preeclampsia.

    Science.gov (United States)

    Spracklen, Cassandra N; Saftlas, Audrey F; Triche, Elizabeth W; Bjonnes, Andrew; Keating, Brendan; Saxena, Richa; Breheny, Patrick J; Dewan, Andrew T; Robinson, Jennifer G; Hoh, Josephine; Ryckman, Kelli K

    2015-07-01

    Large epidemiologic studies support the role of dyslipidemia in preeclampsia; however, the etiology of preeclampsia or whether dyslipidemia plays a causal role remains unclear. We examined the association between the genetic predisposition to dyslipidemia and risk of preeclampsia using validated genetic markers of dyslipidemia. Preeclampsia cases (n = 164) and normotensive controls (n = 110) were selected from live birth certificates to nulliparous Iowa women during the period August 2002 to May 2005. Disease status was verified by medical chart review. Genetic predisposition to dyslipidemia was estimated by 4 genetic risk scores (GRS) (total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides) on the basis of established loci for blood lipids. Logistic regression analyses were used to evaluate the relationships between each of the 4 genotype scores and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. The GRS related to higher levels of TC, LDL-C, and triglycerides demonstrated no association with the risk of preeclampsia in either the Iowa or replication population. The GRS related to lower HDL-C was marginally associated with an increased risk for preeclampsia (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.99-1.07; P = 0.10). In the independent replication population, the association with the HDL-C GRS was also marginally significant (OR = 1.03, 95% CI: 1.00-1.06; P = 0.04). Our data suggest a potential effect between the genetic predisposition to dyslipidemic levels of HDL-C and an increased risk of preeclampsia, and, as such, suggest that dyslipidemia may be a component along the causal pathway to preeclampsia. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Spontaneous preterm birth: advances toward the discovery of genetic predisposition.

    Science.gov (United States)

    Strauss, Jerome F; Romero, Roberto; Gomez-Lopez, Nardhy; Haymond-Thornburg, Hannah; Modi, Bhavi P; Teves, Maria E; Pearson, Laurel N; York, Timothy P; Schenkein, Harvey A

    2018-03-01

    Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control. Because inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches used for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth. Candidate gene studies have sought genetic variants that regulate inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome-wide association studies, an approach to the identification of chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent genome-wide association study that included a large number of White women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing, which examines the DNA sequence of protein-coding regions of the genome. A recent whole exome sequencing study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the

  6. Genetic Predisposition, Nongenetic Risk Factors, and Coronary Infarct

    Science.gov (United States)

    Trichopoulou, Antonia; Yiannakouris, Nikos; Bamia, Christina; Benetou, Vassiliki; Trichopoulos, Dimitrios; Ordovas, Jose M.

    2015-01-01

    Background Using a genetic predisposition score (GPS), additively integrating the associations of 11 polymorphisms with coronary heart disease (CHD), we examined the consequences of the joint presence of a high GPS and nongenetic CHD risk factors. Methods Within the European Prospective Investigation Into Cancer and Nutrition, 202 case patients with medically confirmed incident coronary infarct and 197 control subjects were identified in Greece. Each polymorphism contributed 1 unit (high-risk homozygous), one-half unit (heterozygous), or no units (low-risk homozygous) to the GPS. Odds ratios of coronary infarction for those at high risk because of genetic predisposition and simultaneous presence of an established CHD risk factor were estimated, compared with subjects at low risk, for both GPS and each CHD risk factor. Results The joint presence of a high GPS (≥3.5) and each studied CHD risk factor was in all instances associated with a significantly increased risk of coronary infarction. The odds ratio (95% confidence interval) was 2.62 (1.14–6.02) for ever smoking, 2.88 (1.33–6.24) for hypertension, 3.50 (1.67–7.33) for low high-density lipoprotein (HDL) level, 3.05 (1.53–6.08) for high non-HDL level, and 3.66 (1.75–7.65) for poor adherence to the Mediterranean diet. The odds ratios were always lower and nonsignificant when the GPS was low. There was suggestive evidence for interaction of a high GPS with hypertension (P =.05) and non-HDL cholesterol level (P =.13). Conclusions Genetic predisposition may interact with hypertension and, perhaps, also with the level of non-HDL cholesterol, in the causation of CHD. Genetic predisposition and the other studied exposures seem to have converging effects. Thus, the GPS may identify individuals who could realize disproportional benefits by controlling their hypertension and, possibly, their non-HDL cholesterol level. PMID:18443266

  7. Genetic predisposition to colorectal cancer: Implications for treatment and prevention.

    Science.gov (United States)

    Stoffel, Elena M; Yurgelun, Matthew B

    2016-10-01

    Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women and approximately 5% of cases are associated with identifiable germline mutations associated with hereditary cancer syndromes. Lifetime risks for CRC can approach 50%-80% for mutation carriers in the absence of endoscopic and/or surgical intervention, and early identification of at-risk individuals can guide clinical interventions for cancer prevention and treatment. Personal and family history and molecular phenotype of CRC tumors are used in determining which patients should be referred for clinical genetic evaluation. Outcomes of genetic testing performed using next-generation sequencing (NGS) multigene panels suggest there can be significant overlap in clinical features among the various hereditary cancer syndromes. This review summarizes new developments in diagnosis and management of patients with genetic predisposition to CRC. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. From a genetic predisposition to an interactive predisposition: rethinking the ethical implications of screening for gene-environment interactions.

    Science.gov (United States)

    Tabery, James

    2009-02-01

    In a widely acclaimed study from 2002, researchers found a case of gene-environment interaction for a gene controlling neuroenzymatic activity (low vs. high), exposure to childhood maltreatment, and antisocial personality disorder (ASPD). Cases of gene-environment interaction are generally characterized as evincing a genetic predisposition; for example, individuals with low neuroenzymatic activity are generally characterized as having a genetic predisposition to ASPD. I first argue that the concept of a genetic predisposition fundamentally misconstrues these cases of gene-environment interaction. This misconstrual will be diagnosed, and then a new concept--interactive predisposition--will be introduced. I then show how this conceptual shift reconfigures old questions and raises new questions for genetic screening. Attempts to screen embryos or fetuses for the gene associated with low neuroenzymatic activity with an eye toward selecting against the low-activity variant fall prey to the myth of pre-environmental prediction; attempts to screen newborns for the gene associated with low neuroenzymatic activity with an eye toward early intervention will have to face the interventionist's dilemma.

  9. Genetic predisposition of stroke: understanding the evolving landscape through meta-analysis.

    Science.gov (United States)

    Huang, Hai-Dong; Yang, Chun-Min; Shu, Hai-Feng; Kuang, Yong-Qin; Yang, Tao; He, Wei-Qi; Zhao, Kai; Xia, Xun; Cheng, Jing-Min; Ma, Yuan; Gu, Jian-Wen

    2015-01-01

    Stroke, either ischemic or hemorrhagic, is the leading cause of death and morbidity worldwide. Identifying the risk factors is a prerequisite step for stroke prevention and treatment. It is believed that a major portion of the currently unidentified risk factors is of genetic origin. Consistent with this idea, numerous potential risk alleles for stroke have been reported, however, the genetic evidence so far is not conclusive. The major goal of this review is to update the current knowledge about the genetic predisposition to the common multifactorial stroke, and to provide a bird's-eye view of this fast moving field. We selectively review and meta-analyze the related English literatures in public domain (PubMed) from 2000 onward, including the original reports and meta-analyses, to evaluate the genetic risk factors of common multifactorial stroke. The results indicated that we reviewed and meta-analyzed original reports and existing meta-analyses that studied the genetic predisposition to the common multifactorial stroke. Some original reports and meta-analyses were specific for ischemic stroke and others were for hemorrhagic stroke only. We also evaluated the major evolving issues in this field and discussed the future directions. In conclusion, strong evidences suggest that genetic risk factors contribute to common multifactorial stroke, and many genetic risk genes have been implicated in the literatures. However, not a single risk allele has been conclusively approved.

  10. Micro-social risk factors and genetic predisposition to micro-social risk factors and genetic predisposition to digestive diseases among adolescents living in georgia.

    Science.gov (United States)

    Chikava, M; Bakradze, M; Varsimashvili, M

    2013-02-01

    The purpose of the study was to analyse the genetic predisposition to digestive diseases, micro-social stressors and other risk factors among adolescents and compare them to each other by strength of association with Chronic Digestive Diseases (CDD). One phase epidemiological research was conducted in population of adolescents aged 14-21 years, living in Georgia. The representative contigent - 430 adolescents were selected by the method of simple randomization. The two groups were separated from the research contingent: 84 adolescents with the CDD (the experimental group) and 346 condtionally healthy adolescents (the control group). The degree of relationship between the defined risk factor and CDD among adolescents was studied through case-control study method. Statistical processing of the obtained data was provided through SPSS v.11,5. The risk factors ranking was held according to decrease of OR values. Analysis of micro-social and hereditary risk factors showed that the associations between CDD and the combination of chronic psychological overloads, calculated together, is stronger (OR=15,3 (95% CI: 9,06-37,8)), than with genetic predisposition to digestive diseases (OR=11,5). From chronic psychological overloads, the most strong relationship with CDD have adolescents study overloads (OR=7,1) and conflict situations at the family (OR=6,0), as well as adolescents bad habits (OR=5,14) and unsatisfactory living conditions (OR=3,74). The listed above OR indicies may be used for planning preventive measures, needed for decrease CDD prevalence among adolescents.

  11. Possible genetic predisposition to lymphedema after breast cancer.

    Science.gov (United States)

    Newman, Beth; Lose, Felicity; Kedda, Mary-Anne; Francois, Mathias; Ferguson, Kaltin; Janda, Monika; Yates, Patsy; Spurdle, Amanda B; Hayes, Sandra C

    2012-03-01

    Known risk factors for secondary lymphedema only partially explain who develops lymphedema following cancer, suggesting that inherited genetic susceptibility may influence risk. Moreover, identification of molecular signatures could facilitate lymphedema risk prediction prior to surgery or lead to effective drug therapies for prevention or treatment. Recent advances in the molecular biology underlying development of the lymphatic system and related congenital disorders implicate a number of potential candidate genes to explore in relation to secondary lymphedema. We undertook a nested case-control study, with participants who had developed lymphedema after surgical intervention within the first 18 months of their breast cancer diagnosis serving as cases (n=22) and those without lymphedema serving as controls (n=98), identified from a prospective, population-based, cohort study in Queensland, Australia. TagSNPs that covered all known genetic variation in the genes SOX18, VEGFC, VEGFD, VEGFR2, VEGFR3, RORC, FOXC2, LYVE1, ADM, and PROX1 were selected for genotyping. Multiple SNPs within three receptor genes, VEGFR2, VEGFR3, and RORC, were associated with lymphedema defined by statistical significance (p2.0). These provocative, albeit preliminary, findings regarding possible genetic predisposition to secondary lymphedema following breast cancer treatment warrant further attention for potential replication using larger datasets.

  12. Epidemiology, major risk factors and genetic predisposition for breast cancer in the Pakistani population.

    Science.gov (United States)

    Shaukat, Uzma; Ismail, Muhammad; Mehmood, Nasir

    2013-01-01

    Occurrence of breast cancer is related to genetic as well as cultural, environmental and life-style factors. Variations in diversity of these factors among different ethnic groups and geographical areas emphasize the immense need for studies in all racial-ethnic populations. The incidence of breast cancer in Pakistan is highest in Asians after Jews in Israel and 2.5 times higher than that in neighboring countries like Iran and India, accounting for 34.6% of female cancers. The Pakistani population is deficient in information regarding breast cancer etiology and epidemiology, but efforts done so far had suggested consanguinity as a major risk factor for frequent mutations leading to breast cancer and has also shed light on genetic origins in different ethnic groups within Pakistan. World-wide research efforts on different ethnicities have enhanced our understanding of genetic predisposition to breast cancer but despite these discoveries, 75% of the familial risk of breast cancer remains unexplained, highlighting the fact that the majority of breast cancer susceptibility genes remain unidentified. For this purpose Pakistani population provides a strong genetic pool to elucidate the genetic etiology of breast cancer because of cousin marriages. In this review, we describe the known breast cancer predisposition factors found in the local Pakistani population and the epidemiological research work done to emphasize the importance of exploring factors/variants contributing to breast cance, in order to prevent, cure and decrease its incidence in our country.

  13. Genetic predisposition to acute kidney injury--a systematic review.

    Science.gov (United States)

    Vilander, Laura M; Kaunisto, Mari A; Pettilä, Ville

    2015-12-02

    The risk of an individual to develop an acute kidney injury (AKI), or its severity, cannot be reliably predicted by common clinical risk factors. Whether genetic risk factors have an explanatory role poses an interesting question, however. Thus, we conducted a systematic literature review regarding genetic predisposition to AKI or outcome of AKI patients. We searched Ovid SP (MEDLINE) and EMBASE databases and found 4027 references to AKI. Based on titles and abstracts, we approved 37 articles for further analysis. Nine were published only as abstracts, leaving 28 original articles in the final analysis. We extracted the first author, year of publication, study design, clinical setting, number of studied patients, patients with AKI, ethnicity of patients, studied polymorphisms, endpoints, AKI definition, phenotype, significant findings, and data for quality scoring from each article. We summarized the findings and scored the quality of articles. The articles were quite heterogeneous and of moderate quality (mean 6.4 of 10). Despite different gene polymorphisms with suggested associations with development or severity or outcome of AKI, definitive conclusions would require replication of associations in independent cohort studies and, preferably a hypothesis-free study design.

  14. Unclassified sequence variants (UVS and genetic predisposition to cancer

    Directory of Open Access Journals (Sweden)

    Yves-Jean Bignon

    2011-06-01

    Full Text Available Hereditary breast and ovarian cancers are mainly attributable to predisposition genes whose germinal mutations are responsible for the disease. The most common genes associated with breast/ovarian cancer are BRCA1 and BRCA2 but at least 20 other genes of medium of high penetrance have been associated with these types of cancer. Lifetime risk of breast cancer for BRCA mutations carriers approaches 90%. Appropriate medical follow-up is therefore essential for women carrying mutations in these genes. BRCA mutational spectrum has not been entirely characterized but not all sequence variants are pathogenic. These are classified as benign polymorphisms or unclassified variants (UV with unknown pathological potential. To date, 43,5% of over 3500 genetic variants BRCA1 and BRCA2 are reported as having uncertain clinical significance. Whether one sequence variant has or not a pathogenicity implication is often a hard decision to take, involving important consequences for diagnosis and medical follow-up. Here we present several cases of unclassified sequence variants detection and interpretation by in-silico analysis.

  15. Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma.

    Science.gov (United States)

    Hungate, Eric A; Applebaum, Mark A; Skol, Andrew D; Vaksman, Zalman; Diamond, Maura; McDaniel, Lee; Volchenboum, Samuel L; Stranger, Barbara E; Maris, John M; Diskin, Sharon J; Onel, Kenan; Cohn, Susan L

    2017-10-01

    To investigate genetic predispositions for MYCN-amplified neuroblastoma, we performed a meta-analysis of three genome-wide association studies totaling 615 MYCN-amplified high-risk neuroblastoma cases and 1869 MYCN-nonamplified non-high-risk neuroblastoma cases as controls using a fixed-effects model with inverse variance weighting. All statistical tests were two-sided. We identified a novel locus at 3p21.31 indexed by the single nucleotide polymorphism (SNP) rs80059929 (odds ratio [OR] = 2.95, 95% confidence interval [CI] = 2.17 to 4.02, Pmeta = 6.47 × 10-12) associated with MYCN-amplified neuroblastoma, which was replicated in 127 MYCN-amplified cases and 254 non-high-risk controls (OR = 2.30, 95% CI = 1.12 to 4.69, Preplication = .02). To confirm this signal is exclusive to MYCN-amplified tumors, we performed a second meta-analysis comparing 728 MYCN-nonamplified high-risk patients to identical controls. rs80059929 was not statistically significant in MYCN-nonamplified high-risk patients (OR = 1.24, 95% CI = 0.90 to 1.71, Pmeta = .19). SNP rs80059929 is within intron 16 in the KIF15 gene. Additionally, the previously reported LMO1 neuroblastoma risk locus was statistically significant only in patients with MYCN-nonamplified high-risk tumors (OR = 0.63, 95% CI = 0.53 to 0.75, Pmeta = 1.51 × 10-8; Pmeta = .95). Our results indicate that common genetic variation predisposes to different neuroblastoma genotypes, including the likelihood of somatic MYCN-amplification. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Measuring and Validating a General Cancer Predisposition Perception Scale: An Adaptation of the Revised-IPQ-Genetic Predisposition Scale.

    Directory of Open Access Journals (Sweden)

    Wendy Wing Tak Lam

    Full Text Available Illness perceptions are linked to individual help-seeking and preventive behaviors. Previous illness perception studies have identified five dimensions of illness-related experience and behaviour. The Revised Illness Perception Questionnaire (IPQ-R for genetic predisposition (IPQ-R-GP was developed to measure illness perceptions in those genetically-predisposed to blood disease. We adapted the IPQ-R-GP to measure perceptions of generalized cancer predisposition. This paper describes the development and validation of the Cancer Predisposition Perception Scale (CPPS.The draft CPPS scale was first administered to 167 well Hepatitis B carriers and 123 other healthy individuals and the factor structure was examined using Exploratory Factor Analysis. Then the factor structure was confirmed in a second sample comprising 148 healthy controls, 150 smokers and 152 passive smokers using Confirmatory Factor Analysis (CFA.Six-factors comprising 26 items provided optimal fit by eigen and scree-plot methods, accounting for 58.9% of the total variance. CFA indicated good fit of the six-factor model after further excluding three items. The six factors, Emotional representation (5 items, Illness coherence (4 items, Treatment control (3 items, Consequences (5 items, Internal locus of control (2 items and External locus of control (4 items demonstrated adequate-to-good subscale internal consistency (Cronbach's α = 0.63-0.90. Divergent validity was suggested by low correlations with optimism, self-efficacy, and scales for measuring physical and psychological health symptoms.The CPPS appears to be a valid measure of perceived predisposition to generic cancer risks and can be used to examine cancer-risk-related cognitions in individuals at higher and lower cancer risk.

  17. Measuring and Validating a General Cancer Predisposition Perception Scale: An Adaptation of the Revised-IPQ-Genetic Predisposition Scale.

    Science.gov (United States)

    Lam, Wendy Wing Tak; Liao, Qiuyan; Wong, Jennifer Hiu Fai; Lai, Ching Lung; Yuen, Man Fung; Tsang, Janice Wing Hang; Fielding, Richard

    2015-01-01

    Illness perceptions are linked to individual help-seeking and preventive behaviors. Previous illness perception studies have identified five dimensions of illness-related experience and behaviour. The Revised Illness Perception Questionnaire (IPQ-R) for genetic predisposition (IPQ-R-GP) was developed to measure illness perceptions in those genetically-predisposed to blood disease. We adapted the IPQ-R-GP to measure perceptions of generalized cancer predisposition. This paper describes the development and validation of the Cancer Predisposition Perception Scale (CPPS). The draft CPPS scale was first administered to 167 well Hepatitis B carriers and 123 other healthy individuals and the factor structure was examined using Exploratory Factor Analysis. Then the factor structure was confirmed in a second sample comprising 148 healthy controls, 150 smokers and 152 passive smokers using Confirmatory Factor Analysis (CFA). Six-factors comprising 26 items provided optimal fit by eigen and scree-plot methods, accounting for 58.9% of the total variance. CFA indicated good fit of the six-factor model after further excluding three items. The six factors, Emotional representation (5 items), Illness coherence (4 items), Treatment control (3 items), Consequences (5 items), Internal locus of control (2 items) and External locus of control (4 items) demonstrated adequate-to-good subscale internal consistency (Cronbach's α = 0.63-0.90). Divergent validity was suggested by low correlations with optimism, self-efficacy, and scales for measuring physical and psychological health symptoms. The CPPS appears to be a valid measure of perceived predisposition to generic cancer risks and can be used to examine cancer-risk-related cognitions in individuals at higher and lower cancer risk.

  18. Genetic predisposition increases the tic severity, rate of comorbidities, and psychosocial and educational difficulties in children with Tourette syndrome.

    Science.gov (United States)

    Eysturoy, Absalon Niclas; Skov, Liselotte; Debes, Nanette Mol

    2015-03-01

    This study aimed to examine whether there are differences in tic severity, comorbidities, and psychosocial and educational consequences in children with Tourette syndrome and genetic predisposition to Tourette syndrome compared with children with Tourette syndrome without genetic predisposition to Tourette syndrome. A total of 314 children diagnosed with Tourette syndrome participated in this study. Validated diagnostic tools were used to assess tic severity, comorbidities, and cognitive performance. A structured interview was used to evaluate psychosocial and educational consequences related to Tourette syndrome. The children with Tourette syndrome and genetic predisposition present with statistically significant differences in terms of severity of tics, comorbidities, and a range of psychosocial and educational factors compared with the children with Tourette syndrome without genetic predisposition. Professionals need to be aware of genetic predisposition to Tourette syndrome, as children with Tourette syndrome and genetic predisposition have more severe symptoms than those children with Tourette syndrome who are without genetic predisposition. © The Author(s) 2014.

  19. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

    Science.gov (United States)

    Ware, James S; Li, Jian; Mazaika, Erica; Yasso, Christopher M; DeSouza, Tiffany; Cappola, Thomas P; Tsai, Emily J; Hilfiker-Kleiner, Denise; Kamiya, Chizuko A; Mazzarotto, Francesco; Cook, Stuart A; Halder, Indrani; Prasad, Sanjay K; Pisarcik, Jessica; Hanley-Yanez, Karen; Alharethi, Rami; Damp, Julie; Hsich, Eileen; Elkayam, Uri; Sheppard, Richard; Kealey, Angela; Alexis, Jeffrey; Ramani, Gautam; Safirstein, Jordan; Boehmer, John; Pauly, Daniel F; Wittstein, Ilan S; Thohan, Vinay; Zucker, Mark J; Liu, Peter; Gorcsan, John; McNamara, Dennis M; Seidman, Christine E; Seidman, Jonathan G; Arany, Zoltan

    2016-01-21

    Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

  20. Genetic predisposition syndromes: when should they be considered in the work-up of MDS?

    Science.gov (United States)

    Babushok, Daria V; Bessler, Monica

    2015-03-01

    Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute myeloid leukemia (AML). While sporadic MDS is primarily a disease of the elderly, MDS in children and young and middle-aged adults is frequently associated with underlying genetic predisposition syndromes. In addition to the classic hereditary bone marrow failure syndromes (BMFS) such as Fanconi Anemia and Dyskeratosis Congenita, in recent years there has been an increased awareness of non-syndromic familial MDS/AML predisposition syndromes such as those caused by mutations in GATA2, RUNX1, CEBPA, and SRP72 genes. Here, we will discuss the importance of recognizing an underlying genetic predisposition syndrome a patient with MDS, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common BMFS and familial MDS/AML syndromes which may be encountered in adult patients with MDS. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Cannabis use and genetic predisposition for schizophrenia: a case-control study.

    Science.gov (United States)

    Veling, W; Mackenbach, J P; van Os, J; Hoek, H W

    2008-09-01

    Cannabis use may be a risk factor for schizophrenia. Part of this association may be explained by genotype-environment interaction, and part of it by genotype-environment correlation. The latter issue has not been explored. We investigated whether cannabis use is associated with schizophrenia, and whether gene-environment correlation contributes to this association, by examining the prevalence of cannabis use in groups with different levels of genetic predisposition for schizophrenia. Case-control study of first-episode schizophrenia. Cases included all non-Western immigrants who made first contact with a physician for schizophrenia in The Hague, The Netherlands, between October 2000 and July 2005 (n=100; highest genetic predisposition). Two matched control groups were recruited, one among siblings of the cases (n=63; intermediate genetic predisposition) and one among immigrants who made contact with non-psychiatric secondary health-care services (n=100; lowest genetic predisposition). Conditional logistic regression analyses were used to predict schizophrenia as a function of cannabis use, and cannabis use as a function of genetic predisposition for schizophrenia. Cases had used cannabis significantly more often than their siblings and general hospital controls (59, 21 and 21% respectively). Cannabis use predicted schizophrenia [adjusted odds ratio (OR) cases compared to general hospital controls 7.8, 95% confidence interval (CI) 2.7-22.6; adjusted OR cases compared to siblings 15.9 (95% CI 1.5-167.1)], but genetic predisposition for schizophrenia did not predict cannabis use [adjusted OR intermediate predisposition compared to lowest predisposition 1.2 (95% CI 0.4-3.8)]. Cannabis use was associated with schizophrenia but there was no evidence for genotype-environment correlation.

  2. Considerations for comprehensive assessment of genetic predisposition in familial breast cancer.

    Science.gov (United States)

    Lynch, Henry; Synder, Carrie; Wang, San Ming

    2015-01-01

    About 10-15% of breast cancer cases are family related, classified as familial breast cancer. The disease was first reported in 1866 and determined to be an autosomal dominant genetic disease in 1971. Germline mutations in BRCA1 were discovered and deemed as the first genetic predisposition for the disease in 1994. By now, genetic predispositions for about 40% of familial breast cancer families have been identified. New molecular genetic approaches currently under development should accelerate the process to identify the full spectrum of genetic predispositions for the disease, thereby enabling a better understanding of the genetic basis of the disease and therein providing benefit to high-risk patients. © 2014 Wiley Periodicals, Inc.

  3. Genetic predisposition to testicular germ-cell tumours

    NARCIS (Netherlands)

    Lutke-Holzik, MF; Rapley, EA; Hoekstra, HJ; Sleijfer, DT; Nolte, IM; Sijmons, RH

    Testicular germ-cell tumours (TGCT) are the most common neoplasm in young men. Various studies have suggested the existence of an inherited predisposition to development of these tumours. Genome-wide screens subsequently provided evidence of a TGCT susceptibility gene on chromosome Xq27 (TGCT1) that

  4. Genetic Predisposition to High Blood Pressure Associates With Cardiovascular Complications Among Patients With Type 2 Diabetes

    Science.gov (United States)

    Qi, Qibin; Forman, John P.; Jensen, Majken K.; Flint, Alan; Curhan, Gary C.; Rimm, Eric B.; Hu, Frank B.; Qi, Lu

    2012-01-01

    Hypertension and type 2 diabetes (T2D) commonly coexist, and both conditions are major risk factors for cardiovascular disease (CVD). We aimed to examine the association between genetic predisposition to high blood pressure and risk of CVD in individuals with T2D. The current study included 1,005 men and 1,299 women with T2D from the Health Professionals Follow-up Study and Nurses’ Health Study, of whom 732 developed CVD. A genetic predisposition score was calculated on the basis of 29 established blood pressure–associated variants. The genetic predisposition score showed consistent associations with risk of CVD in men and women. In the combined results, each additional blood pressure–increasing allele was associated with a 6% increased risk of CVD (odds ratio [OR] 1.06 [95% CI 1.03–1.10]). The OR was 1.62 (1.22–2.14) for risk of CVD comparing the extreme quartiles of the genetic predisposition score. The genetic association for CVD risk was significantly stronger in patients with T2D than that estimated in the general populations by a meta-analysis (OR per SD of genetic score 1.22 [95% CI 1.10–1.35] vs. 1.10 [1.08–1.12]; I2 = 71%). Our data indicate that genetic predisposition to high blood pressure is associated with an increased risk of CVD in individuals with T2D. PMID:22829449

  5. KCNQ1OT1 hypomethylation: A Novel disguised genetic predisposition in sporadic pediatric adrenocortical tumors?

    NARCIS (Netherlands)

    Wijnen, Mark; Alders, Mariëlle; Zwaan, Christian M.; Wagner, Anja; van den Heuvel-Eibrink, Marry M.

    2012-01-01

    Pediatric adrenal tumors, other than neuroblastoma, are rare and can be associated with a genetic predisposition. In this report we describe two patients with an isolated and apparently sporadic adrenocortical tumor; one girl with a carcinoma, the other girl with an adenoma. In both patients genetic

  6. The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development.

    Science.gov (United States)

    Hardtke-Wolenski, Matthias; Dywicki, Janine; Fischer, Katja; Hapke, Martin; Sievers, Maren; Schlue, Jerome; Anderson, Mark S; Taubert, Richard; Noyan, Fatih; Manns, Michael P; Jaeckel, Elmar

    2017-03-01

    Autoimmune hepatitis (AIH) is defined as a chronic liver inflammation with loss of tolerance against hepatocytes. The etiology and pathophysiology of AIH are still poorly understood because reliable animal models are limited. Therefore, we recently introduced a model of experimental murine AIH by a self-limited adenoviral infection with the AIH type 2 antigen formiminotransferase cyclodeaminase (FTCD). We could demonstrate that break of humoral tolerance towards liver specific autoantigens like FTCD and cytochrome P450 2D6 (CYP2D6) is not dependent on the genetic background. However, the development of AIH in autoantibody positive animals is determined by genetic background genes. We could also show that the break of humoral tolerance is necessary but not sufficient for the development of AIH. In contrast the break of tolerance against the ubiquitously expressed nuclear antigens (ANAs) is strictly dependent on genetic predisposition. Priming with the UGA suppressor tRNA-associated protein (soluble liver antigen; SLA) is a strong inducer of ANA reactivity, but not sufficient to cause AIH development thereby questioning the importance of anti-SLA immune response as an important driver in AIH. Monogenetic mutations such as Aire-deficiency can cause AIH in otherwise genetically resistant strains. The results have important implications for our understanding of the pathophysiology of AIH development and for the interpretation of humoral antibody responses in AIH. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Genetic predisposition toward suicidal ideation in patients with acute coronary syndrome.

    Science.gov (United States)

    Kang, Hee-Ju; Bae, Kyung-Yeol; Kim, Sung-Wan; Shin, Il-Seon; Hong, Young Joon; Ahn, Youngkeun; Jeong, Myung Ho; Yoon, Jin-Sang; Kim, Jae-Min

    2017-11-07

    The genetic predisposition toward suicidal ideation has been explored to identify subgroups at high risk and to prevent suicide. Acute coronary syndrome (ACS) is associated with an increased risk of suicide, but few studies have explored the genetic predisposition toward suicide in ACS populations. Therefore, this longitudinal study explored the genetic predisposition toward suicidal ideation in ACS patients. In total, of 969 patients within 2 weeks after ACS, 711 were followed at 1 year after ACS. Suicidal ideation was evaluated with the relevant items on the Montgomery-Åsberg Depression Rating Scale. Ten genetic polymorphisms associated with serotonergic systems, neurotrophic factors, carbon metabolism, and inflammatory cytokines were examined. Associations between genetic polymorphisms and suicidal ideation within 2 weeks and 1 year of ACS were investigated using logistic regression models. The 5-HTTLPR s allele was significantly associated with suicidal ideation within 2 weeks of ACS after adjusting for covariates and after the Bonferroni correction. TNF-α -308 G/A , IL-1β -511 C/T , and IL-1β + 3953C/T were significantly associated with suicidal ideation within 2 weeks after ACS, but these associations did not reach significance after the Bonferroni correction in unadjusted analyses and after adjusting for covariance. However, no significant association between genetic polymorphisms and suicidal ideation was found at 1 year. Genetic predisposition, 5-HTTLPR s allele in particular, may confer susceptibility to suicidal ideation in ACS patients during the acute phase of ACS.

  8. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis.

    Science.gov (United States)

    Arner, Peter; Arner, Erik; Hammarstedt, Ann; Smith, Ulf

    2011-04-12

    Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue. We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition. Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess.

  9. Interaction of genetic predisposition and environmental factors in the pathogenesis of idiopathic orthostatic intolerance

    Science.gov (United States)

    Jordan, J.; Shannon, J. R.; Jacob, G.; Pohar, B.; Robertson, D.

    1999-01-01

    BACKGROUND: The hemodynamic and autonomic abnormalities in idiopathic orthostatic intolerance (IOI) have been studied extensively. However, the mechanisms underlying these abnormalities are not understood. If genetic predisposition were important in the pathogenesis of IOI, monozygotic twins of patients with IOI should have similar hemodynamic and autonomic abnormalities. METHODS: We studied two patients with IOI and their identical twins. Both siblings in the first twin pair had orthostatic symptoms, significant orthostatic tachycardia, increased plasma norepinephrine levels with standing, and a greater than normal decrease in systolic blood pressure with trimethaphan infusion. RESULTS: Both siblings had a normal response of plasma renin activity to upright posture. In the second twin pair, only one sibling had symptoms of orthostatic intolerance, an orthostatic tachycardia, and raised plasma catecholamines with standing. The affected sibling had inappropriately low plasma renin activity with standing and was 8-fold more sensitive to the pressor effect of phenylephrine than the unaffected sibling. CONCLUSIONS: We conclude that in some patients, IOI seems to be strongly influenced by genetic factors. In others, however, IOI may be mainly caused by nongenetic factors. These findings suggest that IOI is heterogenous, and that both genetic and environmental factors contribute individually or collectively to create the IOI phenotype.

  10. Maxillary canine displacement and genetically determined predisposition to disturbed development of the dentition.

    Science.gov (United States)

    Stahl, Franka; Grabowski, Rosemarie

    2003-05-01

    The relationship between maxillary canine displacement and the simultaneous occurrence of "genetically determined predisposition to disturbed development of the dentition" as defined by Hoffmeister was investigated in 675 patients. Panoramic radiographs taken of each patient during the first and the second mixed dentition periods were evaluated. Canine inclination and the distance between the tip of the canine and a line connecting the cusps of the molars were computed in five different age groups according to Dausch-Neumann. Statistical analysis revealed 34 patients with "potential canine displacement", who exhibited further symptoms of "genetically determined predisposition to disturbed development of the dentition" significantly more frequently than the total group. The symptoms concerned were agenesia, displaced tooth buds, rotated or tilted incisors, aplasia and microdontia of lateral incisors. Careful follow-ups in patients with a predisposition to disturbed dental development enables risks to be anticipated and canine displacement to be detected at an early stage.

  11. Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

    Science.gov (United States)

    Babushok, Daria V.; Bessler, Monica; Olson, Timothy S.

    2016-01-01

    Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes. PMID:26693794

  12. Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults.

    Science.gov (United States)

    Babushok, Daria V; Bessler, Monica; Olson, Timothy S

    2016-01-01

    Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes.

  13. Interaction between Genetic Predisposition to Adiposity and Dietary Protein in Relation to Subsequent Change in Body Weight and Waist Circumference

    DEFF Research Database (Denmark)

    Ankarfeldt, Mikkel Z; Larsen, Sofus C; Angquist, Lars

    2014-01-01

    BACKGROUND: Genetic predisposition to adiposity may interact with dietary protein in relation to changes of anthropometry. OBJECTIVE: To investigate the interaction between genetic predisposition to higher body mass index (BMI), waist circumference (WC) or waist-hip ratio adjusted for BMI (WHRBMI...

  14. Being at risk for cardiovascular disease: Perceptions and preventive behavior in people with and without a known genetic predisposition

    NARCIS (Netherlands)

    Claassen, E.A.M.; Henneman, L.; van der Weijden, T.; Marteau, T.M.; Timmermans, D.R.M.

    2012-01-01

    This study compares and explains differences in perceptions of cardiovascular disease (CVD) risk and preventive behaviors in people with and without a known genetic predisposition to CVD. A cross-sectional study using two samples was performed. The first sample (genetic predisposition; n=51)

  15. Genetic Predisposition to Central Obesity and Risk of Type 2 Diabetes: Two Independent Cohort Studies.

    Science.gov (United States)

    Huang, Tao; Qi, Qibin; Zheng, Yan; Ley, Sylvia H; Manson, JoAnn E; Hu, Frank B; Qi, Lu

    2015-07-01

    Abdominal obesity is a major risk factor for type 2 diabetes (T2D). We aimed to examine the association between the genetic predisposition to central obesity, assessed by the waist-to-hip ratio (WHR) genetic score, and T2D risk. The current study included 2,591 participants with T2D and 3,052 participants without T2D of European ancestry from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Genetic predisposition to central obesity was estimated using a genetic score based on 14 established loci for the WHR. We found that the central obesity genetic score was linearly related to higher T2D risk. Results were similar in the NHS (women) and HPFS (men). In combined results, each point of the central obesity genetic score was associated with an odds ratio (OR) of 1.04 (95% CI 1.01-1.07) for developing T2D, and the OR was 1.24 (1.03-1.45) when comparing extreme quartiles of the genetic score after multivariate adjustment. The data indicate that genetic predisposition to central obesity is associated with higher T2D risk. This association is mediated by central obesity. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  16. Developing national guidance on genetic testing for breast cancer predisposition: the role of economic evidence?

    NARCIS (Netherlands)

    Sullivan, W.; Evans, D.G.; Newman, W.G.; Ramsden, S.C.; Scheffer, H.; Payne, K.

    2012-01-01

    Advancements in genetic testing to identify predisposition for hereditary breast cancer (HBC) mean that it is important to understand the incremental costs and benefits of the new technologies compared with current testing strategies. This study aimed to (1) identify and critically appraise existing

  17. Integrated screening concept in women with genetic predisposition for breast cancer

    International Nuclear Information System (INIS)

    Bick, U.

    1997-01-01

    Breast cancer is in 5% of cases due to a genetic disposition. BRCA1 and BRCA2 are by far the most common breast cancer susceptibility genes. For a woman with a genetic predisposition, the individual risk of developing breast cancer sometime in her life is between 70 and 90%. Compared to the spontaneous forms of breast cancer, woman with a genetic predisposition often develop breast cancer at a much younger age. This is why conventional screening programs on the basis of mammography alone cannot be applied without modification to this high-risk group. In this article, an integrated screening concept for women with genetic prodisposition for breast cancer using breast self-examination, clinical examination, ultrasound, mammography and magnetic resonance imaging is introduced. (orig.) [de

  18. Effects of early life trauma are dependent on genetic predisposition: a rat study

    Directory of Open Access Journals (Sweden)

    Russell Vivienne A

    2011-05-01

    Full Text Available Abstract Background Trauma experienced early in life increases the risk of developing a number of psychological and/or behavioural disorders. It is unclear, however, how genetic predisposition to a behavioural disorder, such as attention-deficit/hyperactivity disorder (ADHD, modifies the long-term effects of early life trauma. There is substantial evidence from family and twin studies for susceptibility to ADHD being inherited, implying a strong genetic component to the disorder. In the present study we used an inbred animal model of ADHD, the spontaneously hypertensive rat (SHR, to investigate the long-term consequences of early life trauma on emotional behaviour in individuals predisposed to developing ADHD-like behaviour. Methods We applied a rodent model of early life trauma, maternal separation, to SHR and Wistar-Kyoto rats (WKY, the normotensive control strain from which SHR were originally derived. The effects of maternal separation (removal of pups from dam for 3 h/day during the first 2 weeks of life on anxiety-like behaviour (elevated-plus maze and depressive-like behaviour (forced swim test were assessed in prepubescent rats (postnatal day 28 and 31. Basal levels of plasma corticosterone were measured using radioimmunoassay. Results The effect of maternal separation on SHR and WKY differed in a number of behavioural measures. Similar to its reported effect in other rat strains, maternal separation increased the anxiety-like behaviour of WKY (decreased open arm entries but not SHR. Maternal separation increased the activity of SHR in the novel environment of the elevated plus-maze, while it decreased that of WKY. Overall, SHR showed a more active response in the elevated plus-maze and forced swim test than WKY, regardless of treatment, and were also found to have higher basal plasma corticosterone compared to WKY. Maternal separation increased basal levels of plasma corticosterone in SHR females only, possibly through adaptive

  19. Genetic predisposition to salt-sensitivity : a systematic review

    NARCIS (Netherlands)

    Beeks, Esther; Kessels, Alfons G H; Kroon, Abraham A; van der Klauw, Melanie M; de Leeuw, Peter W

    PURPOSE: To assess the role of genetic polymorphisms in salt sensitivity of blood pressure. DATA IDENTIFICATION: We conducted a systematic review by searching the Medline literature from March 1993 to June 2003. Each paper was scrutinized and data concerning study population, method of salt

  20. Genetic counselling for hereditary predisposition to ovarian and breast cancer.

    Science.gov (United States)

    Mackay, J; Szecsei, C M

    2010-10-01

    Since the identification of BRCA 1 and 2 in 1995, testing for mutations in these genes has been offered to cancer patients and their families by clinical genetics services. These services are provided across Europe by a small number of health professionals, and are therefore low volume, and low capacity and patients experience considerable delays, both in seeing a clinician and in laboratory testing. The UK private sector, driven by consumer demand and professional competition, has significantly reduced these delays. The development of a new class of therapeutic agent, the PARP inhibitors, is likely to drive the BRCA testing services towards the UK private sector model with much faster turnaround times. Several new genetic tests are now available including CYP 2D6 genotype analysis and the BCtect test. The clinical interpretation of these tests is complex, and the professional community has been naturally cautious about adopting new tests in clinical care. This article will examine the consequences of expected changes in BRCA testing practice, and consider the positioning of new tests in the patient pathway, and the messages given by health professionals.

  1. Bone sarcoma as a second malignant neoplasm in children: influence of radiation and genetic predisposition

    International Nuclear Information System (INIS)

    Meadows, A.T.; Strong, L.C.; Li, F.P.; D'angio, G.J.; Schweisguth, O.; Freeman, A.I.; Jenkin, R.D.T.; Morris-Jones, P.; Nesbit, M.E.

    1980-01-01

    Osteosarcoma or chondrosarcoma developed as a second malignant neoplasm (SMN) in 40 of 188 individuals with SMN whose first neoplasm occurred in childhood. A genetic susceptibility to cancer was found in 23; the SMN developed in an irradiated field in 32; both factors were present in 16; neither in one. When a genetic predisposition was present, radiation shortened the interval to SMN. The intervals between tumors and the age at which the bone sarcomas developed in relation to genetic disease and therapy were analyzed by a two-mutation hypothesis

  2. Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

    Science.gov (United States)

    De Ruyck, K; de Gelder, V; Van Eijkeren, M; Boterberg, T; De Neve, W; Vral, A; Thierens, H

    2008-01-01

    The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G2 assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (Pgenetic predisposition to head and neck cancer, and the genetic contribution is highest for oral cavity and pharynx cancer patients and for early onset and non- and light smoking patients. PMID:18414410

  3. Genetic predisposition and genomic instability: studies with mouse embryos

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, C. [Universitaetsklinikum Essen (Germany). Inst. fuer Medizinische Strahlenbiologie

    1999-07-01

    The preimplantation mouse embryo is a useful system for radiobiological studies. Chromosomal aberrations were determined after exposure to X-rays and neutrons during the zygote (1-cell stage). New aberrations developed and were expressed during the 2nd and 3rd mitosis after irradiation. These later aberration developed from DNA damage which was originally not a DSB. Further chromosomal aberrations were studied in fibroblasts of fetuses 19 days post conception. A significant increase of chromosome aberrations was found in the fetuses which were irradiated in the 1-cell stage and which had developed a malformation. These data can only be explained by the induction of a genome instability through the radiation exposure which had been performed many cell generations earlier. Until recently it was generally accepted that an exposure to ionizing radiation during the preimplantation period of mammalian development will not induce malformations. However, recently it could be shown that certain sensitive mouse strains exist in which malformations are induced by exposure to X-rays and neutrons during the preimplantation period. It was further demonstrated that this effect can be suppressed if the sensitive mouse strain is crossbred with mice from a resistant mouse strain. These data show that this radiation effect is due to a genetic phenomenon with a recessive trait. Studies on protein patterns in normal fetuses and in fetuses with the malformation showed that characteristic changes occur. There are proteins which are no longer expressed in the malformed fetuses and new proteins may appear. Certain changes in glycoproteins and phosphoproteins were found not only in liver of malformed fetuses but also in skin and kidney of these organisms. The analysis of the genome of these malformed fetuses have given evidence that changes in two or three genes are responsible for the radiation-induced malformation. It was possible to localize 1 gene on chromosome 13 and another gene on

  4. Genetic predisposition to chikungunya ? a blood group study in chikungunya affected families

    OpenAIRE

    Sudarsanareddy, Lokireddy; Sarojamma, Vemula; Ramakrishna, Vadde

    2009-01-01

    Abstract Chikungunya fever is a viral disease transmitted to humans by the bite of CHIKV virus infected Aedes mosquitoes. During monsoon outbreak of chikungunya fever, we carried out the genetic predisposition to chikungunya in disease affected 100 families by doing blood group (ABO) tests by focusing on individuals who were likely to have a risk of chikungunya and identified the blood group involved in susceptibility/resistance to chikungunya. In the present study, based on blood group antig...

  5. Diabetes genetic predisposition score and cardiovascular complications among patients with type 2 diabetes.

    Science.gov (United States)

    Qi, Qibin; Meigs, James B; Rexrode, Kathryn M; Hu, Frank B; Qi, Lu

    2013-03-01

    To examine the association between genetic predisposition to type 2 diabetes (T2D) and risk of cardiovascular disease (CVD) among patients with T2D. The current study included 1,012 men and 1,310 women with T2D from the Health Professionals Follow-up Study and Nurses' Health Study, including 677 patients with CVD and 1,645 non-CVD control subjects. A genetic predisposition score (GPS) was calculated on the basis of 36 established independent diabetes-predisposing variants. Each additional diabetes-risk allele in the GPS was associated with a 3% increased risk of CVD (odds ratio [OR] 1.03 [95% CI 1.00-1.06]). The OR was 1.47 (1.11-1.95) for CVD risk by comparing extreme quartiles of the GPS (P for trend = 0.01). We also found that the GPS was positively associated with hemoglobin A(1c) levels (P = 0.009). Genetic predisposition to T2D is associated with an increased risk of cardiovascular complications in patients with T2D.

  6. Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition.

    Science.gov (United States)

    Diets, I J; Nagtegaal, I D; Loeffen, J; de Blaauw, I; Waanders, E; Hoogerbrugge, N; Jongmans, M C J

    2017-01-17

    Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. Using the Dutch Pathology Registry PALGA, we collected patient- and tumour data of paediatric NETs in the Netherlands between 1991 and 2013 (N=483). The incidence of paediatric NETs in the Netherlands is 5.40 per one million per year. The majority of NETs were appendiceal tumours (N=441;91.3%). Additional surgery in appendiceal NETs was indicated in 89 patients, but performed in only 27 of these patients. Four out of five patients with pancreatic NETs were diagnosed with Von Hippel-Lindau disease (N=2) and Multiple Endocrine Neoplasia type 1 (N=2). In one patient with an appendiceal NET Familial Adenomatous Polyposis was diagnosed. On the basis of second primary tumours or other additional diagnoses, involvement of genetic predisposition was suggestive in several others. We identified a significant number of patients with a confirmed or suspected tumour predisposition syndrome and show that paediatric pancreatic NETs in particular are associated with genetic syndromes. In addition, we conclude that treatment guidelines for appendiceal paediatric NETs need revision and improved implementation.

  7. Genetic predisposition to dyslipidemia and type 2 diabetes risk in two prospective cohorts.

    Science.gov (United States)

    Qi, Qibin; Liang, Liming; Doria, Alessandro; Hu, Frank B; Qi, Lu

    2012-03-01

    Dyslipidemia has been associated with type 2 diabetes, but it remains unclear whether dyslipidemia plays a causal role in type 2 diabetes. We aimed to examine the association between the genetic predisposition to dyslipdemia and type 2 diabetes risk. The current study included 2,447 patients with type 2 diabetes and 3,052 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-up Study. Genetic predisposition to dyslipidemia was estimated by three genotype scores of lipids (LDL cholesterol, HDL cholesterol, and triglycerides) on the basis of the established loci for blood lipids. Linear relation analysis indicated that the HDL cholesterol and triglyceride genotype scores, but not the LDL cholesterol genotype score, were linearly related to elevated type 2 diabetes risk. Each point of the HDL cholesterol and triglyceride genotype scores was associated with a 3% (odds ratio [OR] 1.03 [95% CI 1.01-1.04]) and a 2% (1.02 [1.00-1.04]) increased risk of developing type 2 diabetes, respectively. The ORs were 1.39 (1.17-1.65) and 1.19 (1.01-1.41) for type 2 diabetes by comparing extreme quartiles of the HDL cholesterol genotype score and triglyceride genotype score, respectively. In conclusion, genetic predisposition to low HDL cholesterol or high triglycerides is related to elevated type 2 diabetes risk.

  8. Statin-associated myopathy: from genetic predisposition to clinical management.

    Science.gov (United States)

    Vrablik, M; Zlatohlavek, L; Stulc, T; Adamkova, V; Prusikova, M; Schwarzova, L; Hubacek, J A; Ceska, R

    2014-01-01

    Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.

  9. Comparative phenotypic and cytochemical characteristics of lymphocytes of Wistar rats and rats with genetic predisposition to catalepsy after retabolil administration.

    Science.gov (United States)

    Panteleeva, N G; Shurlygina, A V; Trufakin, V A

    2013-11-01

    We studied the possibility of using anabolic steroid retabolil injections for complex correction of behavioral and immune parameters in rats with genetic predisposition to catalepsy. Subpopulation composition of lymphoid organ and blood cells was compared in rats with genetic predisposition to catalepsy and Wistar rats after retabolil administration. In rats predisposed to catalepsy, retabolil reduced the total content of thymus cells and increased absolute count of CD8 (+) thymocytes. In Wistar rats, retabolil increased the total cell count and the content of CD4 (+) thymocytes, but reduced the number of CD8 (+) cells. Therefore, changes in the subpopulation composition of thymus cells after retabolil administration were opposite in rats with genetic predisposition to catalepsy and Wistar rats. Retabolil injections reduced the severity of catalepsy response in rats with genetic predisposition. However, the time of freezing in Wistar rats significantly increased under these conditions.

  10. Interaction between genetic predisposition to obesity and dietary calcium in relation to subsequent change in body weight and waist circumference

    DEFF Research Database (Denmark)

    Larsen, Sofus C; Angquist, Lars; Ahluwalia, Tarun Veer Singh

    2014-01-01

    Studies indicate an effect of dietary calcium on change in body weight (BW) and waist circumference (WC), but the results are inconsistent. Furthermore, a relation could depend on genetic predisposition to obesity.......Studies indicate an effect of dietary calcium on change in body weight (BW) and waist circumference (WC), but the results are inconsistent. Furthermore, a relation could depend on genetic predisposition to obesity....

  11. Significance of genetic predisposition and genomic instability for individual sensitivity to radiation. Implications for radiation protection

    International Nuclear Information System (INIS)

    Heller, H.

    2001-01-01

    At its closed-door meeting on 20/21 January 2000 the Radiation Protection Committee dedicated much of its attention to the significance of genetic predisposition and genetic instability for individual radiation sensitivity and to the implication of this for radiation protection. The statements and contributions to the closing plenary discussion touched on many aspects of ethics, personal rights, occupational medicine and insurance issues relating to this subject, all of which extend far beyond the purely technical issues of radiation protection. The present volume contains the lecture manuscripts of the meeting as well as a summarising assessment by the Radiation Protection Committee [de

  12. Radiation-induced breast cancer: Influence of age at exposure, latency period, age, and genetic predisposition

    International Nuclear Information System (INIS)

    Kuni, H.

    2001-01-01

    Radiation induced breast cancer: Influence of age at exposure, time since exposure, attained age and genetic predisposition. The amount of undesirable effects of screening with mammography was estimated from mortality studies after radiation exposure. Newer incidence studies demonstrate, however, an underestimation of the health detriment by mortality studies, in particular with increasing age at exposure, which amounts about five- to sixfold after an exposure in an age of 45-50y. The multidimensional analysis of the discrete values of incidence after radiation exposure respecting age at exposure, time since exposure and attained age instead of calculating a steady function simply depending from age at exposure results in an increasing relative and absolute risk of cancer incidence (and mortality) with growing age after an exposure at an age above 40y. Some genes seems to be correlated with an predisposition of breast cancer. In women carrying BRCA-1 the radiosensitivity for induction of breast cancer may exceed the risk in the normal population by about two orders of magnitude. The resulting doubling dose amounts in the order of the natural and medical radiation exposure. At least in part the genetic predisposition is associated with an early onset of the cancer after an additional radiation exposure. This kind of health detriment was not considered in the former discussion of radiation hazards. (orig.) [de

  13. Genetic Predisposition and Cellular Basis for Ischemia-induced ST Segment Changes and Arrhythmias

    Science.gov (United States)

    Hu, Dan; Viskin, Sami; Oliva, Antonio; Cordeiro, Jonathan M.; Guerchicoff, Alejandra; Pollevick, Guido D.; Antzelevitch, Charles

    2007-01-01

    Recent reports have highlighted the importance of a family history of sudden death as a risk for ventricular fibrillation in patients experiencing an acute myocardial infarction (AMI), pointing to the possibility of a genetic predisposition. This report briefly reviews two recent studies designed to examine the hypothesis that there is a genetic predisposition to the development of arrhythmias associated with AMI. Ventricular tachycardia and fibrillation (VT/VF) complicating AMI as well as the arrhythmias associated with Brugada syndrome, a genetic disorder linked to SCN5A mutations, have both been linked to phase 2 reentry. Because of these mechanistic similarities in arrhythmogenesis, we examined the contribution of SCN5A mutations to VT/VF complicating AMI in patients developing VF during AMI. A missense mutation in SCN5A was found in a patient who developed an arrhythmic electrical storm during an evolving MI. All VT/VF episodes were associated with ST segment changes and were initiated by short-coupled extrasystoles. The G400A mutation and a H558R polymorphism were on the same allele and functional expression in TSA201 demonstrated a loss of function of sodium channel activity. These results suggest that a subclinical mutation in SCN5A resulting in a loss of function may predispose to life-threatening arrhythmias during acute ischemia. In another cohort of patients who developed long QT intervals and Torsade de Pointes (TdP) arrhythmias in days 2–11 following an AMI, a genetic screen of all long QT genes was performed. Six of eight patients (75%) in this group displayed the same polymorphism in KCNH2, which encodes the α subunit of the rapidly activating delayed rectifier potassium current, IKr. The K897T polymorphism was detected in only 3 of 14 patients with uncomplicated myocardial infarction (MI) and has been detected in 33% of the Caucasian population. Expression of this polymorphism has previously been shown to cause a loss of function in HERG current

  14. Being at risk for cardiovascular disease: perceptions and preventive behavior in people with and without a known genetic predisposition.

    Science.gov (United States)

    Claassen, L; Henneman, L; van der Weijden, T; Marteau, T M; Timmermans, D R M

    2012-01-01

    This study compares and explains differences in perceptions of cardiovascular disease (CVD) risk and preventive behaviors in people with and without a known genetic predisposition to CVD. A cross-sectional study using two samples was performed. The first sample (genetic predisposition; n = 51) consisted of individuals recently diagnosed with familial hypercholesterolemia (FH) through DNA testing. The second sample (no genetic predisposition; n = 49) was recruited among patients with CVD-risk profiles based on family history of CVD, cholesterol levels, and blood pressure, registered at general practices. Participants filled out a postal questionnaire asking about their perceived risk, causal attributions (i.e. genetic and lifestyle), and about perceived efficacy and adoption of preventive behavior (i.e. medication adherence and adoption of a healthy diet and being sufficiently active). Perceived comparative risk, genetic attributions of CVD, and perceived efficacy of medication were higher in the "genetic predisposition" sample than in the "no genetic predisposition" sample. The samples did not differ on lifestyle attributions, efficacy of a healthy lifestyle, or preventive behavior. Individual differences in perceived risk, genetic attributions, perceived efficacy of medication, and adoption of a healthy lifestyle were best explained by family history of CVD. Our findings suggest that in people diagnosed with a single gene disorder characterized by a family disease history such as FH, family disease history may be more important than DNA information in explaining perceptions of and responses to risk.

  15. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.

    Science.gov (United States)

    Vogelaar, Ingrid P; van der Post, Rachel S; van Krieken, J Han Jm; Spruijt, Liesbeth; van Zelst-Stams, Wendy Ag; Kets, C Marleen; Lubinski, Jan; Jakubowska, Anna; Teodorczyk, Urszula; Aalfs, Cora M; van Hest, Liselotte P; Pinheiro, Hugo; Oliveira, Carla; Jhangiani, Shalini N; Muzny, Donna M; Gibbs, Richard A; Lupski, James R; de Ligt, Joep; Vissers, Lisenka E L M; Hoischen, Alexander; Gilissen, Christian; van de Vorst, Maartje; Goeman, Jelle J; Schackert, Hans K; Ranzani, Guglielmina N; Molinaro, Valeria; Gómez García, Encarna B; Hes, Frederik J; Holinski-Feder, Elke; Genuardi, Maurizio; Ausems, Margreet G E M; Sijmons, Rolf H; Wagner, Anja; van der Kolk, Lizet E; Bjørnevoll, Inga; Høberg-Vetti, Hildegunn; van Kessel, Ad Geurts; Kuiper, Roland P; Ligtenberg, Marjolijn J L; Hoogerbrugge, Nicoline

    2017-11-01

    Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

  16. Genetic predisposition, dietary restraint and disinhibition in relation to short and long-term weight loss.

    Science.gov (United States)

    Verhoef, Sanne P M; Camps, Stefan G J A; Bouwman, Freek G; Mariman, Edwin C M; Westerterp, Klaas R

    2014-04-10

    Interindividual differences in response to weight loss and maintenance thereafter are ascribed to genetic predisposition and behavioral changes. To examine whether body weight and short and long-term body weight loss were affected by candidate single nucleotide polymorphisms (SNPs) and changes in eating behavior or by an interaction between these genetic and behavioral factors. 150 healthy subjects (39 males, 111 females) aged 20-50 y with a BMI of 27-38 kg/m(2) followed a very low energy diet for 8-weeks, followed by a 3-month weight maintenance period. SNPs were selected from six candidate genes: ADRB2, FTO, MC4R, PPARG, PPARD, and PPARGC1A. Changes in eating behavior were determined with the Three Factor Eating Questionnaire. A high genetic predisposition score was associated with a high body weight at baseline and more short-term weight loss. From the six selected obesity-related SNPs, FTO was associated with increased body weight at baseline, and the effect allele of PPARGC1A was positively associated with short-term weight loss, when assessed for each SNP separately. Long-term weight loss was associated with a larger increase in dietary restraint and larger decrease in disinhibition. During long-term weight loss, genetic effects are dominated by changes in eating behavior. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Genetic predisposition to high blood pressure associates with cardiovascular complications among patients with type 2 diabetes: two independent studies.

    Science.gov (United States)

    Qi, Qibin; Forman, John P; Jensen, Majken K; Flint, Alan; Curhan, Gary C; Rimm, Eric B; Hu, Frank B; Qi, Lu

    2012-11-01

    Hypertension and type 2 diabetes (T2D) commonly coexist, and both conditions are major risk factors for cardiovascular disease (CVD). We aimed to examine the association between genetic predisposition to high blood pressure and risk of CVD in individuals with T2D. The current study included 1,005 men and 1,299 women with T2D from the Health Professionals Follow-up Study and Nurses' Health Study, of whom 732 developed CVD. A genetic predisposition score was calculated on the basis of 29 established blood pressure-associated variants. The genetic predisposition score showed consistent associations with risk of CVD in men and women. In the combined results, each additional blood pressure-increasing allele was associated with a 6% increased risk of CVD (odds ratio [OR] 1.06 [95% CI 1.03-1.10]). The OR was 1.62 (1.22-2.14) for risk of CVD comparing the extreme quartiles of the genetic predisposition score. The genetic association for CVD risk was significantly stronger in patients with T2D than that estimated in the general populations by a meta-analysis (OR per SD of genetic score 1.22 [95% CI 1.10-1.35] vs. 1.10 [1.08-1.12]; I² = 71%). Our data indicate that genetic predisposition to high blood pressure is associated with an increased risk of CVD in individuals with T2D.

  18. Genetic predisposition to higher blood pressure increases risk of incident hypertension and cardiovascular diseases in Chinese.

    Science.gov (United States)

    Lu, Xiangfeng; Huang, Jianfeng; Wang, Laiyuan; Chen, Shufeng; Yang, Xueli; Li, Jianxin; Cao, Jie; Chen, Jichun; Li, Ying; Zhao, Liancheng; Li, Hongfan; Liu, Fangcao; Huang, Chen; Shen, Chong; Shen, Jinjin; Yu, Ling; Xu, Lihua; Mu, Jianjun; Wu, Xianping; Ji, Xu; Guo, Dongshuang; Zhou, Zhengyuan; Yang, Zili; Wang, Renping; Yang, Jun; Yan, Weili; Gu, Dongfeng

    2015-10-01

    Although multiple genetic markers associated with blood pressure have been identified by genome-wide association studies, their aggregate effect on risk of incident hypertension and cardiovascular disease is uncertain, particularly among East Asian who may have different genetic and environmental exposures from Europeans. We aimed to examine the association between genetic predisposition to higher blood pressure and risk of incident hypertension and cardiovascular disease in 26 262 individuals in 2 Chinese population-based prospective cohorts. A genetic risk score was calculated based on 22 established variants for blood pressure in East Asian. We found the genetic risk score was significantly and independently associated with linear increases in blood pressure and risk of incident hypertension and cardiovascular disease (P range from 4.57×10(-3) to 3.10×10(-6)). In analyses adjusted for traditional risk factors including blood pressure, individuals carrying most blood pressure-related risk alleles (top quintile of genetic score distribution) had 40% (95% confidence interval, 18-66) and 26% (6-45) increased risk for incident hypertension and cardiovascular disease, respectively, when compared with individuals in the bottom quintile. The genetic risk score also significantly improved discrimination for incident hypertension and cardiovascular disease and led to modest improvements in risk reclassification for cardiovascular disease (all the Pgenetic predisposition to higher blood pressure is an independent risk factor for blood pressure increase and incident hypertension and cardiovascular disease and provides modest incremental information to cardiovascular disease risk prediction. The potential clinical use of this panel of blood pressure-associated polymorphisms remains to be determined. © 2015 American Heart Association, Inc.

  19. Management of women who have a genetic predisposition for breast cancer.

    Science.gov (United States)

    Jatoi, Ismail; Anderson, William F

    2008-08-01

    The management of women who have a genetic predisposition for breast cancer requires careful planning. Women who have BRCA 1 and BRCA 2 mutations are at increased risk for breast cancer and for other cancers as well, particularly ovarian cancer. Screening, prophlyactic surgery, and chemoprevention are commonly utilized strategies in the management of these patients, and women may choose more than one of these strategies. No randomized prospective trials have assessed the impact of these strategies specifically in mutation carriers. All patients should be informed that screening, prophylactic surgery, and chemoprevention have the potential for harm as well as benefit.

  20. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

    DEFF Research Database (Denmark)

    Drost, Mark; Lützen, Anne; van Hees, Sandrine

    2013-01-01

    In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore...... are pathogenic, precludes targeted healthcare for both carriers and their relatives. To facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-based procedure for the large-scale mutagenization, identification, and cataloging of residues of MMR genes critical for MMR gene...

  1. Association between pepsinogen C gene polymorphism and genetic predisposition to gastric cancer

    Science.gov (United States)

    Liu, Hui-Jie; Guo, Xiao-Lin; Dong, Ming; Wang, Lan; Yuan, Yuan

    2003-01-01

    AIM: To identify a molecular marker for gastric cancer, and to investigate the relationship between the polymorphism of pepsinogen C (PGC) gene and the genetic predisposition to gastric cancer. METHODS: A total of 289 cases were involved in this study. 115 cases came from Shenyang area, a low risk area of gastric cancer, including 42 unrelated controls and 73 patients with gastric cancer. 174 cases came from Zhuanghe area, a high-risk area of gastric cancer, including 113 unrelated controls, and 61 cases from gastric cancer kindred families. The polymorphism of PGC gene was detected by polymerase chain reaction (PCR) and the relation between the genetic polymorphism of PGC and gastric cancer was examined. RESULTS: Four alleles, 310 bp (allele 1), 400 bp (allele 2), 450 bp (allele 3), and 480 bp (allele 4) were detected by PCR. The frequency of allele 1 was higher in patients with gastric cancer than that in controls. Genotypes containing homogenous allele 1 were significantly more frequent in patients with gastric cancer than that in controls (0.33, 0.14, χ2 = 3.86, P genetic predisposition to gastric cancer. The distribution of pepsinogen C gene polymorphism in Zhuanghe, a high-risk area of gastric cancer, is different from that in Shenyang, a low risk area of gastric cancer. PMID:12508350

  2. Cerebral small vessel disease in middle age and genetic predisposition to late-onset Alzheimer's disease.

    Science.gov (United States)

    Stefaniak, James D; Su, Li; Mak, Elijah; Sheikh-Bahaei, Nasim; Wells, Katie; Ritchie, Karen; Waldman, Adam; Ritchie, Craig W; O'Brien, John T

    2018-02-01

    Cerebral small vessel disease (CSVD) is associated with late-onset Alzheimer's disease (LOAD) and might contribute to the relationship between apolipoprotein E ε4 (APOE ε4) and LOAD, in older people. However, it is unclear whether CSVD begins in middle age in individuals genetically predisposed to LOAD. We assessed the relationship between radiological markers of CSVD, white matter hyperintensities and microbleeds, and genetic predisposition to LOAD in a cross-sectional analysis of cognitively normal subjects aged 40-59 years recruited from the PREVENT Dementia study. Microbleed prevalence was 14.5%, and mean ± standard deviation white matter hyperintensity percentage of total brain volume was 0.41 ± 0.28%. There was no significant association between APOE ε4 carrier status or history of parental dementia and white matter hyperintensity volume (P = .713, .912 respectively) or microbleeds (P = .082, .562 respectively) on multiple regression. Genetic predisposition to LOAD, through APOE genotype or AD family history, is not associated with CSVD in middle age. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  3. Whole Exome Sequencing Reveals Genetic Predisposition in a Large Family with Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Juan Wu

    2014-01-01

    Full Text Available Next-generation sequencing has become more widely used to reveal genetic defect in monogenic disorders. Retinitis pigmentosa (RP, the leading cause of hereditary blindness worldwide, has been attributed to more than 67 disease-causing genes. Due to the extreme genetic heterogeneity, using general molecular screening alone is inadequate for identifying genetic predispositions in susceptible individuals. In order to identify underlying mutation rapidly, we utilized next-generation sequencing in a four-generation Chinese family with RP. Two affected patients and an unaffected sibling were subjected to whole exome sequencing. Through bioinformatics analysis and direct sequencing confirmation, we identified p.R135W transition in the rhodopsin gene. The mutation was subsequently confirmed to cosegregate with the disease in the family. In this study, our results suggest that whole exome sequencing is a robust method in diagnosing familial hereditary disease.

  4. Recognition of genetic predisposition in pediatric cancer patients: An easy-to-use selection tool.

    Science.gov (United States)

    Jongmans, Marjolijn C J; Loeffen, Jan L C M; Waanders, Esmé; Hoogerbrugge, Peter M; Ligtenberg, Marjolijn J L; Kuiper, Roland P; Hoogerbrugge, Nicoline

    2016-03-01

    Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling. Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist. Copyright © 2016 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

  5. Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.

    Science.gov (United States)

    Dooley, James; Tian, Lei; Schonefeldt, Susann; Delghingaro-Augusto, Viviane; Garcia-Perez, Josselyn E; Pasciuto, Emanuela; Di Marino, Daniele; Carr, Edward J; Oskolkov, Nikolay; Lyssenko, Valeriya; Franckaert, Dean; Lagou, Vasiliki; Overbergh, Lut; Vandenbussche, Jonathan; Allemeersch, Joke; Chabot-Roy, Genevieve; Dahlstrom, Jane E; Laybutt, D Ross; Petrovsky, Nikolai; Socha, Luis; Gevaert, Kris; Jetten, Anton M; Lambrechts, Diether; Linterman, Michelle A; Goodnow, Chris C; Nolan, Christopher J; Lesage, Sylvie; Schlenner, Susan M; Liston, Adrian

    2016-05-01

    Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.

  6. Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

    Science.gov (United States)

    Emdin, Connor A; Khera, Amit V; Klarin, Derek; Natarajan, Pradeep; Zekavat, Seyedeh M; Nomura, Akihiro; Haas, Mary; Aragam, Krishna; Ardissino, Diego; Wilson, James G; Schunkert, Heribert; McPherson, Ruth; Watkins, Hugh; Elosua, Roberto; Bown, Matthew J; Samani, Nilesh J; Baber, Usman; Erdmann, Jeanette; Gormley, Padhraig; Palotie, Aarno; Stitziel, Nathan O; Gupta, Namrata; Danesh, John; Saleheen, Danish; Gabriel, Stacey; Kathiresan, Sekar

    2018-01-16

    Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [ NOS3 ] and Guanylate Cyclase 1, Soluble, Alpha 3 [ GUCY1A3 ]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3 ) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P =5.5*10 -26 ], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P =0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P =0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P =5.6*10 -5

  7. Genetic Predisposition Increases the Tic Severity, Rate of Comorbidities, and Psychosocial and Educational Difficulties in Children With Tourette Syndrome

    DEFF Research Database (Denmark)

    Eysturoy, Absalon Niclas; Skov, Liselotte; Debes, Nanette Mol

    2015-01-01

    This study aimed to examine whether there are differences in tic severity, comorbidities, and psychosocial and educational consequences in children with Tourette syndrome and genetic predisposition to Tourette syndrome compared with children with Tourette syndrome without genetic predisposition...... to Tourette syndrome. A total of 314 children diagnosed with Tourette syndrome participated in this study. Validated diagnostic tools were used to assess tic severity, comorbidities, and cognitive performance. A structured interview was used to evaluate psychosocial and educational consequences related...... to Tourette syndrome. The children with Tourette syndrome and genetic predisposition present with statistically significant differences in terms of severity of tics, comorbidities, and a range of psychosocial and educational factors compared with the children with Tourette syndrome without genetic...

  8. Familiality analysis of provoked vestibulodynia treated by vestibulectomy supports genetic predisposition.

    Science.gov (United States)

    Morgan, Terry K; Allen-Brady, Kristina L; Monson, Martha A; Leclair, Catherine M; Sharp, Howard T; Cannon-Albright, Lisa A

    2016-05-01

    Provoked vestibulodynia is a poorly understood disease that affects 8-15% of women in their lifetime. There is significant inflammation and nerve growth in vestibular biopsies from affected women treated by vestibulectomy compared with matched female population controls without vestibulodynia. The triggers leading to this neurogenic inflammation are unknown, but they are likely multifactorial. Our objective was to determine whether vestibulodynia is more common in close and distantly related female relatives of women diagnosed with the disease and those specifically treated by vestibulectomy. Excess familial clustering would support a potential genetic predisposition for vestibulodynia and warrant further studies to isolate risk alleles. Using population-based genealogy linked to University of Utah Hospital CPT coded data, we estimated the relative risk of vestibulectomy in female relatives of affected women. We also compared the average pairwise relatedness of cases to the expected relatedness of the population and identified high-disease-burden pedigrees. A total of 183 potential vestibulectomy probands were identified using CPT codes. The relative risk of vestibulectomy was elevated in first-degree (20 [6.6-47], P genetic predisposition. Future studies will identify candidate genes by linkage analysis in affected families and sequencing of distantly related probands. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Associated cancers in Waldenström macroglobulinemia: clues for common genetic predisposition.

    Science.gov (United States)

    Morra, Enrica; Varettoni, Marzia; Tedeschi, Alessandra; Arcaini, Luca; Ricci, Francesca; Pascutto, Cristiana; Rattotti, Sara; Vismara, Eleonora; Paris, Laura; Cazzola, Mario

    2013-12-01

    Several population-based and cohort studies have reported an increased risk of second cancers in lymphoproliferative disorders (LPDs). The cause of second cancers in LPDs is probably multifactorial, and the relative contribution of treatments, genetic predisposition, and immune dysfunction typical of LPDs is still unclear. We retrospectively studied 230 patients with Waldenström macroglobulinemia (WM) to assess the frequency, characteristics, and predictive factors of second cancers and to evaluate whether patients with WM are at higher risk of second cancers compared with an age- and sex-matched control population. In a competing-risk model, the cumulative incidence of solid cancers was 6% at 5 years, 11% at 10 years, and 17% at 15 years, whereas the incidence of hematologic malignancies was 4% at 5 years, 7% at 10 years, and 8% at 15 years. Compared with an age- and sex-matched population, the overall risk of second cancers was 1.7-fold higher than expected (95% confidence interval [CI], 1.22-2.38; P = .002). Patients with WM were at increased risk for diffuse large B-cell lymphoma (DLBCL) (standardized incidence ratio [SIR], 8.64; 95% CI, 3.88-19.22; P genetic predisposition. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Genetic predisposition of RSV infection-related respiratory morbidity in preterm infants.

    Science.gov (United States)

    Drysdale, Simon B; Prendergast, Michael; Alcazar, Mireia; Wilson, Theresa; Smith, Melvyn; Zuckerman, Mark; Broughton, Simon; Rafferty, Gerrard F; Johnston, Sebastian L; Hodemaekers, Hennie M; Janssen, Riny; Bont, Louis; Greenough, Anne

    2014-07-01

    The aim of this study was to assess whether prematurely born infants have a genetic predisposition to respiratory syncytial virus (RSV) infection-related respiratory morbidity. One hundred and forty-six infants born at less than 36 weeks of gestation were prospectively followed. Nasopharygeal aspirates were obtained on every occasion the infants had a lower respiratory tract infection (LRTI) regardless of need for admission. DNA was tested for 11 single-nucleotide polymorphisms (SNPs). Chronic respiratory morbidity was assessed using respiratory health-related questionnaires, parent-completed diary cards at a corrected age of 1 year and review of hospital notes. Lung function was measured at a post menstrual age (PMA) of 36 weeks and corrected age of 1 year. A SNP in ADAM33 was associated with an increased risk of developing RSV LRTIs, but not with significant differences in 36-week PMA lung function results. SNPs in several genes were associated with increased chronic respiratory morbidity (interleukin 10 (IL10), nitric oxide synthase 2A (NOS2A), surfactant protein C (SFTPC), matrix metalloproteinase 16 (MMP16) and vitamin D receptor (VDR)) and reduced lung function at 1 year (MMP16, NOS2A, SFTPC and VDR) in infants who had had RSV LRTIs. Our results suggest that prematurely born infants may have a genetic predisposition to RSV LRTIs and subsequent respiratory morbidity which is independent of premorbid lung function.

  11. The Changing Landscape of Genetic Testing for Inherited Breast Cancer Predisposition.

    Science.gov (United States)

    Afghahi, Anosheh; Kurian, Allison W

    2017-05-01

    The advent of multiple-gene germline panel testing has led to significant advances in hereditary breast and ovarian cancer risk assessment. These include guideline-specific cancer risk management recommendations for patients and their families, such as screening with breast magnetic resonance imaging and risk-reducing surgeries, which have the potential to reduce substantially the morbidity and mortality associated with a hereditary cancer predisposition. However, controversy remains about the clinical validity and actionability of genetic testing in a broader patient population. We discuss events leading to the wider availability of commercialized multiple-gene germline panel testing, the recent data that support using this powerful tool to improve cancer risk assessment and reduction strategies, and remaining challenges to clinical optimization of this new genetic technology.

  12. Ethnic and population differences in the genetic predisposition to human obesity.

    Science.gov (United States)

    Stryjecki, C; Alyass, A; Meyre, D

    2018-01-01

    Obesity rates have escalated to the point of a global pandemic with varying prevalence across ethnic groups. These differences are partially explained by lifestyle factors in addition to genetic predisposition to obesity. This review provides a comprehensive examination of the ethnic differences in the genetic architecture of obesity. Using examples from evolution, heritability, admixture, monogenic and polygenic studies of obesity, we provide explanations for ethnic differences in the prevalence of obesity. The debate over definitions of race and ethnicity, the advantages and limitations of multi-ethnic studies and future directions of research are also discussed. Multi-ethnic studies have great potential to provide a better understanding of ethnic differences in the prevalence of obesity that may result in more targeted and personalized obesity treatments. © 2017 World Obesity Federation.

  13. Genetic Predisposition to High Blood Pressure and Lifestyle Factors: Associations With Midlife Blood Pressure Levels and Cardiovascular Events.

    Science.gov (United States)

    Pazoki, Raha; Dehghan, Abbas; Evangelou, Evangelos; Warren, Helen; Gao, He; Caulfield, Mark; Elliott, Paul; Tzoulaki, Ioanna

    2018-02-13

    High blood pressure (BP) is a major risk factor for cardiovascular diseases (CVDs), the leading cause of mortality worldwide. Both heritable and lifestyle risk factors contribute to elevated BP levels. We aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse BP genetic profile and its effect on CVD risk. We constructed a genetic risk score for high BP by using 314 published BP loci in 277 005 individuals without previous CVD from the UK Biobank study, a prospective cohort of individuals aged 40 to 69 years, with a median of 6.11 years of follow-up. We scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. We examined the association between tertiles of genetic risk and tertiles of lifestyle score with BP levels and incident CVD by using linear regression and Cox regression models, respectively. Healthy lifestyle score was strongly associated with BP ( P genetic predisposition to high BP for risk stratification needs careful evaluation. © 2017 American Heart Association, Inc.

  14. Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults.

    Science.gov (United States)

    Pathmanaban, Omar N; Sadler, Katherine V; Kamaly-Asl, Ian D; King, Andrew T; Rutherford, Scott A; Hammerbeck-Ward, Charlotte; McCabe, Martin G; Kilday, John-Paul; Beetz, Christian; Poplawski, Nicola K; Evans, D Gareth; Smith, Miriam J

    2017-09-01

    predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition (P < .001). Of 109 cranial schwannomas, 106 (97.2%) were vestibular. Four of 106 people (3.8%) with a cranial schwannoma had an LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation. A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young patients presenting with a solitary meningioma or schwannoma should be referred for genetic testing.

  15. Serum 25-Hydroxyvitamin D Status and Longitudinal Changes in Weight and Waist Circumference:Influence of Genetic Predisposition to Adiposity

    OpenAIRE

    Larsen, Sofus C; Ängquist, Lars; Moldovan, Max; Huikari, Ville; Sebert, Sylvain; Cavadino, Alana; Singh Ahluwalia, Tarunveer; Skaaby, Tea; Linneberg, Allan; Husemoen, Lise Lotte N; Toft, Ulla; Pedersen, Oluf; Hansen, Torben; Herzig, Karl-Heinz; Jarvelin, Marjo-Riitta

    2016-01-01

    Studies of the relationship between serum 25-hydroxyvitamin D (25(OH)D) and changes in measures of adiposity have shown inconsistent results, and interaction with genetic predisposition to obesity has rarely been examined. We examined whether 25(OH)D was associated with subsequent annual changes in body weight (ΔBW) or waist circumference (ΔWC), and whether the associations were modified by genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHRBMI). The study was ba...

  16. Is there a genetic predisposition to new-onset diabetes after kidney transplantation?

    Science.gov (United States)

    Reddy, Yogesh N V; Abraham, Georgi; Sundaram, Varun; Reddy, Pooja P; Mathew, Milly; Nagarajan, Prethivee; Mehra, Nikita; Ramachandran, A; Ali, Asik Ali Mohammed; Reddy, Yuvaram N V

    2015-11-01

    Kidney transplant recipients may develop new-onset diabetes after transplantation (NODAT) and transplant-associated hyperglycemia (TAH) (NODAT or new-onset impaired glucose tolerance-IGT). We studied 251 consecutive renal transplant South Asian recipients for incidence of NODAT and its risk factors between June 2004 and January 2009. Pre-transplant glucose tolerance test (GTT) identified non-diabetics (n = 102, IGT-24, NGT-78) for analysis. Baseline immunosuppression along with either cyclosporine (CsA) (n = 70) or tacrolimus (Tac) (n = 32) was given. Patients underwent GTT 20 days (mean) post-transplant to identify NODAT, normal (N) or IGT. TAH was observed in 40.2% of the patients (40% in CsA and 40.6% in Tac) (P = 0.5). NODAT developed in 13.7% of the patients (12.9% in CsA and 15.6% in Tac) (P = 0.5). Overall, Hepatitis C (P = 0.007), human leukocyte antigen (HLA) B52 (P = 0.03) and lack of HLA A28 (A68/69) (P = 0.03) were associated with TAH. In the Tac group, higher Day 1 dosage (P genetic predisposition to NODAT and TAH in South Asia as seen by the HLA associations, and a predisposition exists to the individual diabetogenic effects of Tac and CsA based on HLA type. This could lead to more careful selection of calcineurin inhibitors based on HLA types in the South Asian population.

  17. Genetic predisposition to endocrine tumors: Diagnosis, surveillance and challenges in care.

    Science.gov (United States)

    Petr, Elisabeth Joye; Else, Tobias

    2016-10-01

    Endocrine tumor syndromes, eg, multiple endocrine neoplasia types 1 and 2, were among the first recognized hereditary predisposition syndromes to tumor development. Over time, the number of endocrine tumor syndromes has significantly expanded, eg, with the recent inclusion of hereditary paraganglioma syndromes. Associations of non-endocrine tumors with hereditary endocrine tumor syndromes and endocrine tumors with non-classical endocrine tumor syndromes have emerged. These findings have certainly expanded the scope of care, necessitating a multidisciplinary approach by a team of medical professionals and researchers, integrating shared patient decision-making at every step of surveillance, diagnosis, and treatment. In the absence of evidence-based guidelines, multiple aspects of patient care remain individualized, based on a patient's clinical presentation and family pedigree. This is particularly important when determining a surveillance plan for unaffected or disease-free mutation carriers. In this review, we describe the main endocrine tumor manifestations found in familial cancer syndromes in an organ-based approach, focusing on adrenocortical carcinoma, pheochromocytoma and paraganglioma, neuroendocrine tumors, differentiated thyroid cancer, and medullary thyroid cancer. We highlight the challenges in diagnosis, surveillance, and therapy unique to the patient population with hereditary syndromes. Furthermore, we underscore the importance of evaluating for genetic predisposition to tumor development, provide features that can identify index patients, and discuss the approach to screening surveillance for mutation carriers. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Genetic predisposition for high stress reactivity amplifies effects of early-life adversity.

    Science.gov (United States)

    McIlwrick, Silja; Rechenberg, Alexandra; Matthes, Mariana; Burgstaller, Jessica; Schwarzbauer, Thomas; Chen, Alon; Touma, Chadi

    2016-08-01

    A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) axis and the experience of early-life adversity are both well-established risk factors for the development of affective disorders, such as major depression. However, little is known about the interaction of these two factors in shaping endophenotypes of the disease. Here, we studied the gene-environment interaction of a genetic predisposition for HPA axis dysregulation with early-life stress (ELS), assessing the short-, as well as the long-lasting consequences on emotional behavior, neuroendocrine functions and gene expression profiles. Three mouse lines, selectively bred for either high (HR), intermediate (IR), or low (LR) HPA axis reactivity, were exposed to one week of ELS using the limited nesting and bedding material paradigm. Measurements collected during or shortly after the ELS period showed that, regardless of genetic background, ELS exposure led to impaired weight gain and altered the animals' coping behavior under stressful conditions. However, only HR mice additionally showed significant changes in neuroendocrine stress responsiveness at a young age. Accordingly, adult HR mice also showed lasting consequences of ELS, including hyperactive stress-coping, HPA axis hyperreactivity, and gene expression changes in the Crh system, as well as downregulation of Fkbp5 in relevant brain regions. We suggest that the genetic predisposition for high stress reactivity interacts with ELS exposure by disturbing the suppression of corticosterone release during a critical period of brain development, thus exerting lasting programming effects on the HPA axis, presumably via epigenetic mechanisms. In concert, these changes lead to the emergence of important endophenotypes associated with affective disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Utilizing Genetic Predisposition Score in Predicting Risk of Type 2 Diabetes Mellitus Incidence: A Community-based Cohort Study on Middle-aged Koreans.

    Science.gov (United States)

    Park, Hye Yin; Choi, Hyung Jin; Hong, Yun-Chul

    2015-08-01

    Contribution of genetic predisposition to risk prediction of type 2 diabetes mellitus (T2DM) was investigated using a prospective study in middle-aged adults in Korea. From a community cohort of 6,257 subjects with 8 yr' follow-up, genetic predisposition score with subsets of 3, 18, 36 selected single nucleotide polymorphisms (SNPs) (genetic predisposition score; GPS-3, GPS-18, GPS-36) in association with T2DM were determined, and their effect was evaluated using risk prediction models. Rs5215, rs10811661, and rs2237892 were in significant association with T2DM, and hazard ratios per risk allele score increase were 1.11 (95% confidence intervals: 1.06-1.17), 1.09 (1.01-1.05), 1.04 (1.02-1.07) with GPS-3, GPS-18, GPS-36, respectively. Changes in AUC upon addition of GPS were significant in simple and clinical models, but the significance disappeared in full clinical models with glycated hemoglobin (HbA1c). For net reclassification index (NRI), significant improvement observed in simple (range 5.1%-8.6%) and clinical (3.1%-4.4%) models were no longer significant in the full models. Influence of genetic predisposition in prediction ability of T2DM incidence was no longer significant when HbA1c was added in the models, confirming HbA1c as a strong predictor for T2DM risk. Also, the significant SNPs verified in our subjects warrant further research, e.g. gene-environmental interaction and epigenetic studies.

  20. DNA and RNA analyses in detection of genetic predisposition to cancer

    Directory of Open Access Journals (Sweden)

    Kurzawski Grzegorz

    2012-12-01

    Full Text Available Abstract During the past decade many new molecular methods for DNA and RNA analysis have emerged. The most popular thus far have been SSCP, HET, CMC, DGGE, RFLP or ASA, which have now been replaced by methods that are more cost effective and less time consuming. Real-time amplification techniques and particularly those with the capacity of multiplexing have become commonly used in laboratory practice. Novel screening methods enable the very rapid examination of large patients series. Use of liquid handling robotics applied to the isolation of DNA or RNA, the normalisation of sample concentration, and standardization of target amplification by PCR have also contributed to a reduced risk of sample contamination and have resulted in laboratory analysis being easier and faster. The aim of this study is the introduction of a few modern techniques, most commonly used in detection of genetic predisposition to cancer.

  1. Diagnostic criteria, specific mutations, and genetic predisposition in gastrointestinal stromal tumors

    Science.gov (United States)

    Bachet, Jean-Baptiste; Emile, Jean-François

    2010-01-01

    In 1998, gastrointestinal stromal tumor (GIST) emerged as a distinct oncogenetic entity and subsequently became a paradigm of targeted therapies in solid tumors. Diagnosis of GIST relies on both histology and immunohistochemistry. Ninety-five percent of GISTs express either KIT or DOG-1. Approximately 80%–90% of GISTs harbor gain-of-function mutations of either KIT or platelet-derived growth factor receptor alpha polypeptide (PDGFRA) receptor tyrosine kinase (RTK). More than 100 different mutations have been described, some of which are associated with specific clinical and/or histological characteristics. Detection of KIT or PDGFRA mutations is recommended in advanced GISTs because they are highly predictive of tumor response to RTK inhibitors, as well as in KIT-negative cases to confirm diagnosis. In most cases, GISTs are sporadic, but in rare cases, they are related with genetic predisposition, such as neurofibromatosis type 1, Carney triad, Carney–Stratakis syndrome, and inherited KIT or PDGFRA germline mutations. PMID:23776354

  2. Genetic predisposition of IL-10 promoter polymorphisms with risk of multiple sclerosis: A meta-analysis.

    Science.gov (United States)

    Ramakrishnan, V; Akram Husain, R S; Ahmed, Shiek Ssj

    2017-05-15

    Interleukin-10 (IL-10) is a anti-inflammatory cytokine, which controls inflammation by inhibiting the synthesis of several cytokines produced by Th1 cells and macrophages. The association between Interleukin-10 promoter polymorphisms with the risk of multiple sclerosis (MS) remains inconclusive. In this study, a meta-analysis has been performed to assess the relationship between IL-10 gene polymorphisms rs1800896, rs1800871 and rs1800872 with the risk of MS. Nine case-control studies were selected involving 2755 participants. The association between the polymorphisms and MS was examined by the pooled odds ratios (ORs) with 95% confidence intervals (CIs) in allelic, homozygote, heterozygote, dominant and recessive genetic models. Of analyzed genetic models, the pooled ORs and CIs of each SNPs calculated based on random (I 2 >50) or fixed effects (I 2 0.05) of genetic predisposition with MS susceptibility across Asian and Caucasian populations. In addition, assessment based on funnel plot and Egger's linear regression test suggests no publication bias in all analyzed genetic models. Overall, our results demonstrated that rs1800896, rs1800871 and rs1800872 polymorphisms may not be the risk factor for the development of MS in both the populations. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition.

    LENUS (Irish Health Repository)

    Baeyens, A

    2002-12-02

    The chromosomal radiosensitivity of breast cancer patients with a known or putative genetic predisposition was investigated and compared to a group of healthy women. The chromosomal radiosensitivity was assessed with the G2 and the G0-micronucleus assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy (60)Co gamma-rays after 71 h incubation, and chromatid breaks were scored in 50 metaphases. For the micronucleus assay lymphocytes were exposed in vitro to 3.5 Gy (60)Co gamma-rays at a high dose rate or low dose rate. 70 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients with a known or putative genetic predisposition was on the average more radiosensitive than a population of healthy women, and this with the G2 as well as with the high dose rate and low dose rate micronucleus assay. With the G2 assay 43% of the patients were found to be radiosensitive. A higher proportion of the patients were radiosensitive with the micronucleus assay (45% with high dose rate and 61% with low dose rate). No correlation was found between the G2 and the G0-micronucleus chromosomal radiosensitivity. Out of the different subgroups considered, the group of the young breast cancer patients without family history showed the highest percentage of radiosensitive cases in the G2 (50%) as well as in the micronucleus assay (75-78%).

  4. Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation.

    Science.gov (United States)

    Weng, Lu-Chen; Preis, Sarah R; Hulme, Olivia L; Larson, Martin G; Choi, Seung Hoan; Wang, Biqi; Trinquart, Ludovic; McManus, David D; Staerk, Laila; Lin, Honghuang; Lunetta, Kathryn L; Ellinor, Patrick T; Benjamin, Emelia J; Lubitz, Steven A

    2018-03-06

    The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. We estimated the lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of ≈1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF >55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4-9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3-55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition ( P <0.001). In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long-term AF risk. © 2018 American Heart Association, Inc.

  5. Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition

    Science.gov (United States)

    Baeyens, A; Thierens, H; Claes, K; Poppe, B; Messiaen, L; De Ridder, L; Vral, A

    2002-01-01

    The chromosomal radiosensitivity of breast cancer patients with a known or putative genetic predisposition was investigated and compared to a group of healthy women. The chromosomal radiosensitivity was assessed with the G2 and the G0-micronucleus assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy 60Co γ-rays after 71 h incubation, and chromatid breaks were scored in 50 metaphases. For the micronucleus assay lymphocytes were exposed in vitro to 3.5 Gy 60Co γ-rays at a high dose rate or low dose rate. 70 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients with a known or putative genetic predisposition was on the average more radiosensitive than a population of healthy women, and this with the G2 as well as with the high dose rate and low dose rate micronucleus assay. With the G2 assay 43% of the patients were found to be radiosensitive. A higher proportion of the patients were radiosensitive with the micronucleus assay (45% with high dose rate and 61% with low dose rate). No correlation was found between the G2 and the G0-micronucleus chromosomal radiosensitivity. Out of the different subgroups considered, the group of the young breast cancer patients without family history showed the highest percentage of radiosensitive cases in the G2 (50%) as well as in the micronucleus assay (75–78%). British Journal of Cancer (2002) 87, 1379–1385. doi:10.1038/sj.bjc.6600628 www.bjcancer.com © 2002 Cancer Research UK PMID:12454765

  6. Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

    Science.gov (United States)

    Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

    2017-10-01

    Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

  7. Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition

    NARCIS (Netherlands)

    Obdeijn, Inge-Marie A.; Loo, Claudette E.; Rijnsburger, Adriana J.; Wasser, Martin N. J. M.; Bergers, Elisabeth; Kok, Theo; Klijn, Jan G. M.; Boetes, Carla

    In order to assess the characteristics of malignant breast lesions those were not detected during screening by MR imaging. In the Dutch MRI screening study (MRISC), a non-randomized prospective multicenter study, women with high familial risk or a genetic predisposition for breast cancer were

  8. Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition

    NARCIS (Netherlands)

    A.I.M. Obdeijn (Inge-Marie); C.E. Loo (Claudette); A.J. Rijnsburger (Rian); M.N.J.M. Wasser (Martin); E. Bergers (Elisabeth); T. Kok (Theo); J.G.M. Klijn (Jan); C. Boetes (Carla)

    2010-01-01

    textabstractIn order to assess the characteristics of malignant breast lesions those were not detected during screening by MR imaging. In the Dutch MRI screening study (MRISC), a non-randomized prospective multicenter study, women with high familial risk or a genetic predisposition for breast cancer

  9. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition

    NARCIS (Netherlands)

    Kriege, M; Brekelmans, CTM; Boetes, C; Besnard, PE; Zonderland, HM; Obdeijn, IM; Manoliu, RA; Kok, T; Peterse, H; Tilanus-Linthorst, MMA; Muller, SH; Meijer, S; Oosterwijk, JC; Beex, LVAM; Tollenaar, RAEM; de Koning, HJ; Rutgers, EJT; Klijn, JGM

    2004-01-01

    BACKGROUND: The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging (MRI) with that of mammography for screening in this group of high-risk women. METHODS:

  10. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition.

    NARCIS (Netherlands)

    Kriege, M.; Brekelmans, C.T.; Boetes, C.; Besnard, P.E.; Zonderland, H.M.; Obdeijn, I.M.; Manoliu, R.A.; Kok, T.; Peterse, H.L.; Tilanus-Linthorst, M.M.; Muller, S.H.; Meijer, S.; Oosterwijk-Wakka, J.C.; Beex, L.V.A.M.; Tollenaar, R.A.E.M.; Koning, H.J. de; Rutgers, E.; Klijn, J.G.M.

    2004-01-01

    BACKGROUND: The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging (MRI) with that of mammography for screening in this group of high-risk women. METHODS:

  11. Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation

    NARCIS (Netherlands)

    Postema, Floor A. M.; Hopman, Saskia M. J.; Aalfs, Cora M.; Berger, Lieke P. V.; Bleeker, Fonnet E.; Dommering, Charlotte J.; Jongmans, Marjolijn C. J.; Letteboer, Tom G. W.; Olderode-Berends, Maran J. W.; Wagner, Anja; Hennekam, Raoul C.; Merks, Johannes H. M.

    2017-01-01

    Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic

  12. Interaction between genetic predisposition to adiposity and dietary protein in relation to subsequent change in body weight and waist circumference.

    Science.gov (United States)

    Ankarfeldt, Mikkel Z; Larsen, Sofus C; Ängquist, Lars; Husemoen, Lise Lotte N; Roswall, Nina; Overvad, Kim; Jakobsen, Marianne Uhre; Halkjær, Jytte; Tjønneland, Anne; Linneberg, Allan; Toft, Ulla; Hansen, Torben; Pedersen, Oluf; Heitmann, Berit L; Astrup, Arne; Sørensen, Thorkild I A

    2014-01-01

    Genetic predisposition to adiposity may interact with dietary protein in relation to changes of anthropometry. To investigate the interaction between genetic predisposition to higher body mass index (BMI), waist circumference (WC) or waist-hip ratio adjusted for BMI (WHRBMI) and dietary protein in relation to subsequent change in body weight (ΔBW) or change in WC (ΔWC). Three different Danish cohorts were used. In total 7,054 individuals constituted the study population with information on diet, 50 single-nucleotide polymorphisms (SNPs) associated with BMI, WC or WHRBMI, as well as potential confounders. Mean follow-up time was ∼5 years. Four genetic predisposition-scores were based on the SNPs; a complete-score including all selected adiposity- associated SNPs, and three scores including BMI, WC or WHRBMI associated polymorphisms, respectively. The association between protein intake and ΔBW or ΔWC were examined and interactions between SNP-score and protein were investigated. Analyses were based on linear regressions using macronutrient substitution models and meta-analyses. When protein replaced carbohydrate, meta-analyses showed no associations with ΔBW (41.0 gram/y/5 energy% protein, [95% CI: -32.3; 114.3]) or ΔWC (genetic predisposition to general and abdominal adiposity, assessed by gene-scores, does not seem to modulate the influence of dietary protein on ΔBW or ΔWC.

  13. Genetic predisposition to higher body mass index or type 2 diabetes and leukocyte telomere length in the Nurses' Health Study.

    Directory of Open Access Journals (Sweden)

    Mengmeng Du

    Full Text Available Although cross-sectional studies have linked higher body mass index (BMI and type 2 diabetes (T2D to shortened telomeres, whether these metabolic conditions play a causal role in telomere biology is unknown. We therefore examined whether genetic predisposition to higher BMI or T2D was associated with shortened leukocyte telomere length (LTL.We conducted an analysis of 3,968 women of European ancestry aged 43-70 years from the Nurses' Health Study, who were selected as cases or controls in genome-wide association studies and studies of telomeres and disease. Pre-diagnostic relative telomere length in peripheral blood leukocytes, collected in 1989-1990, was measured by quantitative PCR. We combined information from multiple risk variants by calculating genetic risk scores based on 32 polymorphisms near 32 loci for BMI, and 36 polymorphisms near 35 loci for T2D.After adjustment for age and case-control status, there was no association between the BMI genetic risk score and LTL (β per standard deviation increase: -0.01; SE: 0.02; P = 0.52. Similarly, the T2D genetic score was not associated with LTL (β per standard deviation increase: -0.006; SE: 0.02; P = 0.69.In this population of middle-aged and older women of European ancestry, those genetically predisposed to higher BMI or T2D did not possess shortened telomeres. Although we cannot exclude weak or modest effects, our findings do not support a causal relation of strong magnitude between these metabolic conditions and telomere dynamics.

  14. A genetic predisposition score associates with reduced aerobic capacity in response to acute normobaric hypoxia in lowlanders.

    Science.gov (United States)

    Masschelein, Evi; Puype, Joke; Broos, Siacia; Van Thienen, Ruud; Deldicque, Louise; Lambrechts, Diether; Hespel, Peter; Thomis, Martine

    2015-03-01

    Given the high inter-individual variability in the sensitivity to high altitude, we hypothesize the presence of underlying genetic factors. The aim of this study was to construct a genetic predisposition score based on previously identified high-altitude gene variants to explain the inter-individual variation in the reduced maximal O2 uptake (ΔVo2max) in response to acute hypoxia. Ninety-six healthy young male Belgian lowlanders were included. In both normobaric normoxia (Fio2=20.9%) and acute normobaric hypoxia (Fio2=10.7%-12.5%) Vo2max was measured. Forty-one SNPs in 21 genes were genotyped. A stepwise regression analysis was applied to detect a subset of SNPs to be associated with ΔVo2max. This subset of SNPs was included in the genetic predisposition score. A general linear model and regression analysis with age, weight, height, hypoxic protocol group, and Vo2max in normoxia as covariates were used to test the explained variance of the genetic predisposition score. A ROC analysis was performed to discriminate between the low- and high ΔVo2max subgroups. A stepwise regression analysis revealed a subset of SNPs [rs833070 (VEGFA), rs4253778 (PPARA), rs6735530 (EPAS1), rs4341 (ACE), rs1042713 (ADRB2), and rs1042714 (ADRB2)] to be associated with ΔVo2max. The genetic predisposition score was found to be an independent predictive variable with a partial explained variance of 23% (pgenetic predisposition score showed a significantly predictive value for ΔVo2max.

  15. A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

    Science.gov (United States)

    Marzec, Jacek; Mao, Xueying; Li, Meiling; Wang, Meilin; Feng, Ninghan; Gou, Xin; Wang, Guomin; Sun, Zan; Xu, Jianfeng; Xu, Hua; Zhang, Xiaoping; Zhao, Shan-Chao; Ren, Guoping; Yu, Yongwei; Wu, Yudong; Wu, Ji; Xue, Yao; Zhou, Bo; Zhang, Yanling; Xu, Xingxing; Li, Jie; He, Weiyang; Benlloch, Sara; Ross-Adams, Helen; Chen, Li; Li, Jucong; Hong, Yingqia; Kote-Jarai, Zsofia; Cui, Xingang; Hou, Jianguo; Guo, Jianming; Xu, Lei; Yin, Changjun; Zhou, Yuanping; Neal, David E; Oliver, Tim; Cao, Guangwen; Zhang, Zhengdong; Easton, Douglas F; Chelala, Claude; Al Olama, Ali Amin; Eeles, Rosalind A; Zhang, Hongwei; Lu, Yong-Jie

    2016-04-19

    Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.

  16. Nutritional habits, lifestyle, and genetic predisposition in cardiovascular and metabolic traits in Turkish population.

    Science.gov (United States)

    Karaca, Sefayet; Erge, Sema; Cesuroglu, Tomris; Polimanti, Renato

    2016-06-01

    Cardiovascular and metabolic traits (CMT) are influenced by complex interactive processes including diet, lifestyle, and genetic predisposition. The present study investigated the interactions of these risk factors in relation to CMTs in the Turkish population. We applied bootstrap agglomerative hierarchical clustering and Bayesian network learning algorithms to identify the causative relationships among genes involved in different biological mechanisms (i.e., lipid metabolism, hormone metabolism, cellular detoxification, aging, and energy metabolism), lifestyle (i.e., physical activity, smoking behavior, and metropolitan residency), anthropometric traits (i.e., body mass index, body fat ratio, and waist-to-hip ratio), and dietary habits (i.e., daily intakes of macro- and micronutrients) in relation to CMTs (i.e., health conditions and blood parameters). We identified significant correlations between dietary habits (soybean and vitamin B12 intakes) and different cardiometabolic diseases that were confirmed by the Bayesian network-learning algorithm. Genetic factors contributed to these disease risks also through the pleiotropy of some genetic variants (i.e., F5 rs6025 and MTR rs180508). However, we also observed that certain genetic associations are indirect since they are due to the causative relationships among the CMTs (e.g., APOC3 rs5128 is associated with low-density lipoproteins cholesterol and, by extension, total cholesterol). Our study applied a novel approach to integrate various sources of information and dissect the complex interactive processes related to CMTs. Our data indicated that complex causative networks are present: causative relationships exist among CMTs and are affected by genetic factors (with pleiotropic and non-pleiotropic effects) and dietary habits. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Local-regional control in breast cancer patients with a possible genetic predisposition

    International Nuclear Information System (INIS)

    Freedman, Laura M.; Buchholz, Thomas A.; Thames, Howard D.; Strom, Eric A.; McNeese, Marsha D.; Hortobagyi, Gabriel N.; Singletary, S. Eva; Heaton, Keith M.; Hunt, Kelly K.

    2000-01-01

    %, respectively. Conclusions: Patients with a possible genetic predisposition to breast cancer had low 5-year rates of local recurrence when treated with breast conserving surgery and radiation, but the local failure rate exceeded 50% when radiation was omitted. Our data are consistent with the hypothesis that patients with an underlying genetic predisposition develop cancers with radiosensitive phenotypes

  18. Is There a Genetic Predisposition to Anterior Cruciate Ligament Tear? A Systematic Review.

    Science.gov (United States)

    John, Rakesh; Dhillon, Mandeep Singh; Sharma, Siddhartha; Prabhakar, Sharad; Bhandari, Mohit

    2016-12-01

    Injuries to the anterior cruciate ligament (ACL) are among the most common knee ligament injuries and frequently warrant reconstruction. The etiopathogenesis of these injuries has focused mainly on mechanism of trauma, patient sex, and anatomic factors as predisposing causes. Several genetic factors that could predispose to an ACL tear have recently been reported. This systematic review summarizes the current evidence for a genetic predisposition to ACL tears. The principal research question was to identify genetic factors, based on the available literature, that could predispose an individual to an ACL tear. Systematic review. The PubMed, EMBASE, Cochrane, and HuGE databases were searched; the search was run from the period of inception until June 21, 2015. A secondary search was performed by screening the references of full-text articles obtained and by manually searching selected journals. Articles were screened with prespecified inclusion criteria. The quality of studies included in the review was assessed for risk of bias by 2 reviewers using the Newcastle-Ottawa Scale. A total of 994 records were identified by the search, out of which 17 studies (16 case-control studies and 1 cross-sectional study) were included in the final review. Two studies observed a familial predisposition to an ACL tear. Fourteen studies looked at specific gene polymorphisms in 20 genes, from which different polymorphisms in 10 genes were positively associated with an ACL tear. In addition to these polymorphisms, 8 haplotypes were associated with ACL tear. One study looked at gene expression analysis. Although specific gene polymorphisms and haplotypes have been identified, it is difficult to come to a conclusion on the basis of the existing literature. Several sources of bias have been identified in these studies, and the results cannot be extrapolated to the general population. More studies are needed in larger populations of different ethnicities. Gene-gene interactions and gene

  19. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

    Science.gov (United States)

    Sawyer, Elinor; Roylance, Rebecca; Petridis, Christos; Brook, Mark N; Nowinski, Salpie; Papouli, Efterpi; Fletcher, Olivia; Pinder, Sarah; Hanby, Andrew; Kohut, Kelly; Gorman, Patricia; Caneppele, Michele; Peto, Julian; Dos Santos Silva, Isabel; Johnson, Nichola; Swann, Ruth; Dwek, Miriam; Perkins, Katherine-Anne; Gillett, Cheryl; Houlston, Richard; Ross, Gillian; De Ieso, Paolo; Southey, Melissa C; Hopper, John L; Provenzano, Elena; Apicella, Carmel; Wesseling, Jelle; Cornelissen, Sten; Keeman, Renske; Fasching, Peter A; Jud, Sebastian M; Ekici, Arif B; Beckmann, Matthias W; Kerin, Michael J; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Benitez, Javier; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Lichtner, Peter; Schmutzler, Rita K; Lochmann, Magdalena; Brauch, Hiltrud; Fischer, Hans-Peter; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Investigators, Kconfab; Lambrechts, Diether; Weltens, Caroline; Van Limbergen, Erik; Hatse, Sigrid; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Volorio, Sara; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; McLean, Catriona A; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Devillee, Peter; Tollenaar, Rob A E M; Seynaeve, Caroline M; Kriege, Mieke; Figueroa, Jonine; Chanock, Stephen J; Sherman, Mark E; Hooning, Maartje J; Hollestelle, Antoinette; van den Ouweland, Ans M W; van Deurzen, Carolien H M; Li, Jingmei; Czene, Kamila; Humphreys, Keith; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Shah, Mitul; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Swerdlow, Anthony; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk; Couch, Fergus J; Hallberg, Emily; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Dunning, Alison M; Hall, Per; Easton, Doug; Pharoah, Paul; Schmidt, Marjanka K; Tomlinson, Ian; Garcia-Closas, Montserrat

    2014-04-01

    Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at Plobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

  20. Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

    Science.gov (United States)

    Petridis, Christos; Brook, Mark N.; Nowinski, Salpie; Papouli, Efterpi; Fletcher, Olivia; Pinder, Sarah; Hanby, Andrew; Kohut, Kelly; Gorman, Patricia; Caneppele, Michele; Peto, Julian; dos Santos Silva, Isabel; Johnson, Nichola; Swann, Ruth; Dwek, Miriam; Perkins, Katherine-Anne; Gillett, Cheryl; Houlston, Richard; Ross, Gillian; De Ieso, Paolo; Southey, Melissa C.; Hopper, John L.; Provenzano, Elena; Apicella, Carmel; Wesseling, Jelle; Cornelissen, Sten; Keeman, Renske; Fasching, Peter A.; Jud, Sebastian M.; Ekici, Arif B.; Beckmann, Matthias W.; Kerin, Michael J.; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Benitez, Javier; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Lichtner, Peter; Schmutzler, Rita K.; Lochmann, Magdalena; Brauch, Hiltrud; Fischer, Hans-Peter; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Investigators, kConFab; Lambrechts, Diether; Weltens, Caroline; Van Limbergen, Erik; Hatse, Sigrid; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Volorio, Sara; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Mclean, Catriona A.; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Devillee, Peter; Tollenaar, Rob A. E. M.; Seynaeve, Caroline M.; Kriege, Mieke; Figueroa, Jonine; Chanock, Stephen J.; Sherman, Mark E.; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; van Deurzen, Carolien H. M.; Li, Jingmei; Czene, Kamila; Humphreys, Keith; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Shah, Mitul; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Swerdlow, Anthony; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk; Couch, Fergus J.; Hallberg, Emily; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Dunning, Alison M.; Hall, Per; Easton, Doug; Pharoah, Paul; Schmidt, Marjanka K.; Tomlinson, Ian; Garcia-Closas, Montserrat

    2014-01-01

    Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at Pbreast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes. PMID:24743323

  1. Myc contribution to γ-ray induced thymic lymphomas in mice of different genetic predispositions

    International Nuclear Information System (INIS)

    Sato, Toshihiro

    2008-01-01

    Myc gene has been suggested to be one of radiation targets in early genesis of γ ray-induced thymic lymphoma where Myc trisomy often occurs, and Myc activation results in p53 activation and apoptosis. The purpose of this study is to see the effects of radiation and mutation on Myc activation in the mouse. The lymphoma was induced by a single exposure of 3 Gy γ ray in BALB/c Bcl11b/Rit+/- and MSM p53-/- mice at 4 weeks after birth and by 4 weekly exposures of 2.5 Gy in p53+/- mouse. Genetic allele analysis for trisomy identification in the lymphoma was done by quantitative PCR using brain DNA as a control. Myc trisomy was found in the lymphoma of p53+/- mouse in 62% (23/37 animals) and of p53+/+, 66% (23/25), a similar frequency, suggesting that the target of radiation was not only the Myc activation. In addition, Myc trisomy frequency was 15% (4/27) in the lymphoma of Bcl11b+/+p53+/- and 36% (9/25), in heterozygote Bcl11b+/-. This finding suggested that the functional failure of Bcl11b reduced the contribution of Myc trisomy to the genesis. It was concluded that contribution of Myc trisomy to genesis of the lymphoma was dependent on genetic predisposition, and Myc-activated-, Bcl11b/Rit1-signal pathways played a parallel role in the genesis. (R.T.)

  2. Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry.

    Science.gov (United States)

    Cetica, Valentina; Sieni, Elena; Pende, Daniela; Danesino, Cesare; De Fusco, Carmen; Locatelli, Franco; Micalizzi, Concetta; Putti, Maria Caterina; Biondi, Andrea; Fagioli, Franca; Moretta, Lorenzo; Griffiths, Gillian M; Luzzatto, Lucio; Aricò, Maurizio

    2016-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. From our registry, we have analyzed a total of 500 unselected patients with HLH. Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having "sporadic" HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Effect of Genetic Predisposition on Blood Lipid Traits Using Cumulative Risk Assessment in the Korean Population

    Directory of Open Access Journals (Sweden)

    Min Jin Go

    2012-06-01

    Full Text Available Dyslipidemia, mainly characterized by high triglyceride (TG and low high-density lipoprotein cholesterol (HDL-C levels, is an important etiological factor in the development of cardiovascular disease (CVD. Considering the relationship between childhood obesity and CVD risk, it would be worthwhile to evaluate whether previously identified lipid-related variants in adult subjects are associated with lipid variations in a childhood obesity study (n = 482. In an association analysis for 16 genome-wide association study (GWAS-based candidate loci, we confirmed significant associations of a genetic predisposition to lipoprotein concentrations in a childhood obesity study. Having two loci (rs10503669 at LPL and rs16940212 at LIPC that showed the strongest association with blood levels of TG and HDL-C, we calculated a genetic risk score (GRS, representing the sum of the risk alleles. It has been observed that increasing GRS is significantly associated with decreased HDL-C (effect size, -1.13 ± 0.07 compared to single nucleotide polymorphism combinations without two risk variants. In addition, a positive correlation was observed between allelic dosage score and risk allele (rs10503669 at LPL on high TG levels (effect size, 10.89 ± 0.84. These two loci yielded consistent associations in our previous meta-analysis. Taken together, our findings demonstrate that the genetic architecture of circulating lipid levels (TG and HDL-C overlap to a large extent in childhood as well as in adulthood. Post-GWAS functional characterization of these variants is further required to elucidate their pathophysiological roles and biological mechanisms.

  4. Genetic predisposition and genomic instability in murine stem cells exposed to low LET radiation

    International Nuclear Information System (INIS)

    Macdonald, D.A.; Bowler, D.A.; Moore, S.R.; Papworth, D.; Kadhim, M.A.; Goodhead, D.T.

    2003-01-01

    Full text: The contribution of genetic factors to the initiation of radiation-induced genomic instability remains poorly understood. Studies with high LET α-particles and very high doses of low LET radiation have described several common mouse strains that differ in their sensitivity to the induction of genomic instability and apoptosis. The aim here was to investigate whether low doses of low LET radiation would elucidate a similar genetic predisposition. To assess the influence of genetic factors on the initiation of genomic instability by low doses of low LET radiation, we irradiated stem cells from two mouse strains known to differ in susceptibility to radiation-induced delayed chromosomal instability. The frequency of delayed chromosomal aberrations was measured in bone marrow cells from CBA/H and C57BL/6 mice after exposure to 0.1 - 2 Gy of 250 kV X-rays. The yield of both chromosomal and chromatid-type aberrations were assessed 13-15 cell divisions post-irradiation in the clonal descendents of surviving stem cells. The apoptotic index of these surviving clones was scored as morphological changes by electron microscopy. At low doses, the frequency of cells with aberrations increased significantly in both strains, contrary to the strain differences observed with high LET α-particles in earlier studies (Watson et al. 1997). The percentage of apoptotic cells was similar between the strains at low doses, with both showing comparable levels of cells with aberrations and apoptotic cells. However, at higher doses, strain differences became evident: CBA/H cells had a substantially higher fraction of cells with aberrations to apoptotic cells, while the converse was true for C57/Bl/6. This data indicates that low doses may be insufficient to initiate the apoptotic pathway, while still resulting in significant induction of delayed chromosomal instability. Overall, these observations have important implications for low dose low LET radiation risk assessment and human

  5. Diagnosis of genetic predisposition for lactose intolerance by high resolution melting analysis.

    Science.gov (United States)

    Delacour, Hervé; Leduc, Amandine; Louçano-Perdriat, Andréa; Plantamura, Julie; Ceppa, Franck

    2017-02-01

    Lactose, the principle sugar in milk, is a disaccharide hydrolyzed by intestinal lactase into glucose and galactose, which are absorbed directly by diffusion in the intestine. The decline of lactase expression (or hypolactasia) in intestinal microvilli after weaning is a normal phenomenon in mammals known as lactase deficiency. It is observed in nearly 75% of the world population and is an inherited autosomal recessive trait with incomplete penetrance. It is caused by SNPs in a regulatory element for lactase gene. In Indo-European, lactase deficiency is associated with rs4982235 SNP (or -13910C>T). The aim of this study is to describe a method based on high resolution melting for rapidly detecting genetic predisposition to lactose intolerance. Analytical performance of the assay was assessed by evaluating within and betwwen-run precision and by comparing the results (n = 50 patients) obtained with the HRM assay to those obtained with the gold standard (Sanger sequencing of the region of interest). In silico prediction of HRM curves was performed to evaluate the potential impact of the other SNPs described within the PCR product on the HRM analytical performances. The assay has good performance (CV lactose intolerance.

  6. Modelling the Interplay between Lifestyle Factors and Genetic Predisposition on Markers of Type 2 Diabetes Mellitus Risk.

    Science.gov (United States)

    Walker, Celia G; Solis-Trapala, Ivonne; Holzapfel, Christina; Ambrosini, Gina L; Fuller, Nicholas R; Loos, Ruth J F; Hauner, Hans; Caterson, Ian D; Jebb, Susan A

    2015-01-01

    The risk of developing type 2 diabetes mellitus (T2DM) is determined by a complex interplay involving lifestyle factors and genetic predisposition. Despite this, many studies do not consider the relative contributions of this complex array of factors to identify relationships which are important in progression or prevention of complex diseases. We aimed to describe the integrated effect of a number of lifestyle changes (weight, diet and physical activity) in the context of genetic susceptibility, on changes in glycaemic traits in overweight or obese participants following 12-months of a weight management programme. A sample of 353 participants from a behavioural weight management intervention were included in this study. A graphical Markov model was used to describe the impact of the intervention, by dividing the effects into various pathways comprising changes in proportion of dietary saturated fat, physical activity and weight loss, and a genetic predisposition score (T2DM-GPS), on changes in insulin sensitivity (HOMA-IR), insulin secretion (HOMA-B) and short and long term glycaemia (glucose and HbA1c). We demonstrated the use of graphical Markov modelling to identify the importance and interrelationships of a number of possible variables changed as a result of a lifestyle intervention, whilst considering fixed factors such as genetic predisposition, on changes in traits. Paths which led to weight loss and change in dietary saturated fat were important factors in the change of all glycaemic traits, whereas the T2DM-GPS only made a significant direct contribution to changes in HOMA-IR and plasma glucose after considering the effects of lifestyle factors. This analysis shows that modifiable factors relating to body weight, diet, and physical activity are more likely to impact on glycaemic traits than genetic predisposition during a behavioural intervention.

  7. Genetic predisposition to albuminuria is associated with increased arterial stiffness: role of elastin.

    Science.gov (United States)

    Gil-Ortega, M; García-Prieto, C F; Ruiz-Hurtado, G; Steireif, C; González, M C; Schulz, A; Kreutz, R; Fernández-Alfonso, M S; Arribas, S; Somoza, B

    2015-09-01

    The Munich Wistar Frömter (MWF) rat strain represents an experimental model to study cardiovascular alterations under conditions of progressive albuminuria. The aim of this study was to evaluate the association between genetic predisposition to albuminuria and the development of arterial stiffness and/or vascular remodelling. Experiments were performed in mesenteric arteries from 12-week-old MWF, Wistar Kyoto (WKY) and consomic MWF-6(SHR) and MWF-8(SHR) rats in which chromosomes 6 or 8 associated with albuminuria from MWF were replaced by the respective chromosome from spontaneously hypertensive rats (SHR). Incremental distensibility, wall stress and strain were reduced, and arterial stiffness was significantly increased in albuminuric MWF compared with WKY. Albuminuria suppression in both consomic strains was associated with lower β-values in MWF-8(SHR) and MWF-6(SHR) compared with MWF. Moreover, elastin content was significantly lower in MWF external elastic lamina compared with WKY and both consomic strains. In addition, a reduction in arterial external and internal diameter and cross-sectional area was detected in MWF compared with WKY, thus exhibiting an inward hypotrophic remodelling. However, these alterations remained unchanged in both consomic strains. These data demonstrate that albuminuria in MWF is associated with increased arterial stiffness due to a reduction of elastin content in the external elastic lamina. Moreover, inward hypotrophic remodelling in MWF is not directly associated with albuminuria. In contrast, we demonstrated that two major genetic loci affect both the development of albuminuria and arterial stiffness, thus linking albuminuria and impairment of mechanical properties of resistance arteries. © 2015 The British Pharmacological Society.

  8. Television watching, leisure time physical activity, and the genetic predisposition in relation to body mass index in women and men.

    Science.gov (United States)

    Qi, Qibin; Li, Yanping; Chomistek, Andrea K; Kang, Jae H; Curhan, Gary C; Pasquale, Louis R; Willett, Walter C; Rimm, Eric B; Hu, Frank B; Qi, Lu

    2012-10-09

    Previous studies on gene-lifestyle interaction and obesity have focused mostly on the FTO gene and physical activity, whereas little attention has been paid to sedentary behavior as indicated by television (TV) watching. We analyzed interactions between TV watching, leisure time physical activity, and genetic predisposition in relation to body mass index (BMI) in 7740 women and 4564 men from 2 prospective cohorts: The Nurses' Health Study and the Health Professionals Follow-up Study. Data on physical activity and TV watching were collected 2 years before assessment of BMI. A weighted genetic risk score was calculated on the basis of 32 established BMI-associated variants. In both women and men, the genetic associations with BMI strengthened with increased hours of TV watching. An increment of 10 points in the weighted genetic risk score was associated with 0.8 (SE, 0.4), 0.8 (SE, 0.2), 1.4 (SE, 0.2), 1.5 (SE, 0.2), and 3.4 (SE, 1.0) kg/m(2) higher BMI across the 5 categories of TV watching (0-1, 2-5, 6-20, 21-40, and >40 h/wk; P for interaction=0.001). In contrast, the genetic association with BMI weakened with increased levels of physical activity. An increment of 10 points in the weighted genetic risk score was associated with 1.5 (SE, 0.2), 1.3 (SE, 0.2), 1.2 (SE, 0.2), 1.2 (SE, 0.2), and 0.8 (SE, 0.2) kg/m(2) higher BMI across the quintiles of physical activity. The interactions of TV watching and physical activity with genetic predisposition in relation to BMI were independent of each other. A sedentary lifestyle, indicated by prolonged TV watching, may accentuate the predisposition to elevated adiposity, whereas greater leisure time physical activity may attenuate the genetic association.

  9. Serum 25-Hydroxyvitamin D Status and Longitudinal Changes in Weight and Waist Circumference: Influence of Genetic Predisposition to Adiposity.

    Science.gov (United States)

    Larsen, Sofus C; Ängquist, Lars; Moldovan, Max; Huikari, Ville; Sebert, Sylvain; Cavadino, Alana; Ahluwalia, Tarunveer Singh; Skaaby, Tea; Linneberg, Allan; Husemoen, Lise Lotte N; Toft, Ulla; Pedersen, Oluf; Hansen, Torben; Herzig, Karl-Heinz; Jarvelin, Marjo-Riitta; Power, Chris; Hyppönen, Elina; Heitmann, Berit L; Sørensen, Thorkild I A

    2016-01-01

    Studies of the relationship between serum 25-hydroxyvitamin D (25(OH)D) and changes in measures of adiposity have shown inconsistent results, and interaction with genetic predisposition to obesity has rarely been examined. We examined whether 25(OH)D was associated with subsequent annual changes in body weight (ΔBW) or waist circumference (ΔWC), and whether the associations were modified by genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHRBMI). The study was based on 10,898 individuals from the Danish Inter99, the 1958 British Birth Cohort and the Northern Finland Birth Cohort 1966. We combined 42 adiposity-associated Single Nucleotide Polymorphisms (SNPs) into four scores indicating genetic predisposition to BMI, WC and WHRBMI, or all three traits combined. Linear regression was used to examine the association between serum 25(OH)D and ΔBW or ΔWC, SNP-score × 25(OH)D interactions were examined, and results from the individual cohorts were meta-analyzed. In the meta-analyses, we found no evidence of an association between 25(OH)D and ΔBW (-9.4 gram/y per 10 nmol/L higher 25(OH)D [95% CI: -23.0, +4.3; P = 0.18]) or ΔWC (-0.06 mm/y per 10 nmol/L higher 25(OH)D [95% CI: -0.17, +0.06; P = 0.33]). Furthermore, we found no statistically significant interactions between the four SNP-scores and 25(OH)D in relation to ΔBW or ΔWC. Thus, in view of the narrow CIs, our results suggest that an association between 25(OH)D and changes in measures of adiposity is absent or marginal. Similarly, the study provided evidence that there is either no or very limited dependence on genetic predisposition to adiposity.

  10. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

    Directory of Open Access Journals (Sweden)

    Elinor Sawyer

    2014-04-01

    Full Text Available Invasive lobular breast cancer (ILC accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+ and often associated with lobular carcinoma in situ (LCIS. Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI for ILC = 1.13 (1.09-1.18, P = 6.0 × 10(-10; P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4. Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03; and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04. In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365 and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7. In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity

  11. Genetic predisposition to radiation induced sarcoma: possible role for BRCA and p53 mutations.

    Science.gov (United States)

    Kadouri, Luna; Sagi, Michal; Goldberg, Yael; Lerer, Israela; Hamburger, Tamar; Peretz, Tamar

    2013-07-01

    The estimated incidence of radiation-associated sarcoma (RAS) is 0.03-0.2 % in 5 years post treatment. Most cancer predisposing genes are involved in DNA repair; therefore, elevated RAS risk in these patients is plausible. Cases of angiosarcoma post breast cancer treatment were reported in BRCA1 and BRCA2 carriers. We report the genetic evaluation of seven cases with suspected RAS from patients counseled in our cancer-genetic clinic. Of 2,885 breast cancer patient, 470 were BRCA1 or two mutation carriers and three were p53 mutation carriers. Of them seven developed sarcoma in the field of irradiation; five in the chest wall and two in other sites. Genetic evaluation revealed BRCA1 mutation in two, BRCA2 mutation in additional patient and a carrier of p53 mutation. The estimation of risk for RAS in patients with genetic predisposition is limited due to the rarity of this event, and the bias in referral to the clinic toward younger age. With these limitations the rate of RAS is 0.43 % (2/470, 95 % CI -0.17 to 1.02, SE = 0.3) in this group in a median follow-up of 8.2 years (range 1 month to 51 years). If we assume irradiation for the breast in 80 % of the patients than rate of RAS in group is proximately 0.53 % (2/376, 95 % CI -0.21 to 1.26, SE = 0.37). A BRCA1 carrier which had sarcoma after irradiation to head and neck carcinoma was not included in these analyses. In conclusion, we found a high frequency of BRCA1/2 mutation among our patients diagnosed with RAS. However, we estimated approximately twofold increase in the risk of RAS in BRCA1/2 carriers which was not significant compared to reports in general population. Therefore, RAS is a rare event in BRCA carriers as in the general population, and should not be considered in the decision regarding irradiation treatment in this population.

  12. Is There a Genetic Predisposition to Frozen Shoulder?: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Prodromidis, Apostolos D; Charalambous, Charalambos P

    2016-02-23

    Frozen shoulder is a common disorder that leads to substantial functional loss for patients by impairing activities of daily living. It also adversely affects patients and society by impairing the ability to work. Its pathogenesis is not fully understood. The aim of the present study was to perform a systematic review and meta-analysis to assess the evidence suggesting a genetic link to frozen shoulder. A literature search of MEDLINE, EMBASE, and CINAHL databases using relevant keywords revealed 5506 studies. After appropriate screening of titles, abstracts, and full studies, seven studies were analyzed. Three studies investigated rates of frozen shoulder among relatives. One study (n = 1828 twin pairs) showed an 11.6% prevalence in twin pairs and demonstrated a heritability of 42% for frozen shoulder after adjusting for age. A second study (n = 273) showed that 20% of patients with frozen shoulder had a positive family history involving a first-degree relative. The relative risk of frozen shoulder was 4:1 when all patients with frozen shoulder were compared with a control population. A third study (n = 87) showed that 29% of patients with frozen shoulder had a first-degree relative with frozen shoulder. Two studies evaluated racial predilection for frozen shoulder. One study (n = 50) reported a substantially higher number of white patients (76%) with frozen shoulder than black patients (24%). A second study (n = 87) showed that being born or having parents or grandparents born in the British Isles were risk factors for frozen shoulder. Four immunological studies investigated human leukocyte antigen (HLA)-B27 as a risk factor for frozen shoulder. Meta-analysis of two of these studies with clearly defined controls showed significantly higher rates of HLA-B27 positivity in patients with frozen shoulder as compared with controls (p genetic predisposition to frozen shoulder. However, as there is a lack of unbiased genetic approaches, there is an opportunity for genome

  13. Association between Maternal Fish Consumption and Gestational Weight Gain: Influence of Molecular Genetic Predisposition to Obesity.

    Directory of Open Access Journals (Sweden)

    Sofus C Larsen

    Full Text Available Studies suggest that fish consumption can restrict weight gain. However, little is known about how fish consumption affects gestational weight gain (GWG, and whether this relationship depends on genetic makeup.To examine the association between fish consumption and GWG, and whether this relationship is dependent on molecular genetic predisposition to obesity.A nested case-cohort study based on the Danish National Birth Cohort (DNBC sampling the most obese women (n = 990 and a random sample of the remaining participants (n = 1,128. Replication of statistically significant findings was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC (n = 4,841. We included 32 body mass index (BMI associated single nucleotide polymorphisms (SNPs and 5 SNPs found associated with GWG. BMI associated SNPs were combined in a genetic risk score (GRS. Associations between consumption of fish, GRS or individual variants and GWG were analysed, and interactions between fish and the GRS or individual variants were examined.In the DNBC, each portion/week (150 g of fatty fish was associated with a higher GWG of 0.58 kg (95% CI: 0.16, 0.99, P<0.01. For total fish and lean fish, similar patterns were observed, but these associations were not statistically significant. We found no association between GRS and GWG, and no interactions between GRS and dietary fish on GWG. However, we found an interaction between the PPARG Pro12Ala variant and dietary fish. Each additional Pro12Ala G-allele was associated with a GWG of -0.83 kg (95% CI: -1.29, -0.37, P<0.01 per portion/week of dietary fish, with the same pattern for both lean and fatty fish. In ALSPAC, we were unable to replicate these findings.We found no consistent evidence of association between fish consumption and GWG, and our results indicate that the association between dietary fish and GWG has little or no dependency on GRS or individual SNPs.

  14. Association between Maternal Fish Consumption and Gestational Weight Gain: Influence of Molecular Genetic Predisposition to Obesity.

    Science.gov (United States)

    Larsen, Sofus C; Ängquist, Lars; Laurin, Charles; Morgen, Camilla S; Jakobsen, Marianne U; Paternoster, Lavinia; Smith, George Davey; Olsen, Sjurdur F; Sørensen, Thorkild I A; Nohr, Ellen A

    2016-01-01

    Studies suggest that fish consumption can restrict weight gain. However, little is known about how fish consumption affects gestational weight gain (GWG), and whether this relationship depends on genetic makeup. To examine the association between fish consumption and GWG, and whether this relationship is dependent on molecular genetic predisposition to obesity. A nested case-cohort study based on the Danish National Birth Cohort (DNBC) sampling the most obese women (n = 990) and a random sample of the remaining participants (n = 1,128). Replication of statistically significant findings was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 4,841). We included 32 body mass index (BMI) associated single nucleotide polymorphisms (SNPs) and 5 SNPs found associated with GWG. BMI associated SNPs were combined in a genetic risk score (GRS). Associations between consumption of fish, GRS or individual variants and GWG were analysed, and interactions between fish and the GRS or individual variants were examined. In the DNBC, each portion/week (150 g) of fatty fish was associated with a higher GWG of 0.58 kg (95% CI: 0.16, 0.99, P<0.01). For total fish and lean fish, similar patterns were observed, but these associations were not statistically significant. We found no association between GRS and GWG, and no interactions between GRS and dietary fish on GWG. However, we found an interaction between the PPARG Pro12Ala variant and dietary fish. Each additional Pro12Ala G-allele was associated with a GWG of -0.83 kg (95% CI: -1.29, -0.37, P<0.01) per portion/week of dietary fish, with the same pattern for both lean and fatty fish. In ALSPAC, we were unable to replicate these findings. We found no consistent evidence of association between fish consumption and GWG, and our results indicate that the association between dietary fish and GWG has little or no dependency on GRS or individual SNPs.

  15. Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia.

    Science.gov (United States)

    Spracklen, Cassandra N; Smith, Caitlin J; Saftlas, Audrey F; Triche, Elizabeth W; Bjonnes, Andrew; Keating, Brendan J; Saxena, Richa; Breheny, Patrick J; Dewan, Andrew T; Robinson, Jennifer G; Hoh, Josephine; Ryckman, Kelli K

    2017-02-01

    To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein. Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002-May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82-0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99). Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.

  16. Functional and genetic predisposition to rhinovirus lower respiratory tract infections in prematurely born infants.

    Science.gov (United States)

    Drysdale, Simon B; Alcazar, Mireia; Wilson, Theresa; Smith, Melvyn; Zuckerman, Mark; Hodemaekers, Hennie M; Janssen, Riny; Bont, Louis; Johnston, Sebastian L; Greenough, Anne

    2016-12-01

    Term born infants are predisposed to human rhinovirus (HRV) lower respiratory tract infections (LRTI) by reduced neonatal lung function and genetic susceptibility. Our aim was to investigate whether prematurely born infants were similarly predisposed to HRV LRTIs or any other viral LRTIs. Infants born less than 36 weeks of gestational age were recruited. Prior to neonatal/maternity unit discharge, lung function (functional residual capacity by helium gas dilution and multiple breath washout, lung clearance index and compliance (C rs ), and resistance (R rs ) of the respiratory system) was assessed and DNA samples assessed for eight single nucleotide polymorphisms (SNPs) in seven genes: ADAM33, IL10, MMP16 NFκB1A,SFTPC, VDR, and NOS2A. Infants were prospectively followed until 1 year corrected age. Nasopharyngeal aspirates (NPAs) were sent whenever an infant developed a LRTI and tested for 13 viruses. One hundred and thirty-nine infants were included in the analysis. Infants who developed HRV LRTIs had reduced C rs (1.6 versus 1.2 mL/cmH 2 O/kg, p = 0.044) at 36 weeks postmenstrual age. A SNP in the gene coding for the vitamin D receptor was associated with the development of HRV LRTIs and any viral LRTIs (p = 0.02). Prematurely born infants may have both a functional and genetic predisposition to HRV LRTIs. What is Known: • Term born infants are predisposed to rhinovirus lower respiratory tract (HRV LRTIs) infection by reduced neonatal lung function. • Term born infants requiring hospitalisation due to HRV bronchiolitis were more likely to have single nucleotide polymorphism (SNP) in the IL-10 gene. What is New: • Prematurely born infants who developed a HRV LRTI had lower C rs before maternity unit discharge. • A SNP in the gene coding for the vitamin D receptor was associated with the development of HRV LRTIs and overall respiratory viral LRTIs in prematurely born infants.

  17. Environmental effect and genetic influence: a regional cancer predisposition survey in the Zonguldak region of Northwest Turkey

    Science.gov (United States)

    Kadir, Selahattin; Önen-Hall, A. Piril; Aydin, S. Nihal; Yakicier, Cengiz; Akarsu, Nurten; Tuncer, Murat

    2008-03-01

    The Cretaceous-Eocene volcano-sedimentary units of the Zonguldak region of the western Black Sea consist of subalkaline andesite and tuff, and sandstone dominated by smectite, kaolinite, accessory chlorite, illite, mordenite, and analcime associated with feldspar, quartz, opal-CT, amphibole, and calcite. Kaolinization, chloritization, sericitization, albitization, Fe-Ti-oxidation, and the presence of zeolite, epidote, and illite in andesitic rocks and tuffaceous materials developed as a result of the degradation of a glass shards matrix, enclosed feldspar, and clinopyroxene-type phenocrysts, due to alteration processes. The association of feldspar and glass with smectite and kaolinite, and the suborientation of feldspar-edged, subparallel kaolinite plates to fracture axes may exhibit an authigenic smectite or kaolinite. Increased alteration degree upward in which Al, Fe, and Ti are gained, and Si, Na, K, and Ca are depleted, is due to the alteration following possible diagenesis and hydrothermal activities. Micromorphologically, fibrous mordenite in the altered units and the presence of needle-type chrysotile in the residential buildings in which cancer cases lived were detected. In addition, the segregation pattern of cancer susceptibility in the region strongly suggested an environmental effect and a genetic influence on the increased cancer incidence in the region. The most likely diagnosis was Li-Fraumeni syndrome, which is one of the hereditary cancer predisposition syndromes; however, no mutations were observed in the p53 gene, which is the major cause of Li-Fraumeni syndrome. The micromorphology observed in the altered units in which cancer cases were detected may have a role in the expression of an unidentified gene, but does not explain alone the occurrence of cancer as a primary cause in the region.

  18. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

    Science.gov (United States)

    Mikropoulos, Christos; Selkirk, Christina G Hutten; Saya, Sibel; Bancroft, Elizabeth; Vertosick, Emily; Dadaev, Tokhir; Brendler, Charles; Page, Elizabeth; Dias, Alexander; Evans, D Gareth; Rothwell, Jeanette; Maehle, Lovise; Axcrona, Karol; Richardson, Kate; Eccles, Diana; Jensen, Thomas; Osther, Palle J; van Asperen, Christi J; Vasen, Hans; Kiemeney, Lambertus A; Ringelberg, Janneke; Cybulski, Cezary; Wokolorczyk, Dominika; Hart, Rachel; Glover, Wayne; Lam, Jimmy; Taylor, Louise; Salinas, Monica; Feliubadaló, Lidia; Oldenburg, Rogier; Cremers, Ruben; Verhaegh, Gerald; van Zelst-Stams, Wendy A; Oosterwijk, Jan C; Cook, Jackie; Rosario, Derek J; Buys, Saundra S; Conner, Tom; Domchek, Susan; Powers, Jacquelyn; Ausems, Margreet Gem; Teixeira, Manuel R; Maia, Sofia; Izatt, Louise; Schmutzler, Rita; Rhiem, Kerstin; Foulkes, William D; Boshari, Talia; Davidson, Rosemarie; Ruijs, Marielle; Helderman-van den Enden, Apollonia Tjm; Andrews, Lesley; Walker, Lisa; Snape, Katie; Henderson, Alex; Jobson, Irene; Lindeman, Geoffrey J; Liljegren, Annelie; Harris, Marion; Adank, Muriel A; Kirk, Judy; Taylor, Amy; Susman, Rachel; Chen-Shtoyerman, Rakefet; Pachter, Nicholas; Spigelman, Allan; Side, Lucy; Zgajnar, Janez; Mora, Josefina; Brewer, Carole; Gadea, Neus; Brady, Angela F; Gallagher, David; van Os, Theo; Donaldson, Alan; Stefansdottir, Vigdis; Barwell, Julian; James, Paul A; Murphy, Declan; Friedman, Eitan; Nicolai, Nicola; Greenhalgh, Lynn; Obeid, Elias; Murthy, Vedang; Copakova, Lucia; McGrath, John; Teo, Soo-Hwang; Strom, Sara; Kast, Karin; Leongamornlert, Daniel A; Chamberlain, Anthony; Pope, Jenny; Newlin, Anna C; Aaronson, Neil; Ardern-Jones, Audrey; Bangma, Chris; Castro, Elena; Dearnaley, David; Eyfjord, Jorunn; Falconer, Alison; Foster, Christopher S; Gronberg, Henrik; Hamdy, Freddie C; Johannsson, Oskar; Khoo, Vincent; Lubinski, Jan; Grindedal, Eli Marie; McKinley, Joanne; Shackleton, Kylie; Mitra, Anita V; Moynihan, Clare; Rennert, Gad; Suri, Mohnish; Tricker, Karen; Moss, Sue; Kote-Jarai, Zsofia; Vickers, Andrew; Lilja, Hans; Helfand, Brian T; Eeles, Rosalind A

    2018-01-01

    Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml -l , PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

  19. Integrated screening concept in women with genetic predisposition for breast cancer; Integriertes Frueherkennungskonzept bei Frauen mit genetischer Praedisposition fuer Brustkrebs

    Energy Technology Data Exchange (ETDEWEB)

    Bick, U. [Muenster Univ. (Germany). Inst. fuer Klinische Radiologie

    1997-08-01

    Breast cancer is in 5% of cases due to a genetic disposition. BRCA1 and BRCA2 are by far the most common breast cancer susceptibility genes. For a woman with a genetic predisposition, the individual risk of developing breast cancer sometime in her life is between 70 and 90%. Compared to the spontaneous forms of breast cancer, woman with a genetic predisposition often develop breast cancer at a much younger age. This is why conventional screening programs on the basis of mammography alone cannot be applied without modification to this high-risk group. In this article, an integrated screening concept for women with genetic prodisposition for breast cancer using breast self-examination, clinical examination, ultrasound, mammography and magnetic resonance imaging is introduced. (orig.) [Deutsch] Mammakarzinome sind in etwa 5% auf eine genetische Disposition zurueckzufuehren. Am haeufigsten finden sich Mutationen im Bereich der Gene BRCA1 und BRCA2. Frauen mit einer genetischen Disposition erkranken in etwa 70-90% im Laufe ihres Lebens an einem Mammakarzinom. Das Erkrankungsalter bei diesen Frauen liegt in der Regel deutlich niedriger als bei den spontanen Formen des Mammakarzinoms, so dass vorhandene Frueherkennungskonzepte auf der Basis eines Mammographiescrennings nicht ohne weiteres auf dieses Hochrisikokollektiv uebertragbar sind. Im folgenden wird ein integriertes Konzept zur Frueherkennung bei Frauen mit genetischer Praedisposition fuer ein Mammakarzinom auf der Basis von Brustselbstuntersuchung, klinischer Untersuchung, Sonographie, Mammographie und Magnetresonanztomographie vorgestellt. (orig.)

  20. Genetic predisposition to obesity is associated with insulin secretion in Chinese adults: The Cardiometabolic Risk in Chinese (CRC) study.

    Science.gov (United States)

    Liang, Jun; Sun, Yuting; Liu, Xuekui; Zhu, Yan; Pei, Ying; Wang, Yu; Qiu, Qinqin; Yang, Manqing; Qi, Lu

    2016-01-01

    The etiological role of obesity in determining diabetes risk among Asians may be different from that among Caucasians. The current study aimed to investigate the association between genetic predisposition to obesity and measures of insulin secretion and resistance in a large Chinese cohort. Study samples were from a community-based health examination survey in central China. A total of 2058 subjects with available biomarkers levels were included in the present study. A genetic risk score (GRS) of obesity was derived on the basis of thirteen Asian-specific body mass index (BMI)-associated variants. High obesity GRS was significantly associated with increased homeostasis model assessment (HOMA)-B score (β=7.309; P=0.001) but not related to measures of insulin resistance. Adjustment for age, sex, BMI, and levels of lipids did not appreciably change the results. In addition, we found significant interactions between the obesity GRS and measures of body fat distribution including waist circumference (WC; P for interaction=0.004) and neck circumference (NC; P for interaction=0.014) on HOMA-B score. Our results suggest that genetic predisposition to obesity may affect beta cell function in Chinese; and body fat distribution may modify the genetic effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Habitual coffee consumption and genetic predisposition to obesity: gene-diet interaction analyses in three US prospective studies.

    Science.gov (United States)

    Wang, Tiange; Huang, Tao; Kang, Jae H; Zheng, Yan; Jensen, Majken K; Wiggs, Janey L; Pasquale, Louis R; Fuchs, Charles S; Campos, Hannia; Rimm, Eric B; Willett, Walter C; Hu, Frank B; Qi, Lu

    2017-05-09

    Whether habitual coffee consumption interacts with the genetic predisposition to obesity in relation to body mass index (BMI) and obesity is unknown. We analyzed the interactions between genetic predisposition and habitual coffee consumption in relation to BMI and obesity risk in 5116 men from the Health Professionals Follow-up Study (HPFS), in 9841 women from the Nurses' Health Study (NHS), and in 5648 women from the Women's Health Initiative (WHI). The genetic risk score was calculated based on 77 BMI-associated loci. Coffee consumption was examined prospectively in relation to BMI. The genetic association with BMI was attenuated among participants with higher consumption of coffee than among those with lower consumption in the HPFS (P interaction  = 0.023) and NHS (P interaction  = 0.039); similar results were replicated in the WHI (P interaction  = 0.044). In the combined data of all cohorts, differences in BMI per increment of 10-risk allele were 1.38 (standard error (SE), 0.28), 1.02 (SE, 0.10), and 0.95 (SE, 0.12) kg/m 2 for coffee consumption of  3 cup(s)/day, respectively (P interaction  coffee consumption among participants at lower genetic risk and slightly lower BMI with higher coffee consumption among those at higher genetic risk. Each increment of 10-risk allele was associated with 78% (95% confidence interval (CI), 59-99%), 48% (95% CI, 36-62%), and 43% (95% CI, 28-59%) increased risk for obesity across these subgroups of coffee consumption (P interaction  = 0.008). From another perspective, differences in BMI per increment of 1 cup/day coffee consumption were 0.02 (SE, 0.09), -0.02 (SE, 0.04), and -0.14 (SE, 0.04) kg/m 2 across tertiles of the genetic risk score. Higher coffee consumption might attenuate the genetic associations with BMI and obesity risk, and individuals with greater genetic predisposition to obesity appeared to have lower BMI associated with higher coffee consumption.

  2. Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment.

    Science.gov (United States)

    Smit, Roelof Aj; Postmus, Iris; Trompet, Stella; Barnes, Michael R; Warren, Helen; Arsenault, Benoit J; Chasman, Daniel I; Cupples, L Adrienne; Hitman, Graham A; Krauss, Ronald M; Li, Xiaohui; Psaty, Bruce M; Stein, Charles M; Rotter, Jerome I; Jukema, J Wouter

    2016-10-01

    To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response. We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia. Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels. Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.

  3. Genetic predisposition to an adverse lipid profile limits the improvement in total cholesterol in response to weight loss.

    Science.gov (United States)

    Walker, Celia G; Holzapfel, Christina; Loos, Ruth J F; Mander, Adrian P; Klopp, Norman; Illig, Thomas; Caterson, Ian D; Hauner, Hans; Jebb, Susan A

    2013-12-01

    Overweight and obesity are associated with a dyslipidaemia which can be improved by weight loss. Whether genetic predisposition to an adverse lipid profile modifies such beneficial effects of weight loss on lipid levels in overweight and obese individuals was examined. White European participants (n = 374) who completed a 12-month weight loss trial were genotyped for 36 lipid-associated single nucleotide polymorphisms (SNPs), previously identified in genome-wide association studies (GWAS). Genetic predisposition scores (GPSs) were calculated for four lipid traits by summing the number of risk alleles (RA) for each participant. The associations of each GPS with four lipid traits were assessed at baseline, and with lipid changes in response to weight change after 12 months. At baseline, the trait-specific GPSs were associated with 0.11 ± 0.04 mM higher total cholesterol/RA (P = 0.004), 0.05 ± 0.02 mM higher low density lipoprotein cholesterol/RA (P = 0.005), 0.03 ± 0.007 mM lower high density lipoprotein cholesterol/RA (P = 0.00002) and 0.04 ± 0.01 mM higher triglyceride/RA (P = 0.00002). After the intervention, weight loss was associated with improvements in all lipids (P Genetic predisposition is an important determinant of lipid levels and appears to limit the improvement in TC and to some extent LDLC levels, but not in other plasma lipids, in response to weight loss. © 2013 American Institute of Chemical Engineers AIChE J, 2013. Copyright © 2013 The Obesity Society.

  4. Interaction between genetic predisposition to adiposity and dietary protein in relation to subsequent change in body weight and waist circumference.

    Directory of Open Access Journals (Sweden)

    Mikkel Z Ankarfeldt

    Full Text Available Genetic predisposition to adiposity may interact with dietary protein in relation to changes of anthropometry.To investigate the interaction between genetic predisposition to higher body mass index (BMI, waist circumference (WC or waist-hip ratio adjusted for BMI (WHRBMI and dietary protein in relation to subsequent change in body weight (ΔBW or change in WC (ΔWC.Three different Danish cohorts were used. In total 7,054 individuals constituted the study population with information on diet, 50 single-nucleotide polymorphisms (SNPs associated with BMI, WC or WHRBMI, as well as potential confounders. Mean follow-up time was ∼5 years. Four genetic predisposition-scores were based on the SNPs; a complete-score including all selected adiposity- associated SNPs, and three scores including BMI, WC or WHRBMI associated polymorphisms, respectively. The association between protein intake and ΔBW or ΔWC were examined and interactions between SNP-score and protein were investigated. Analyses were based on linear regressions using macronutrient substitution models and meta-analyses.When protein replaced carbohydrate, meta-analyses showed no associations with ΔBW (41.0 gram/y/5 energy% protein, [95% CI: -32.3; 114.3] or ΔWC (<-0.1 mm/y/5 energy % protein, [-1.1; 1.1]. Similarly, there were no interactions for any SNP-scores and protein for either ΔBW (complete SNP-score: 1.8 gram/y/5 energy% protein/risk allele, [-7.0; 10.6] or ΔWC (complete SNP-score: <0.1 mm/y/5 energy% protein/risk allele, [-0.1; 0.1]. Similar results were seen when protein replaced fat.This study indicates that the genetic predisposition to general and abdominal adiposity, assessed by gene-scores, does not seem to modulate the influence of dietary protein on ΔBW or ΔWC.

  5. Interaction between genetic predisposition to obesity and dietary calcium in relation to subsequent change in body weight and waist circumference.

    Science.gov (United States)

    Larsen, Sofus C; Ängquist, Lars; Ahluwalia, Tarunveer Singh; Skaaby, Tea; Roswall, Nina; Tjønneland, Anne; Halkjær, Jytte; Overvad, Kim; Pedersen, Oluf; Hansen, Torben; Linneberg, Allan; Husemoen, Lise Lotte N; Toft, Ulla; Heitmann, Berit L; Sørensen, Thorkild Ia

    2014-04-01

    Studies indicate an effect of dietary calcium on change in body weight (BW) and waist circumference (WC), but the results are inconsistent. Furthermore, a relation could depend on genetic predisposition to obesity. The objective was to examine whether genetic predisposition to higher body mass index (BMI), WC, or waist-hip ratio (WHR) interacts with dietary calcium in relation to subsequent annual change in BW (ΔBW) and WC (ΔWC). The study was based on 7569 individuals from the MONItoring trends and determinants of CArdiovascular disease Study, a sample from the Danish Diet, Cancer and Health Study and the INTER99 study, with information on diet; 54 single-nucleotide polymorphisms (SNPs) associated with BMI, WC, or WHR adjusted for BMI; and potential confounders. The SNPs were combined in 4 scores as indicators of genetic predisposition; all SNPs in a general score and a score for each of 3 phenotypes: BMI, WC, and WHR. Linear regression was used to examine the association between calcium intake and ΔBW or ΔWC adjusted for concurrent ΔBW. SNP score × calcium interactions were examined by adding product terms to the models. We found a significant ΔBW of -0.076 kg (P = 0.021; 95% CI: -0.140, -0.012) per 1000 mg Ca. No significant association was observed between dietary calcium and ΔWC. In the analyses with ΔBW as outcome, we found no significant interactions between the developed predisposition scores and calcium. However, we found a significant interaction between a score of 6 WC-associated SNPs and calcium in relation to ΔWC. Each risk allele was associated with a ΔWC of -0.043 cm (P = 0.038; 95% CI: -0.083, -0.002) per 1000 mg Ca. Our study suggests that dietary calcium relates weakly to BW loss. We found no evidence of a general association between calcium and ΔWC, but calcium may reduce WC among people genetically predisposed to a high WC. However, further replication of this finding is needed.

  6. A genetic predisposition score for muscular endophenotypes predicts the increase in aerobic power after training: the CAREGENE study

    Science.gov (United States)

    2011-01-01

    Background It is widely accepted that genetic variability might explain a large part of the observed heterogeneity in aerobic capacity and its response to training. Significant associations between polymorphisms of different genes with muscular strength, anaerobic phenotypes and body composition have been reported. Muscular endophenotypes are positively correlated with aerobic capacity, therefore, we tested the association of polymorphisms in twelve muscular related genes on aerobic capacity and its response to endurance training. Methods 935 Coronary artery disease patients (CAD) who performed an incremental exercise test until exhaustion at baseline and after three months of training were included. Polymorphisms of the genes were detected using the invader assay. Genotype-phenotype association analyses were performed using ANCOVA. Different models for a genetic predisposition score (GPS) were constructed based on literature and own data and were related to baseline and response VO2 scores. Results Carriers of the minor allele in the R23K polymorphism of the glucocorticoid receptor gene (GR) and the ciliary neurotrophic factor gene (CNTF) had a significantly higher increase in peakVO2 after training (p genetic predisposition score (GPS) showed a significant predictive value for the increase in peakVO2. PMID:21967077

  7. Another Report of Acalculous Cholecystitis in a Greek Patient with Infectious Mononucleosis: A Matter of Luck or Genetic Predisposition?

    Directory of Open Access Journals (Sweden)

    Theocharis Koufakis

    2016-01-01

    Full Text Available We here report a case of a young, male patient who presented with jaundice and was diagnosed with acalculous cholecystitis during the course of a primary Epstein-Barr Virus (EBV infection. The coexistence of cholestatic hepatitis and acalculous cholecystitis in patients with infectious mononucleosis is extremely uncommon and only few cases can be found in the literature. Moreover, almost one-fourth of the total reports of this rare entity are coming from Greece. Whether this is a result of physicians’ high index of suspicion due to previous reports or a consequence of genetic predisposition is an issue that deserves further investigation in the future. More studies are required in order to clarify the pathophysiological and genetic backgrounds that connect acalculous cholecystitis and EBV infection.

  8. Short-term psychological impact of the BRCA1/2 test result in women with breast cancer according to their perceived probability of genetic predisposition to cancer.

    Science.gov (United States)

    Brédart, A; Kop, J L; Depauw, A; Caron, O; Sultan, S; Leblond, D; Fajac, A; Buecher, B; Gauthier-Villars, M; Noguès, C; Flahault, C; Stoppa-Lyonnet, D; Dolbeault, S

    2013-03-19

    The effect of BRCA1/2 gene test result on anxiety, depression, cancer-related thought intrusion or avoidance and perceived control over cancer risk was assessed in breast cancer (BC) patients, according to their perceived probability of genetic predisposition to cancer. Two hundred and forty-three (89% response rate) women with BC completed questionnaires after an initial genetic counselling visit (T1), of which 180 (66%) completed questionnaires again after receiving the BRCA1/2 results (T2). The discrepancy between women's perceived probability of cancer genetic predisposition at T1 and the geneticist's computed estimates was assessed. In all, 74% of women received a negative uninformative (NU), 11% a positive BRCA1/2 and 15% an unclassified variant (UV) result. On hierarchical regression analysis, in women with a positive BRCA1/2 result (vs NU or UV), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted lower levels of anxiety at T2 (β=-0.28; Pgenetic predisposition than objective estimates at T1 predicted higher levels of anxiety (β=0.20; Pgenetic predisposition before testing.

  9. Genetic predisposition to obesity affects behavioural traits including food reward and anxiety-like behaviour in rats.

    Science.gov (United States)

    Vogel, Heike; Kraemer, Maria; Rabasa, Cristina; Askevik, Kaisa; Adan, Roger A H; Dickson, Suzanne L

    2017-06-15

    Here we sought to define behavioural traits linked to anxiety, reward, and exploration in different strains of rats commonly used in obesity research. We hypothesized that genetic variance may contribute not only to their metabolic phenotype (that is well documented) but also to the expression of these behavioural traits. Rat strains that differ in their susceptibility to develop an obese phenotype (Sprague-Dawley, Obese Prone, Obese Resistant, and Zucker rats) were exposed to a number of behavioural tests starting at the age of 8 weeks. We found a similar phenotype in the obesity susceptible models, Obese Prone and Zucker rats, with a lower locomotor activity, exploratory activity, and higher level of anxiety-like behaviour in comparison to the leaner Obese Resistant strain. We did not find evidence that rat strains with a genetic predisposition to obesity differed in their ability to experience reward from chocolate (in a condition place preference task). However, Zucker rats show higher motivated behaviour for sucrose compared to Obese Resistant rats when the effort required to obtain palatable food is relatively low. Together our data demonstrate that rat strains that differ in their genetic predisposition to develop obesity also differ in their performance in behavioural tests linked to anxiety, exploration, and reward and that these differences are independent of body weight. We conclude that genetic variations which determine body weight and the aforementioned behaviours co-exist but that future studies are required to identify whether (and which) common genes are involved. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Ovarian hyperstimulation syndrome after gonadotropin-releasing hormone agonist triggering and "freeze-all": in-depth analysis of genetic predisposition.

    Science.gov (United States)

    Santos-Ribeiro, Samuel; Polyzos, Nikolaos P; Stouffs, Katrien; De Vos, Michel; Seneca, Sara; Tournaye, Herman; Blockeel, Christophe

    2015-07-01

    We report on the results of the whole-genome analysis performed in a patient who developed severe ovarian hyperstimulation syndrome (OHSS) following gonadotropin-releasing hormone (GnRH) agonist triggering in a "freeze-all" protocol. A 30-year-old patient with polycystic ovary syndrome who developed severe early-onset OHSS with clinical ascites, and slight renal and hepatic dysfunction was admitted for monitoring and treatment with cabergoline and intravenous albumin. Exome sequencing to assess for any known genetic predisposition for OHSS was performed. No known genetic variants associated with OHSS predisposition were found. Case reports of severe OHSS following a "freeze-all" strategy are starting to arise, showing that OHSS has not been completely eliminated with this approach. Further studies should be conducted to confirm if such cases may be due to genetic predisposition or not.

  11. A Combination of Naltrexone + Varenicline Retards the Expression of a Genetic Predisposition Toward High Alcohol Drinking.

    Science.gov (United States)

    Froehlich, Janice C; Fischer, Stephen M; Nicholson, Emily R; Dilley, Julian E; Filosa, Nicholas J; Smith, Teal N; Rademacher, Logan C

    2017-03-01

    This study examined whether naltrexone (NTX) or varenicline (VAR), alone or in combination, can retard the phenotypic expression of a genetic predisposition toward high alcohol drinking in rats selectively bred for high alcohol intake when drug treatment is initiated prior to, or concomitantly with, the onset of alcohol drinking. Alcohol-naïve P rats were treated daily with NTX (15.0 mg/kg BW), VAR (1.0 mg/kg BW), a combination of NTX (15.0 mg/kg BW) + VAR (1.0 mg/kg BW), or vehicle (VEH) for 2 weeks prior to, or concomitantly with, their first opportunity to drink alcohol and throughout 21 days of daily 2-hour alcohol access. Drug treatment was then discontinued for 3 weeks followed by reinstatement of drug treatment for an additional 3 weeks. When P rats were pretreated with drug for 2 weeks prior to onset of alcohol access, only NTX + VAR in combination blocked the acquisition of alcohol drinking in alcohol-naïve P rats. When drug treatment was initiated concomitantly with the first opportunity to drink alcohol, NTX alone, VAR alone, and NTX + VAR blocked the acquisition of alcohol drinking. Following termination of drug treatment, NTX + VAR and VAR alone continued to reduce alcohol drinking but by the end of 3 weeks without drug treatment, alcohol intake in all groups was comparable to that seen in the vehicle-treated group as the expression of a genetic predisposition toward high alcohol drinking emerged in the drug-free P rats. After 3 weeks without drug treatment, reinstatement of NTX + VAR treatment again reduced alcohol intake. A combination of NTX + VAR, when administered prior to, or concomitantly with, the first opportunity to drink alcohol, blocks the acquisition of alcohol drinking during both initial access to alcohol and during a later period of alcohol access in P rats with a genetic predisposition toward high alcohol intake. The results suggest that NTX + VAR may be effective in curtailing alcohol drinking in individuals

  12. A genetic predisposition score for muscular endophenotypes predicts the increase in aerobic power after training: the CAREGENE study

    Directory of Open Access Journals (Sweden)

    Schepers Dirk

    2011-10-01

    Full Text Available Abstract Background It is widely accepted that genetic variability might explain a large part of the observed heterogeneity in aerobic capacity and its response to training. Significant associations between polymorphisms of different genes with muscular strength, anaerobic phenotypes and body composition have been reported. Muscular endophenotypes are positively correlated with aerobic capacity, therefore, we tested the association of polymorphisms in twelve muscular related genes on aerobic capacity and its response to endurance training. Methods 935 Coronary artery disease patients (CAD who performed an incremental exercise test until exhaustion at baseline and after three months of training were included. Polymorphisms of the genes were detected using the invader assay. Genotype-phenotype association analyses were performed using ANCOVA. Different models for a genetic predisposition score (GPS were constructed based on literature and own data and were related to baseline and response VO2 scores. Results Carriers of the minor allele in the R23K polymorphism of the glucocorticoid receptor gene (GR and the ciliary neurotrophic factor gene (CNTF had a significantly higher increase in peakVO2 after training (p AMPD1 gene had a significantly lower relative increase (p 2. GPS of data driven models were significantly associated with the increase in peakVO2 after training. Conclusions In CAD patients, suggestive associations were found in the GR, CNTF and the AMPD1 gene with an improved change in aerobic capacity after three months of training. Additionally data driven models with a genetic predisposition score (GPS showed a significant predictive value for the increase in peakVO2.

  13. The RadGenomics project. Prediction for radio-susceptibility of individuals with genetic predisposition

    International Nuclear Information System (INIS)

    Imai, Takashi

    2003-01-01

    The ultimate goal of our project, named RadGenomics, is to elucidate the heterogeneity of the response to ionizing radiation arising from genetic variation among individuals, for the purpose of developing personalized radiation therapy regimens for cancer patients. Cancer patients exhibit patient-to-patient variability in normal tissue reactions after radiotherapy. Several observations support the hypothesis that the radiosensitivity of normal tissue is influenced by genetic factors. The rapid progression of human genome sequencing and the recent development of new technologies in molecular biology are providing new opportunities for elucidating the genetic basis of individual differences in susceptibility to radiation exposure. The development of a sufficiently robust, predictive assay enabling individual dose adjustment would improve the outcome of radiation therapy in patients. Our strategy for identification of DNA polymorphisms that contribute to the individual radiosensitivity is as follows. First, we have been categorizing DNA samples obtained from cancer patients, who have been kindly introduced to us through many collaborators, according to their clinical characteristics including the method and effect of treatment and side effects as scored by toxicity criteria, and also the result of an in vitro radiosensitivity assay, e.g., the micronuclei assay of their lymphocytes. Second, we have identified candidate genes for genotyping mainly by using our custom-designed oligonucleotide array with RNA samples, in which the probes were obtained from more than 40 cancer and 3 fibroblast cell lines whose radiosensitivity level was quite heterogeneous. We have also been studying the modification of proteins after irradiation of cells which may be caused by mainly phosphorylation or dephosphorylation, using mass spectrometry. Genes encoding the modified proteins and/or other proteins with which they interact such as specific protein kinases and phosphatases are also

  14. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

    DEFF Research Database (Denmark)

    Mikropoulos, Christos; Selkirk, Christina G Hutten; Saya, Sibel

    2018-01-01

    BACKGROUND: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PS...... elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. RESULTS: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV...

  15. Early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition

    OpenAIRE

    Husted, Janice A.; Ahmed, Rashid; Chow, Eva W.C.; Brzustowicz, Linda M.; Bassett, Anne S.

    2012-01-01

    There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood tr...

  16. Development of genetic testing for breast, ovarian and colorectal cancer predisposition: a step closer to targeted cancer prevention.

    Science.gov (United States)

    Eccles, D M

    2011-12-01

    Individuals who inherit a high penetrance cancer susceptibility gene represent a population in which cancer diagnoses occur at younger ages and much more frequently than in the general population. Screening regimens aimed at early detection of cancer may reduce cancer mortality but in order to reduce cancer incidence, surgery and medical therapies have been advocated. In high genetic risk patients, either surgical or medical intervention may provide long term protection against cancer and at young ages co-morbidities will be low. The use of genetic testing for high risk predisposition genes to refine risk estimates and inform choices about cancer prevention is now readily available in many countries and routinely used to target cancer prevention strategies. Surgical approaches to cancer prevention are currently the mainstay in many conditions where a high risk is identified but medical prevention strategies also have demonstrated some efficacy in lowering cancer risk. Using the genetic status of an individual to target cancer treatment and prevent recurrence is increasingly gaining momentum as clinical trials involving known high risk gene carriers are now being conducted using both established cytotoxic drugs and novel targeted agents. Translation of new mechanistic insights into beneficial clinical care strategies requires more research. Robust evidence supporting medical approaches to cancer prevention in particular will require well designed large international collaborative clinical trials.

  17. Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23.

    Science.gov (United States)

    Bachinski, Linda L; Olufemi, Shodimu-Emmanuel; Zhou, Xiaojun; Wu, Chih-Chieh; Yip, Linwah; Shete, Sanjay; Lozano, Guillermina; Amos, Christopher I; Strong, Louise C; Krahe, Ralf

    2005-01-15

    Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. Most cases ( approximately 70%) identified and characterized to date are associated with dominantly inherited germ line mutations in the tumor suppressor gene TP53 (p53) in chromosome 17p13.1. In a subset of non-p53 patients with LFS, CHEK2 in chromosome 22q11 has been identified as another predisposing locus. Studying a series of non-p53 LFS kindred, we have shown that there is additional genetic heterogeneity in LFS kindred with inherited predisposition at loci other than p53 or CHEK2. Using a genome-wide scan for linkage with complementing parametric and nonparametric analysis methods, we identified linkage to a region of approximately 4 cM in chromosome 1q23, a genomic region not previously implicated in this disease. Identification ofa third predisposing gene and its underlying mutation(s) should provide insight into other genetic events that predispose to the genesis of the diverse tumor types associated with LFS and its variants.

  18. Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation.

    Science.gov (United States)

    Postema, Floor A M; Hopman, Saskia M J; Aalfs, Cora M; Berger, Lieke P V; Bleeker, Fonnet E; Dommering, Charlotte J; Jongmans, Marjolijn C J; Letteboer, Tom G W; Olderode-Berends, Maran J W; Wagner, Anja; Hennekam, Raoul C; Merks, Johannes H M

    2017-07-01

    Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation. We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist. The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS. We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Genetic association of SNPs in the FTO gene and predisposition to obesity in Malaysian Malays

    Directory of Open Access Journals (Sweden)

    Y.D. Apalasamy

    2012-12-01

    Full Text Available The common variants in the fat mass- and obesity-associated (FTO gene have been previously found to be associated with obesity in various adult populations. The objective of the present study was to investigate whether the single nucleotide polymorphisms (SNPs and linkage disequilibrium (LD blocks in various regions of the FTO gene are associated with predisposition to obesity in Malaysian Malays. Thirty-one FTO SNPs were genotyped in 587 (158 obese and 429 non-obese Malaysian Malay subjects. Obesity traits and lipid profiles were measured and single-marker association testing, LD testing, and haplotype association analysis were performed. LD analysis of the FTO SNPs revealed the presence of 57 regions with complete LD (D’ = 1.0. In addition, we detected the association of rs17817288 with low-density lipoprotein cholesterol. The FTO gene may therefore be involved in lipid metabolism in Malaysian Malays. Two haplotype blocks were present in this region of the FTO gene, but no particular haplotype was found to be significantly associated with an increased risk of obesity in Malaysian Malays.

  20. Genetic association of SNPs in the FTO gene and predisposition to obesity in Malaysian Malays

    International Nuclear Information System (INIS)

    Apalasamy, Y.D.; Ming, M.F.; Rampal, S.; Bulgiba, A.; Mohamed, Z.

    2012-01-01

    The common variants in the fat mass- and obesity-associated (FTO) gene have been previously found to be associated with obesity in various adult populations. The objective of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) blocks in various regions of the FTO gene are associated with predisposition to obesity in Malaysian Malays. Thirty-one FTO SNPs were genotyped in 587 (158 obese and 429 non-obese) Malaysian Malay subjects. Obesity traits and lipid profiles were measured and single-marker association testing, LD testing, and haplotype association analysis were performed. LD analysis of the FTO SNPs revealed the presence of 57 regions with complete LD (D' = 1.0). In addition, we detected the association of rs17817288 with low-density lipoprotein cholesterol. The FTO gene may therefore be involved in lipid metabolism in Malaysian Malays. Two haplotype blocks were present in this region of the FTO gene, but no particular haplotype was found to be significantly associated with an increased risk of obesity in Malaysian Malays

  1. Genetic association of SNPs in the FTO gene and predisposition to obesity in Malaysian Malays

    Energy Technology Data Exchange (ETDEWEB)

    Apalasamy, Y.D. [Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur (Malaysia); Ming, M.F.; Rampal, S.; Bulgiba, A. [Julius Centre University of Malaya, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur (Malaysia); Mohamed, Z. [Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur (Malaysia)

    2012-08-24

    The common variants in the fat mass- and obesity-associated (FTO) gene have been previously found to be associated with obesity in various adult populations. The objective of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) blocks in various regions of the FTO gene are associated with predisposition to obesity in Malaysian Malays. Thirty-one FTO SNPs were genotyped in 587 (158 obese and 429 non-obese) Malaysian Malay subjects. Obesity traits and lipid profiles were measured and single-marker association testing, LD testing, and haplotype association analysis were performed. LD analysis of the FTO SNPs revealed the presence of 57 regions with complete LD (D' = 1.0). In addition, we detected the association of rs17817288 with low-density lipoprotein cholesterol. The FTO gene may therefore be involved in lipid metabolism in Malaysian Malays. Two haplotype blocks were present in this region of the FTO gene, but no particular haplotype was found to be significantly associated with an increased risk of obesity in Malaysian Malays.

  2. Genetic predisposition to radiation-related cancer and potential implications for risk assessment

    International Nuclear Information System (INIS)

    Sigurdson, A.J.; Stram, D.O.

    2012-01-01

    Several lines of evidence suggest that risk estimates for cancer associated with radiation exposure incorporate individuals who are more and less inherently susceptible to the carcinogenic effects of radiation, and the technology to further evaluate this issue is now available. For example, genome-wide association scan studies could be undertaken to address, at least in part, the direction of causality in the observations of differential sensitivity to radiomimetic agents in cancer cases compared with normal individuals, thereby building on previous observations that sensitivity to these agents is higher in apparently normal individuals carrying gene mutations in NBS and ATM. Direct studies of risk of second cancers in relation to radiation are underway, and some results have been reported (e.g. for the PRDM1 gene as related to sensitivity to radiation-related cancers after treatment for Hodgkin’s lymphoma). It is important to understand the risk synergies between variants affecting associations with various cancers defining susceptibility in unexposed populations and the excess risk in populations therapeutically or occupationally exposed to radiation for the purpose of risk protection, especially as additional baseline risk variants are discovered in increasingly large-scale analyses. While there are studies that are beginning to address these questions, there have been no compelling new discoveries, to date, to indicate that predisposition information should be included in risk assessment. The conclusions in ICRP Publications 79 and 103 appear relevant today.

  3. Evidence of genetic predisposition for metabolically healthy obesity and metabolically obese normal weight

    DEFF Research Database (Denmark)

    Huang, Lam Opal; Loos, Ruth JF; Oskari Kilpeläinen, Tuomas

    2018-01-01

    metabolically obese normal weight (MONW). Recent large-scale genomic studies have provided evidence that a number of genetic variants show an association with increased adiposity but a favorable cardiometabolic profile, an indicator for the genetic basis of the MHO and MONW phenotypes. Many of these loci...... storage capacity could lead to ectopic lipid accumulation in non-adipose tissues such as liver, muscle, heart, and pancreatic beta cells. Understanding the genetic aspects of the mechanisms that underpin MHO and MONW is crucial to define appropriate public health action points and to develop effective...

  4. Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

    DEFF Research Database (Denmark)

    Julvez, Jordi; Smith, George Davey; Golding, Jean

    2013-01-01

    Cognitive consequences at school age associated with prenatal methylmercury (MeHg) exposure may need to take into account nutritional and sociodemographic cofactors as well as relevant genetic polymorphisms....

  5. Genome sequencing of Ewing sarcoma patients reveals genetic predisposition | Center for Cancer Research

    Science.gov (United States)

    The largest and most comprehensive genomic analysis of individuals with Ewing sarcoma performed to date reveals that some patients are genetically predisposed to developing the cancer.  Learn more...

  6. Genetic predisposition of variants in TLR2 and its co-receptors to severe malaria in Odisha, India.

    Science.gov (United States)

    Panigrahi, Subhendu; Kar, Avishek; Tripathy, Sagnika; Mohapatra, Manoj K; Dhangadamajhi, Gunanidhi

    2016-02-01

    Although the role of TLRs signalling in malaria pathogenesis is well established, contribution of individual TLR to clinical outcome of malaria still remains inconclusive. Given the importance of TLR2 and its co-receptors in recognising distinct structural forms of key malaria toxins and mediating innate immune response, it is essential to delineate their genetic contribution. Variants in TLR1 (I602S) and TLR6 (P249S) were genotyped by PCR-RFLP methods, and TLR2 (I/D) was genotyped by PCR in 200 samples each from uncomplicated malaria (UM) and severe malaria (SM). Further, SM was categorised into its sub-clinical groups (CM and NCSM or SOD and MODS) and analysed. The results showed the PP genotype of TLR6 (P249S) to be significantly more common in UM (P genetic predisposition to SM and that its association with either TLR2 'D' or TLR1 '602S' modulates for CM development. The present study opens up several new avenues for their exploration and validation in future studies in different global settings for malaria.

  7. Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex.

    Science.gov (United States)

    Traylor, Matthew; Rutten-Jacobs, Loes C A; Holliday, Elizabeth G; Malik, Rainer; Sudlow, Cathie; Rothwell, Peter M; Maguire, Jane M; Koblar, Simon A; Bevan, Steve; Boncoraglio, Giorgio; Dichgans, Martin; Levi, Chris; Lewis, Cathryn M; Markus, Hugh S

    2015-11-01

    Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084). Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations. © 2015 The Authors.

  8. [Genetic predisposition to breast and ovarian cancer: importance of test results].

    Science.gov (United States)

    Julian-Reynier, Claire

    2011-01-01

    Oncogenetic consultations and predictive BRCA1/2 testing are intertwined processes and the specific impact of these genetic tests if performed alone through direct-to-consumer offers remains unknown. Noteworthy, the expectations of patients vary with their own status, whether they are affected or not by breast cancer at the time genetic testing is performed. The prescription of genetic tests for BCRA mutations has doubled in France between 2003 and 2009. There is a consensus on the fact that genetic results disclosure led to a significant increase in the knowledge and understanding that the patients have of the genetic risk and also changed the medical follow-up of these patients. Evaluating the psychological burden of tests disclosure did not reveal any major distress in patients who are followed by high-quality multidisciplinary teams. Longitudinal cohorts studies have now evaluated the perception and behaviour of these patients, and observed sociodemographic as well as geographic and psychosocial differences both in the acceptation of prophylactic strategies such as surgery, and time to surgery. © 2011 médecine/sciences - Inserm / SRMS.

  9. Evidence that periweaning failure-to-thrive syndrome (PFTS) has a genetic predisposition.

    Science.gov (United States)

    Ramis, G; Marco, E; Magaña, V; González-Contreras, P; Swierczynski, G; Abellaneda, J M; Sáez-Acosta, A; Mrowiec, A; Pallarés, F J

    2015-06-06

    Genetic susceptibility or resistance to diseases is currently drawing increasing attention. This work describes two different breeding herds showing signs of periweaning failure-to-thrive syndrome (PFTS), an emergent swine disease. The disease was diagnosed based on clinical picture and confirmed by histopathology. The possibility of main infectious pathogens was ruled out by immunohistochemistry and PCR. In a simple approach, sires of the affected piglets have been determined using microsatellite paternity analysis, including a healthy group in each case. In each of the two farms, a single boar was found to have sired 45-50 per cent sick animals. Removal of this sire from two farms resulted in a significant decrease in the prevalence of the disease among the offspring, in accordance with other two cases diagnosed, although without including a control group. Since the analysed animals belonged to three different genetic lines, these findings point to the existence of individual genetic susceptibility to this syndrome. British Veterinary Association.

  10. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis.

    Science.gov (United States)

    Proitsi, Petroula; Lupton, Michelle K; Velayudhan, Latha; Newhouse, Stephen; Fogh, Isabella; Tsolaki, Magda; Daniilidou, Makrina; Pritchard, Megan; Kloszewska, Iwona; Soininen, Hilkka; Mecocci, Patrizia; Vellas, Bruno; Williams, Julie; Stewart, Robert; Sham, Pak; Lovestone, Simon; Powell, John F

    2014-09-01

    Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD. We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n=10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at pGenetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD. Please see later in the article for the Editors' Summary.

  11. Genetic predisposition to adiposity is associated with increased objectively assessed sedentary time in young children

    DEFF Research Database (Denmark)

    Schnurr, Theresia Maria; Viitasalo, A; Eloranta, A-M

    2018-01-01

    Increased sedentariness has been linked to the growing prevalence of obesity in children, but some longitudinal studies suggest that sedentariness may be a consequence rather than a cause of increased adiposity. We used Mendelian randomization to examine the causal relations between body mass index......=0.072). Childhood BMI may have a causal influence on sedentary time but not on total physical activity or MVPA in young children. Our results provide important insights into the regulation of movement behaviour in childhood.International Journal of Obesity accepted article preview online, 26...... (BMI) and objectively assessed sedentary time and physical activity in 3-8 year-old children from one Finnish and two Danish cohorts [NTOTAL=679]. A genetic risk score (GRS) comprised of 15 independent genetic variants associated with childhood BMI was used as the instrumental variable to test causal...

  12. Evidence of genetic predisposition for metabolically healthy obesity and metabolically obese normal weight

    DEFF Research Database (Denmark)

    Huang, Lam Opal; Loos, Ruth JF; Oskari Kilpeläinen, Tuomas

    2018-01-01

    and cardiovascular disease. However, many obese individuals, often called metabolically healthy obese (MHO), seem to be protected from these cardiometabolic complications. Conversely, there is a group of individuals who suffer from cardiometabolic complications despite being of normal weight; a condition termed...... metabolically obese normal weight (MONW). Recent large-scale genomic studies have provided evidence that a number of genetic variants show an association with increased adiposity but a favorable cardiometabolic profile, an indicator for the genetic basis of the MHO and MONW phenotypes. Many of these loci...... are located in or near genes that implicate pathways involved in adipogenesis, fat distribution, insulin signaling, and insulin resistance. It has been suggested that a threshold for subcutaneous adipose tissue expandability may be at play in the manifestation of MHO and MONW, where expiry of adipose tissue...

  13. Molecular Characterization of Melanoma Cases in Denmark Suspected of Genetic Predisposition

    DEFF Research Database (Denmark)

    Wadt, Karin A. W.; Aoude, Lauren G.; Krogh, Lotte

    2015-01-01

    Both environmental and host factors influence risk of cutaneousmelanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E3...... cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma....

  14. Genetic predisposition for radiation-induced bone tumors; Genetische Veranlagung fuer strahleninduzierte Knochentumoren

    Energy Technology Data Exchange (ETDEWEB)

    Rosemann, M.; Luz, A.; Kuosaite, V.; Favor, J.; Atkinson, M.J. [Gesellschaft fuer Strahlen- und Umweltforschung mbH Muenchen, Neuherberg (Germany). Inst. fuer Pathologie]|[Gesellschaft fuer Strahlen- und Umweltforschung mbH Muenchen, Neuherberg (Germany). Inst. fuer Saeugetiergenetik

    1999-07-01

    The interaction between environmental factors and genetic determinants is crucial for the development of malignant tumours. However, the hereditary factors involved in the development of cancer that have been recognised so far are only responsible for at the most ten percent of tumours. It is still a matter of dispute whether the remaining 90 percent - so-called sporadic tumours - really have a cause that is free of genetic influence. There are good reasons for believing that there are a large number of genes in the human genome that confer resistance or susceptibility for tumorigenesis, and thus lead to natural genetic variability. (orig.) [German] Die Wechselwirkung von Umweltfaktoren und genetischen Determinanten ist entscheidend fuer die Entstehung von malignen Tumoren. Die bisher bekannten an der Krebsentstehung beteiligten erheblichen Faktoren sind allerdings fuer hoechstens zehn Prozent aller auftretenden Tumoren verantwortlich. Nach wie vor umstritten ist, ob die verbleibenden 90 Prozent - die sogenannten sporadischen Tumoren - tatsaechlich eine Ursache ohne erhebliche Komponente haben. Es gibt aber gute Gruende anzunehmen, dass im menschlichen Erbgut eine Vielzahl von Genen existiert, die Resistenz beziehungsweise Empfindlichkeit (Suszeptibilitaet) fuer die Tumorigenese vermitteln und so zu der natuerlichen genetischen Variabilitaet fuehren. (orig.)

  15. Genetic predisposition of six well-defined polymorphisms in HMGB1/RAGE pathway to breast cancer in a large Han Chinese population.

    Science.gov (United States)

    Yue, Liling; Zhang, Qibing; He, Lan; Zhang, Minglong; Dong, Jing; Zhao, Dalong; Ma, Hongxing; Pan, Hongming; Zheng, Lihong

    2016-10-01

    Breast cancer constitutes an enormous burden in China. A strong familial clustering of breast cancer suggests a genetic component in its carcinogenesis. To examine the genetic predisposition of high mobility group box-1/receptor for advanced glycation end products (HMGB1/RAGE) pathway to breast cancer, we genotyped six well-defined polymorphisms in this pathway among 524 breast cancer patients and 518 cancer-free controls from Heilongjiang province, China. There were no deviations from Hardy-Weinberg equilibrium for all polymorphisms. In single-locus analysis, the frequency of rs1800624 polymorphism mutant A allele in RAGE gene was significantly higher in patients than in controls (24.52% versus 19.50%, P = 0.006), with the carriers of rs1800624-A allele being 1.51 times more likely to develop breast cancer relative to those with rs1800624-GG genotype after adjustment (95% confidence interval or CI: 1.17-1.94, P = 0.001). In HMGB1 gene, haplotype analysis did not reveal any significance, while in RAGE gene, haplotypes C-T-A and C-A-G (alleles in order of rs1800625, rs18006024, rs2070600) were significantly associated with an increased risk of breast cancer (adjusted OR = 2.72 and 10.35; 95% CI: 1.20-6.18 and 1.58-67.80; P = 0.017 and 0.015 respectively). In further genetic score analysis, per unit and quartile increments of unfavourable alleles were significantly associated with an increased risk of breast cancer after adjustment (odds ratio or OR = 1.20 and 1.26; 95% CI: 1.09-1.32 and 1.12-1.42; P breast cancer risk, and more importantly a cumulative impact of multiple risk associated polymorphisms in HMGB1/RAGE pathway on breast carcinogenesis. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  16. Breast Cancer Screening in Women with a Familial or Genetic Predisposition: the role of MRI

    NARCIS (Netherlands)

    M. Kriege (Mieke)

    2006-01-01

    textabstractWomen with a strong family history of breast and/or ovarian cancer combined with young ages at diagnosis of affected family members have an increased risk of these types of cancer. In 1994 and 1995 respectively, the BRCA1 and BRCA2 genes were identified. A germline mutation in one of

  17. Breast Cancer Screening in Women with a Familial or Genetic Predisposition: the role of MRI

    NARCIS (Netherlands)

    M. Kriege (Mieke)

    2006-01-01

    textabstractWomen with a strong family history of breast and/or ovarian cancer combined with young ages at diagnosis of affected family members have an increased risk of these types of cancer. In 1994 and 1995 respectively, the BRCA1 and BRCA2 genes were identified. A germline mutation in one

  18. AIRE genetic variants and predisposition to polygenic autoimmune disease: The case of Graves' disease and a systematic literature review.

    Science.gov (United States)

    Colobran, Roger; Giménez-Barcons, Mireia; Marín-Sánchez, Ana; Porta-Pardo, Eduard; Pujol-Borrell, Ricardo

    2016-08-01

    Autoimmune Regulator (AIRE) is a transcriptional regulator that is crucial for establishing central tolerance as illustrated by the Mendelian Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome associated with AIRE-inactivating recessive or dominant mutations. Polymorphisms in AIRE have been proposed to be implicated in genetic susceptibility to non-Mendelian organ specific autoimmune diseases. Because there is evidence that in predisposition to Graves' disease (GD) central tolerance is crucial, we investigated whether AIRE polymorphisms could modulate risk of GD. A case-control association study using 29 variants and conducted in 150 GD patients and 200 controls did not detect any significant association. This result is not exceptional: a systematic review of the literature, including GWAS, on the association of AIRE variants with organ specific autoimmune diseases did not show clear associations; similarly heterozygous recessive mutations are not associated to non-Mendelian autoimmunity. Dominant negative mutations of AIRE are associated to autoimmunity but as mild forms of APECED rather than to non-Mendelian organ specific autoimmunity. The lack of association of common AIRE polymorphisms with polygenic autoimmune diseases is counterintuitive as many other genes less relevant for immunological tolerance have been found to be associated. These findings give rise to the intriguing possibility that evolution has excluded functionally modifying polymorphisms in AIRE. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  19. Younger age of onset and multiple primary lesions associated with esophageal squamous cell carcinoma cases with a positive family history of the cancer suggests genetic predisposition.

    Science.gov (United States)

    Jia, Nan; Wen, Xiaoduo; Zhang, Nan; Yang, Yi; Zhang, Liwei; Wang, Xiaoling; Wang, Na; Wen, Denggui

    2014-01-01

    Previous epidemiological studies have consistently found a positive family history of esophageal cancer is associated with a significantly increased risk of the cancer. However, whether the elevated risk could be attributed to common household exposure or inherited susceptibility is uncertain. This study aimed to highlight the effect of genetic predisposition by noting the significant differences in onset age and multiple primary cancers between esophageal squamous cell carcinoma (ESCC) cases with or without a positive family history of the cancer. Age at onset and the percentage of multiple primary cancers were compared between ESCCs with (n = 766) or without (n = 1 776) a positive family history of the cancer in a consecutive surgery cohort at the Department of Thoracic Surgery of Hebei Tumor Hospital and the Fourth Hospital of Hebei Medical University. Overall, ESCCs with a positive family history of the cancer featured both a significantly younger age of onset and significantly more multiple primary cancers than those with a negative family history (onset age 51.83 vs. 53.49 years old, P genetic predisposition. The results of subgroup analyses indicate a younger age of ESCC development results from the interaction of environmental and genetic risk factors, but multiple primary cancers may be related only to genetic predisposition.

  20. Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor. alpha. : Relevance to genetic predisposition to systemic lupus erythematosus

    Energy Technology Data Exchange (ETDEWEB)

    Jacob, C.O.; Fronek, Z.; Koo, M.; McDevitt, H.O. (Stanford Univ. School of Medicine, CA (USA)); Lewis, G.C. (Genentech Inc., San Francisco, CA (USA)); Hansen, J.A. (Fred Hutchinson Cancer Research Center, Seattle, WA (USA))

    1990-02-01

    The authors report on the production of tumor necrosis factor (TNF)-{alpha} and TNF-{beta} by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2- and DQw1-positive donors frequently exhibit low production of TNF-{alpha}, whereas DR3- and DR4-positive subjects show high levels of TNF-{alpha} production. No correlation between TNF-{alpha} levels and HLA-A, -B, and -C genotype was found. The relevance of this quantitative polymorphism to the genetic predisposition to lupus nephritis in systemic lupus erythematosus (SLE) patients was investigated. DR2, DQw1-positive SLE patients show low levels of TNF-{alpha} inducibility; this genotype is also associated with an increased incidence of lupus nephritis. DR3-positive SLE patients, on the other hand, are not predisposed to nephritis, and these patients have high TNF-{alpha} production. DR4 haplotype is associated with high TNF-{alpha} inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQw1 in SLE patients and their susceptibility to nephritis.

  1. Genetic predisposition to left ventricular dysfunction: a multigenic and multi-analytical approach.

    Science.gov (United States)

    Mishra, Avshesh; Srivastava, Anshika; Mittal, Tulika; Garg, Naveen; Mittal, Balraj

    2014-08-10

    Left ventricular dysfunction (LVD) is a complex, multifactorial condition, caused by mechanical, neurohormonal, and genetic factors. We have previously observed association of renin-angiotensin-aldosterone system (RAAS), matrix metalloproteinases (MMPs) and inflammatory pathway genes with LVD. Therefore the present study was undertaken to identify the combination of genetic variants and their possible interactions contributing towards genetic susceptibility to LVD in the background of coronary artery disease (CAD). The study included 230 healthy controls and 510 consecutive patients with angiographically confirmed CAD. Among them, 162 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as having LVD. We analyzed 11 polymorphisms of RAAS, MMPs and inflammatory pathways. Single locus analysis showed that AT1 A1166C (p value<0.001; OR=3.67), MMP9 R668Q (p value=0.007; OR=3.48) and NFKB1-94 ATTG ins/del (p value=0.013; OR=2.01) polymorphisms were independently associated with LVD when compared with both non-LVD patients and healthy controls. High-order gene-gene interaction analysis, using classification and regression tree (CART) and multifactor dimensionality reduction (MDR) revealed that AT1 A1166C and NFKB1-94 ATTG ins/del polymorphisms jointly increased the risk of LVD to great extent (p-value=0.001; OR=8.55) and best four-factor interaction model consisted of AT1 A1166C, MMP7 A-181G, MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms with testing accuracy of 0.566 and cross validation consistency (CVC)=9/10 (permutation p<0.001) showed increased risk for LVD respectively. AT1 A1166C independently and in combination with MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms plays important role in conferring genetic susceptibility to LVD in CAD patients. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Genetic predisposition to ischaemic stroke byRAGEandHMGB1gene variants in Chinese Han population.

    Science.gov (United States)

    Li, You; Zhu, Jing; Chen, Linfa; Hu, Weidong; Wang, Mengxu; Li, Shengnan; Gu, Xuefeng; Tao, Hua; Zhao, Bin; Ma, Guoda; Li, Keshen

    2017-11-21

    Emerging evidence suggests that the multiligand receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 protein (HMGB1) contribute to the pathophysiology of ischaemic stroke (IS). The present study aimed to investigate the association of RAGE and HMGB1 variants with the risk of IS. A total of 1,034 patients and 1,015 age- and sex-matched healthy controls were genotyped to detect five genetic variants of the RAGE gene and four genetic variants of the HMGB1 gene using the Multiplex SNaPshot assay. We found that the rs2070600 variant of RAGE was associated with an increased risk of IS (OR = 1.19, 95% CI: 1.02-1.38, P = 0.043), whereas the rs2249825 variant of HMGB1 was associated with a decreased risk of IS (OR = 0.83, 95% CI: 0.71-0.98, P = 0.041). Further stratification by IS subtypes revealed that the presence of the TT genotype of the RAGE rs2070600 variant confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.036). Moreover, patients with the variant T allele of the RAGE rs2070600 variant presented with reduced serum soluble RAGE production. Patients carrying the variant G allele of the HMGB1 rs2249825 variant exhibited significantly lower infarct volumes than those with the major CC genotype. These clues may help in the development of optimal personalized therapeutic approaches for IS patients.

  3. Personalized prostate cancer screening among men with high risk genetic predisposition- study protocol for a prospective cohort study

    Science.gov (United States)

    2014-01-01

    Background Prostate cancer screening among the general population is highly debatable. Nevertheless, screening among high-risk groups is appealing. Prior data suggests that men carrying mutations in the BRCA1& 2 genes may be at increased risk of developing prostate cancer. Additionally, they appear to develop prostate cancer at a younger age and with a more aggressive course. However, prior studies did not systematically perform prostate biopsies and thus cannot determine the true prevalence of prostate cancer in this population. Methods This will be a prospective diagnostic trial of screening for prostate cancer among men with genetic predisposition. The target population is males (40–70 year old) carrying a BRCA1 and/or BRCA2 germ line mutation. They will be identified via our Genetic counseling unit. All men after signing an informed consent will undergo the following tests: PSA, free to total PSA, MRI of prostate and prostate biopsy. The primary endpoint will be to estimate the prevalence, stage and grade of prostate cancer in this population. Additionally, the study aims to estimate the impact of these germ line mutations on benign prostatic hyperplasia. Furthermore, this study aims to create a bio-bank of tissue, urine and serum of this unique cohort for future investigations. Finally, this study will identify an inception cohort for future interventional studies of primary and secondary prevention. Discussion The proposed research is highly translational and focuses not only on the clinical results, but on the future specimens that will be used to advance our understanding of prostate cancer patho-physiology. Most importantly, these high-risk germ-line mutation carriers are ideal candidates for primary and secondary prevention initiatives. Trial registration ClinicalTrials.gov: NCT02053805. PMID:25047061

  4. The Synergistic Effect of TNFA and IL10 Promoter Polymorphisms on Genetic Predisposition to Systemic Lupus Erythematosus.

    Science.gov (United States)

    Manolova, Irena; Miteva, Lyuba; Ivanova, Mariana; Kundurzhiev, Todor; Stoilov, Rumen; Stanilova, Spaska

    2018-02-01

    We investigated the individual and combined effect of functional TNFA -308G/A and IL10 -1082G/A single nucleotide polymorphisms (SNPs) and their genotypes on the susceptibility to systemic lupus erythematosus (SLE) in a Bulgarian population. Genotyping for -1082A/G IL10 (rs1800896) and -308G/A TNFA (rs1800629) polymorphisms was performed for 154 SLE patients and 224 healthy controls. An association between SLE and the rs1800629 polymorphism was established under the allelic model (allele A vs. allele G; odds ratios [OR] = 2.317), the dominant model (GA+AA vs. GG; OR = 3.214), and the overdominant model (GA vs. AA+GG; OR = 3.494). There was no association between rs1800896 and SLE, although a tendency for genetic predisposition to SLE was observed for the IL10 -1082 GG genotype under the recessive genetic model (OR = 1.454). When analyzing the influence of the combined TNFA/IL10 genotypes on SLE occurrence, we found that the carriage of both high cytokine-producing genotypes of two SNPs (TNFA -308AA/GA and IL10 -1082GG) significantly increased the risk of developing SLE with OR of 9.026 (p = 0.006). Our findings suggest that the combinatorial complexity of TNFA and IL10 promoter polymorphisms impacts SLE susceptibility. Notably, we found that a TNFA promoter polymorphism is a leading risk factor for SLE susceptibility in a Bulgarian population, while the IL10 -1082 locus appears to act as a significant modifier.

  5. Genetic predisposition to alcoholism, schizophrenia and Alzheimer’s disease with psychodiagnostic characteristics in russian population

    Directory of Open Access Journals (Sweden)

    A. V. Marusin

    2016-01-01

    Full Text Available The purpose of this paper is to identify genetic factors connected with personal features using the panel of 12 polymorphic markers associated with the risk of developing dementia in patients with Alzheimer’s disease, schizophrenia and alcoholism.Materials and methods. The correlation among quantitative traits of personality, temperament and character determined with Cattell’s (the Sixteen personality factor questionnaire (16PF, Leonhard-Schmieschek’s, Spielberger-Khanin’s, and Eysenck’s (IQ tests were analyzed with polymorphic variants of 12 genes involved in the development of severe mental disorders such as alcoholism, schizophrenia and Alzheimer’s disease. DNA samples of 150 students were genotyped using PCR-RPLF method. The data were processed by nonparametric statistical methods.Results. Interallelic nonrandom associations in paired combinations of GABRA2-PICALM, PICALMADCY3, CLU-CBX7 and CLU-ADCY3 polymorphisms were detected. This may indicate the adaptive selection influencing the maintenance of behavioral homeostasis in population. A number of statistically significant associations of genetic variation were found: CLU with perfectionism(Q3 of 16PF and the exaltation of the Leonhard’s tests, PICALM with tension (Q4 of 16PF and the imbalance of Leonhard’s tests, DISC1 with vigilance(L of 16PF, and exaltation, cyclothymia of Leonhard’s tests, ZNF804A with imbalance by Leonhard’s test, SLC6A4 with reasoning(B of 16PF test, ADCY3 with self-reliance(Q2 and extraversion(F2 of 16PF test, MIR9-2 emotional stability(C, liveliness(F, social boldness(H, extraversion(F2 of 16PF, and dysthymia, hyperthymia of Leonhard’s tests, with the personal anxiety of Spielberger-Khanin’s test, CBX7 with vigilance(L, warmth(A of 16PF test, SLC6A3 with IQ.Conclusion. These findings support the idea of overlapping genetic component in common mental and neurological disorders and variability of human cognitive and personality traits.

  6. A genetic risk tool for obesity predisposition assessment and personalized nutrition implementation based on macronutrient intake.

    Science.gov (United States)

    Goni, Leticia; Cuervo, Marta; Milagro, Fermín I; Martínez, J Alfredo

    2015-01-01

    There is little evidence about genetic risk score (GRS)-diet interactions in order to provide personalized nutrition based on the genotype. The aim of the study was to assess the value of a GRS on obesity prediction and to further evaluate the interactions between the GRS and dietary intake on obesity. A total of 711 seekers of a Nutrigenetic Service were examined for anthropometric and body composition measurements and also for dietary habits and physical activity. Oral epithelial cells were collected for the identification of 16 SNPs (related with obesity or lipid metabolism) using DNA zip-coded beads. Genotypes were coded as 0, 1 or 2 according to the number of risk alleles, and the GRS was calculated by adding risk alleles with such a criterion. After being adjusted for gender, age, physical activity and energy intake, the GRS demonstrated that individuals carrying >7 risk alleles had in average 0.93 kg/m(2) of BMI, 1.69 % of body fat mass, 1.94 cm of waist circumference and 0.01 waist-to-height ratio more than the individuals with ≤7 risk alleles. Significant interactions for GRS and the consumption of energy, total protein, animal protein, vegetable protein, total fat, saturated fatty acids, polyunsaturated fatty acids, total carbohydrates, complex carbohydrates and fiber intake on adiposity traits were found after adjusted for confounders variables. The GRS confirmed that the high genetic risk group showed greater values of adiposity than the low risk group and demonstrated that macronutrient intake modifies the GRS association with adiposity traits.

  7. Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model.

    Science.gov (United States)

    Wang, Xuexiang; Johnson, Ashley C; Williams, Jan M; White, Tiffani; Chade, Alejandro R; Zhang, Jie; Liu, Ruisheng; Roman, Richard J; Lee, Jonathan W; Kyle, Patrick B; Solberg-Woods, Leah; Garrett, Michael R

    2015-07-01

    Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%-75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney. Copyright © 2015 by the American Society of Nephrology.

  8. Genetic predisposition influences plasma lipids of participants on habitual diet, but not the response to reductions in dietary intake of saturated fatty acids

    Science.gov (United States)

    Walker, C.G.; Loos, R.J.F.; Olson, A.D.; Frost, G.S.; Griffin, B.A.; Lovegrove, J.A.; Sanders, T.A.B.; Jebb, S.A.

    2011-01-01

    Objective SNPs identified from genome-wide association studies associate with lipid risk markers of cardiovascular disease. This study investigated whether these SNPs altered the plasma lipid response to diet in the ‘RISCK’ study cohort. Methods Participants (n = 490) from a dietary intervention to lower saturated fat by replacement with carbohydrate or monounsaturated fat, were genotyped for 39 lipid-associated SNPs. The association of each individual SNP, and of the SNPs combined (using genetic predisposition scores), with plasma lipid concentrations was assessed at baseline, and on change in response to 24 weeks on diets. Results The associations between SNPs and lipid concentrations were directionally consistent with previous findings. The genetic predisposition scores were associated with higher baseline concentrations of plasma total (P = 0.02) and LDL (P = 0.002) cholesterol, triglycerides (P = 0.001) and apolipoprotein B (P = 0.004), and with lower baseline concentrations of HDL cholesterol (P genetic predisposition was associated with an unfavourable plasma lipid profile at baseline, but did not influence the improvement in lipid profiles by the low-saturated-fat diets. PMID:21292264

  9. TNF-α Genetic Predisposition and Higher Expression of Inflammatory Pathway Components in Keratoconus.

    Science.gov (United States)

    Arbab, Muneeza; Tahir, Saira; Niazi, Muhammad Khizar; Ishaq, Mazhar; Hussain, Alamdar; Siddique, Pir Muhammad; Saeed, Sadia; Khan, Wajid Ali; Qamar, Raheel; Butt, Azeem Mehmood; Azam, Maleeha

    2017-07-01

    To date keratoconus (KC) pathogenesis is undefined; however, the involvement of inflammatory pathways in disease development is becoming apparent. In the present study, we investigated the role of a promoter region polymorphism rs1800629 (-308G>A) in the inflammatory pathway component TNF-α and its effects on the expression of TNF-α and downstream molecules tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2), v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), and interleukin 6 (IL-6) in KC development. TNF-α promoter polymorphism rs1800629 (-308G>A), was genotyped in 257 sporadic KC patients and 253 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was performed to assess for the -308G>A genotypes. Quantitative polymerase chain reaction (qPCR) was carried out to compare the mRNA expression of TNF-α, TNFR1, TNFR2, RELA, and IL6 in the corneal tissues of 20 KC patients and 20 donor controls. The -308G>A genotype GA was found to be significantly associated with KC development (dominant model [odds ratio (OR) = 6.67 (95% confidence interval [CI] = 4.28-10.42), P A polymorphism is a significant genetic risk factor for the pathogenesis of KC. Moreover, this single nucleotide polymorphism (SNP) was observed to be associated with deregulated expression of downstream molecules, thus further reinforcing the role of the inflammatory pathway components in the development of KC.

  10. Pros and cons of HaloPlex enrichment in cancer predisposition genetic diagnosis

    Directory of Open Access Journals (Sweden)

    Agnès Collet

    2015-12-01

    Full Text Available Panel sequencing is a practical option in genetic diagnosis. Enrichment and library preparation steps are critical in the diagnostic setting. In order to test the value of HaloPlex technology in diagnosis, we designed a custom oncogenetic panel including 62 genes. The procedure was tested on a training set of 71 controls and then blindly validated on 48 consecutive hereditary breast/ovarian cancer (HBOC patients tested negative for BRCA1/2 mutation. Libraries were sequenced on HiSeq2500 and data were analysed with our academic bioinformatics pipeline. Point mutations were detected using Varscan2, median size indels were detected using Pindel and large genomic rearrangements (LGR were detected by DESeq. Proper coverage was obtained. However, highly variable read depth was observed within genes. Excluding pseudogene analysis, all point mutations were detected on the training set. All indels were also detected using Pindel. On the other hand, DESeq allowed LGR detection but with poor specificity, preventing its use in diagnostics. Mutations were detected in 8% of BRCA1/2-negative HBOC cases. HaloPlex technology appears to be an efficient and promising solution for gene panel diagnostics. Data analysis remains a major challenge and geneticists should enhance their bioinformatics knowledge in order to ensure good quality diagnostic results.

  11. Genetic predisposition, parity, age at first childbirth and risk for breast cancer

    Directory of Open Access Journals (Sweden)

    Butt Salma

    2012-08-01

    Full Text Available Abstract Background Recent studies have identified several single-nucleotide polymorphisms (SNPs associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk. Methods The Malmö Diet and Cancer Study (MDCS included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR with 95% confidence intervals (CI. Results Six of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2, rs3803662 (TNRC9, rs12443621 (TNRC9, rs889312 (MAP3K1, rs3817198 (LSP1 and rs2107425 (H19. We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons. Conclusions The results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.

  12. Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition.

    Directory of Open Access Journals (Sweden)

    Karin A W Wadt

    Full Text Available Both environmental and host factors influence risk of cutaneous melanoma (CM, and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.

  13. Assessing the Genetic Predisposition of Education on Myopia: A Mendelian Randomization Study.

    Science.gov (United States)

    Cuellar-Partida, Gabriel; Lu, Yi; Kho, Pik Fang; Hewitt, Alex W; Wichmann, H-Erich; Yazar, Seyhan; Stambolian, Dwight; Bailey-Wilson, Joan E; Wojciechowski, Robert; Wang, Jie Jin; Mitchell, Paul; Mackey, David A; MacGregor, Stuart

    2016-01-01

    Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta-analysis of the three cohorts, using the PGRS as an IV, we estimated that each z-score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z-score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error. © 2015 WILEY PERIODICALS, INC.

  14. Genetic Predisposition To Acquire a Polybasic Cleavage Site for Highly Pathogenic Avian Influenza Virus Hemagglutinin

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    Naganori Nao

    2017-02-01

    Full Text Available Highly pathogenic avian influenza viruses with H5 and H7 hemagglutinin (HA subtypes evolve from low-pathogenic precursors through the acquisition of multiple basic amino acid residues at the HA cleavage site. Although this mechanism has been observed to occur naturally only in these HA subtypes, little is known about the genetic basis for the acquisition of the polybasic HA cleavage site. Here we show that consecutive adenine residues and a stem-loop structure, which are frequently found in the viral RNA region encoding amino acids around the cleavage site of low-pathogenic H5 and H7 viruses isolated from waterfowl reservoirs, are important for nucleotide insertions into this RNA region. A reporter assay to detect nontemplated nucleotide insertions and deep-sequencing analysis of viral RNAs revealed that an increased number of adenine residues and enlarged stem-loop structure in the RNA region accelerated the multiple adenine and/or guanine insertions required to create codons for basic amino acids. Interestingly, nucleotide insertions associated with the HA cleavage site motif were not observed principally in the viral RNA of other subtypes tested (H1, H2, H3, and H4. Our findings suggest that the RNA editing-like activity is the key mechanism for nucleotide insertions, providing a clue as to why the acquisition of the polybasic HA cleavage site is restricted to the particular HA subtypes.

  15. Analysis of the contribution of HLA genes to genetic predisposition in inflammatory bowel disease

    Energy Technology Data Exchange (ETDEWEB)

    Naom, I.; Haris, I.; Hodgson, S.V.; Mathew, C.G. [and others

    1996-07-01

    Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology. First-degree relatives of IBD patients have a 10-fold increase in risk of developing the same disease, and distinct associations between specific HLA types and both CD and UC have been reported. We have evaluated the contribution of genes at the HLA locus to susceptibility in IBD by linkage analysis of highly informative microsatellite polymorphisms in 43 families with multiple affected cases. No evidence for linkage of HLA to IBD was obtained under any of the four models tested. Analysis of HLA haplotype sharing in affected relatives indicated that the relative risk to a sibling conferred by the HLA locus was 1.11 in UC and 0.75 in CD, with upper (95%) confidence limits of 2.41 and 1.37, respectively. This suggests that other genetic or environmental factors are responsible for most of the familial aggregation in IBD. 31 refs., 1 fig., 2 tabs.

  16. The interaction of genetic predisposition and socioeconomic position with type 2 diabetes mellitus: cross-sectional and longitudinal analyses from the Lifelines Cohort and Biobank Study.

    Science.gov (United States)

    van Zon, Sander K R; Reijneveld, Sijmen A; van der Most, Peter J; Swertz, Morris A; Bültmann, Ute; Snieder, Harold

    2018-01-29

    A strong genetic predisposition for type 2 diabetes mellitus (T2DM) may aggravate the negative effects of low socioeconomic position (SEP) in the etiology of the disorder. This study aimed to examine cross-sectional and longitudinal associations and interactions of a genetic risk score (GRS) and SEP with T2DM, and to investigate whether clinical and behavioral risk factors can explain these associations and interactions. We used data from 13,027 genotyped participants from the Lifelines study. The GRS was based on single-nucleotide polymorphisms (SNPs) genome-wide associated with T2DM and was categorized into tertiles. SEP was measured as educational level. T2DM was based on biological markers, recorded medication use, and self-reports. Cross-sectional and longitudinal associations, and interactions, between the GRS and SEP on T2DM were examined. The combination of a high GRS and low SEP had the strongest association with T2DM in cross-sectional (OR: 3.84; 95% CI: 2.28, 6.46) and longitudinal analyses (HR: 2.71; 1.39, 5.27), compared to a low GRS and high SEP. Interaction between a high GRS and a low SEP was observed in cross-sectional (relative excess risk due to interaction: 1.85; 0.65, 3.05) but not in longitudinal analyses. Clinical and behavioral risk factors mostly explained the observed associations and interactions. A high GRS combined with a low SEP provides the highest risk for T2DM. These factors also exacerbated each other's impact cross-sectionally but not longitudinally. Preventive measures should target individual and contextual factors of this high-risk group to reduce the risk of T2DM.

  17. Some Molecular and Clinical Aspects of Genetic Predisposition to Malignant Melanoma and Tumours of Various Site of Origin

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    Dębniak Tadeusz

    2007-06-01

    Full Text Available Abstract Based on epidemiological data we can assume that at least some malignant melanoma (MM and breast cancer cases can be caused by the same genetic factors. CDKN2A, which encodes the p16 protein, a cyclin-dependent kinase inhibitor suppressing cell proliferation, is regarded as a major melanoma susceptibility gene and the literature has also implicated this gene in predisposition to breast cancer. Genes also known to predispose to MM include XPD and MC1R. We studied CDKN2A/ARF, XPD and MC1R for their associations with melanoma and breast cancer risk in Polish patients and controls. We found that CDKN2A and ARF do not contribute significantly to either familial melanoma or malignant melanoma within the context of a cancer familial aggregation of disease with breast cancer. However, the common variant of the CDKN2A gene A148T, previously regarded as non-pathogenic, may predispose to malignant melanoma, early-onset breast cancer and lung cancer. Compound carriers of common XPD variants may be at slightly increased risk of breast cancer or late–onset malignant melanoma. Common recurrent variants of the MC1R gene (V60L, R151C, R163Q and R160W may predispose to malignant melanoma. In general, the establishment of surveillance protocols proposed as an option for carriers of common alterations in CDKN2A, XPD or MC1R variants requires additional studies. It is possible that missense variants of genes for which truncating mutations are clearly pathogenic may also be deleterious, but with reduced penetrance. This may be overlooked unless large numbers of patients and controls are studied. A registry that includes 2000 consecutive breast cancer cases, 3500 early onset breast cancer patients, 500 unselected malignant melanoma and over 700 colorectal cancer patients has been established in the International Hereditary Cancer Centre and can contribute to these types of large association studies.

  18. Progressive Fibrosis Is Driven by Genetic Predisposition, Allo-immunity, and Inflammation in Pediatric Liver Transplant Recipients.

    Science.gov (United States)

    Varma, S; Ambroise, J; Komuta, M; Latinne, D; Baldin, P; Reding, R; Smets, F; Stephenne, X; Sokal, E M

    2016-07-01

    To determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients. Protocol biopsies (PB) from stable liver transplant (LT) recipient children frequently exhibit idiopathic fibrosis. The relation between allograft inflammation, humoral immune response and fibrosis is uncertain. Also the role of HLA-DRB1 genotype has not been evaluated, though it's associated with fibrosis in autoimmune hepatitis. This observational study, included 89 stable LT recipient transplanted between 2004-2012 with mean follow-up of 4.3years, 281 serial PBs (3.1 biopsy/child) and human leukocyte antigen (HLA) antibody data. PBs were taken 1-2, 2-3, 3-5, 5-7, and 7-10years post-LT, and evaluated for inflammation and fibrosis using liver allograft fibrosis score (LAFSc). The evolution of fibrosis, inflammation and related predisposing factors were analysed. HLA-DRB1*03/04 allele and Class II DSA were significantly associated with portal fibrosis (p=0.03; p=0.03, respectively). Portal inflammation was predisposed by Class II DSA (p=0.02) and non-HLA antibody presence (p=0.01). Non-portal fibrosis wasn't predisposed by inflammation. Lobular inflammation was associated with non-HLA antibodies. We conclusively demonstrated that allograft inflammation results in fibrosis and is associated with post-LT Class II DSA and non-HLA antibodies. The HLA-DRB1*03/04 allele caused genetic predisposition for fibrosis. None. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Television Watching, Leisure-Time Physical Activity and the Genetic Predisposition in Relation to Body Mass Index in Women and Men

    Science.gov (United States)

    Qi, Qibin; Li, Yanping; Chomistek, Andrea K.; Kang, Jae H.; Curhan, Gary C.; Pasquale, Louis R.; Willett, Walter C.; Rimm, Eric B.; Hu, Frank B.; Qi, Lu

    2013-01-01

    Background Previous studies on gene-lifestyle interaction and obesity have mostly focused on the FTO gene and physical activity, while little attention has been paid to sedentary behavior as indicated by television (TV) watching. Methods and Results We analyzed interactions between TV watching, leisure-time physical activity and genetic predisposition in relation to body mass index (BMI) in 7740 women and 4564 men from 2 prospective cohorts: the Nurses’ Health Study and Health Professionals Follow-up Study. Data on physical activity and TV watching were collected 2 years prior to assessment of BMI. A weighted genetic risk score (GRS) was calculated on the basis of 32 established BMI-associated variants. In both women and men, the genetic associations with BMI strengthened with increased hours of TV watching. An increment of 10 points in the weighted GRS was associated with 0.8 [SE 0.4], 0.8 [0.2], 1.4 [0.2], 1.5 [0.2] and 3.4 [1.0] kg/m2 higher BMI across the 5 categories of TV watching (0-1, 2-5, 6-20, 21-40, and >40h/wk) (P for interaction=0.001). In contrast, the genetic association with BMI weakened with increased levels of physical activity. An increment of 10 points in the weighted GRS was associated with 1.5 [0.2], 1.3 [0.2], 1.2 [0.2], 1.2 [0.2] and 0.8 [0.2] kg/m2 higher BMI across the quintiles of physical activity. The interactions of TV watching and physical activity with genetic predisposition in relation to BMI were independent of each other. Conclusions Sedentary lifestyle indicated by prolonged TV watching may accentuate predisposition to elevated adiposity, whereas greater leisure-time physical activity may attenuate the genetic association. PMID:22949498

  20. Bovine neonatal pancytopenia (BNP): novel insights into the incidence, vaccination-associated epidemiological factors and a potential genetic predisposition for clinical and subclinical cases.

    Science.gov (United States)

    Demasius, W; Weikard, R; Kromik, A; Wolf, C; Müller, K; Kühn, C

    2014-06-01

    Bovine neonatal pancytopenia (BNP) is a haemorrhagic disease of newborn calves elicited by colostrum from specific cows. Two studies have indicated that BNP-inducing colostrum might be associated with alloantibodies directed against MHC class I in response to vaccination with a distinct inactivated viral vaccine. However, the proportion of alloantibody-producing individuals by far exceeds the proportion of clinical BNP cases in the vaccinated population. This raises the question about the incidence of subclinical, unrecognised cases and also suggests further factors involved in BNP pathogenesis, e.g., genetic predisposition. Our results on neonatal calves from a closely monitored resource population confirmed the hypothesis of a genetic predisposition for clinical BNP and suggest that the predisposition is also involved in subclinical BNP-cases. No indication was obtained for a higher frequency of subclinical BNP-cases compared with clinical cases. Neither time point nor frequency of vaccination was a relevant factor for BNP in our resource population. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Strong genetic overlap between executive functions and intelligence.

    Science.gov (United States)

    Engelhardt, Laura E; Mann, Frank D; Briley, Daniel A; Church, Jessica A; Harden, K Paige; Tucker-Drob, Elliot M

    2016-09-01

    Executive functions (EFs) are cognitive processes that control, monitor, and coordinate more basic cognitive processes. EFs play instrumental roles in models of complex reasoning, learning, and decision making, and individual differences in EFs have been consistently linked with individual differences in intelligence. By middle childhood, genetic factors account for a moderate proportion of the variance in intelligence, and these effects increase in magnitude through adolescence. Genetic influences on EFs are very high, even in middle childhood, but the extent to which these genetic influences overlap with those on intelligence is unclear. We examined genetic and environmental overlap between EFs and intelligence in a racially and socioeconomically diverse sample of 811 twins ages 7 to 15 years (M = 10.91, SD = 1.74) from the Texas Twin Project. A general EF factor representing variance common to inhibition, switching, working memory, and updating domains accounted for substantial proportions of variance in intelligence, primarily via a genetic pathway. General EF continued to have a strong, genetically mediated association with intelligence even after controlling for processing speed. Residual variation in general intelligence was influenced only by shared and nonshared environmental factors, and there remained no genetic variance in general intelligence that was unique of EF. Genetic variance independent of EF did remain, however, in a more specific perceptual reasoning ability. These results provide evidence that genetic influences on general intelligence are highly overlapping with those on EF. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  2. Strong Genetic Overlap Between Executive Functions and Intelligence

    Science.gov (United States)

    Engelhardt, Laura E.; Mann, Frank D.; Briley, Daniel A.; Church, Jessica A.; Harden, K. Paige; Tucker-Drob, Elliot M.

    2016-01-01

    Executive functions (EFs) are cognitive processes that control, monitor, and coordinate more basic cognitive processes. EFs play instrumental roles in models of complex reasoning, learning, and decision-making, and individual differences in EFs have been consistently linked with individual differences in intelligence. By middle childhood, genetic factors account for a moderate proportion of the variance in intelligence, and these effects increase in magnitude through adolescence. Genetic influences on EFs are very high, even in middle childhood, but the extent to which these genetic influences overlap with those on intelligence is unclear. We examined genetic and environmental overlap between EFs and intelligence in a racially and socioeconomically diverse sample of 811 twins ages 7-15 years (M = 10.91, SD = 1.74) from the Texas Twin Project. A general EF factor representing variance common to inhibition, switching, working memory, and updating domains accounted for substantial proportions of variance in intelligence, primarily via a genetic pathway. General EF continued to have a strong, genetically-mediated association with intelligence even after controlling for processing speed. Residual variation in general intelligence was influenced only by shared and nonshared environmental factors, and there remained no genetic variance in general intelligence that was unique of EF. Genetic variance independent of EF did remain, however, in a more specific perceptual reasoning ability. These results provide evidence that genetic influences on general intelligence are highly overlapping with those on EF. PMID:27359131

  3. Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation

    NARCIS (Netherlands)

    Postema, Floor A M; Hopman, Saskia M J; Aalfs, Cora M; Berger, Lieke P V; Bleeker, Fonnet E; Dommering, Charlotte J; Jongmans, Marjolijn C J|info:eu-repo/dai/nl/314344349; Letteboer, Tom G W|info:eu-repo/dai/nl/304815837; Olderode-Berends, Maran J W; Wagner, Anja; Hennekam, Raoul C; Merks, Johannes H M

    2017-01-01

    INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a

  4. Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation

    NARCIS (Netherlands)

    Postema, Floor A. M.; Hopman, Saskia M. J.; Aalfs, Cora M.; Berger, Lieke P. V.; Bleeker, Fonnet E.; Dommering, Charlotte J.; Jongmans, Marjolijn C. J.; Letteboer, Tom G. W.; Olderode - Berends, Maran J.W.; Wagner, Anja; Hennekam, Raoul C.; Merks, Johannes H. M.

    Introduction: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a

  5. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis.

    Directory of Open Access Journals (Sweden)

    Petroula Proitsi

    2014-09-01

    Full Text Available Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n=10,578. We constructed weighted genotype risk scores (GRSs for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013. Both full GRSs using all SNPs associated with each trait at p<5×10-8 and trait specific scores using SNPs associated exclusively with each trait at p<5 × 10-8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR]=1.005, 95% CI 0.82-1.24, p = 0.962 per 1 unit increase in HDL-c; OR=0.901, 95% CI 0.65-1.25, p=0.530 per 1 unit increase in LDL-c; OR=1.104, 95% CI 0.89-1.37, p=0.362 per 1 unit increase in triglycerides; and OR=0.954, 95% CI 0.76-1.21, p=0.688 per 1 unit increase in total cholesterol. Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.Genetic predisposition to increased blood cholesterol and

  6. ANALYSIS OF ACE, ACTN3, ENOS, PPARG, PPARA, HIF-15, PPARGC1B GENE POLYMORPHISMS FOR DETERMINATION A GENETIC PREDISPOSITION TO A VARIETY OF SPORTS

    Directory of Open Access Journals (Sweden)

    S. B. Drozdovska

    2013-05-01

    Full Text Available To establishing the possibility of assessing genetic iinherited predisposition to various sports, the differences in the distribution of genotypes of the complex polymorphisms in groups of athletes, specializing in sports with different types of energy supply of muscular work were studied. The paper examined the DNA 332 persons, of which 110 athletes involved in speed- power sports, 85 - in endurance sports , 51 - in sports that require a combination of strength and endurance, 86 - with no experience regular exercise.

  7. Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study.

    Directory of Open Access Journals (Sweden)

    Shengxu Li

    2010-08-01

    Full Text Available We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study.We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39-79 y from the European Prospective Investigation of Cancer (EPIC-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error [SE] 0.012 kg/m(2 (p = 6.73 x 10(-37 increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall. This association was significantly (p(interaction = 0.005 more pronounced in inactive people (0.205 [SE 0.024] kg/m(2 [p = 3.62 x 10(-18; 592 g in weight] than in active people (0.131 [SE 0.014] kg/m(2 [p = 7.97 x 10(-21; 379 g in weight]. Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval [CI] 1.093-1.139, p = 3.37 x 10(-26 in the whole population, but significantly (p(interaction = 0.015 more in inactive individuals (odds ratio [OR] = 1.158 [95% CI 1.118-1.199; p = 1.93 x 10(-16] than in active individuals (OR = 1.095 (95% CI 1.068-1.123; p = 1

  8. Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study.

    Science.gov (United States)

    Li, Shengxu; Zhao, Jing Hua; Luan, Jian'an; Ekelund, Ulf; Luben, Robert N; Khaw, Kay-Tee; Wareham, Nicholas J; Loos, Ruth J F

    2010-08-31

    We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS) increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study. We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39-79 y) from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI)-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error [SE] 0.012) kg/m(2) (p = 6.73 x 10(-37)) increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall). This association was significantly (p(interaction) = 0.005) more pronounced in inactive people (0.205 [SE 0.024] kg/m(2) [p = 3.62 x 10(-18); 592 g in weight]) than in active people (0.131 [SE 0.014] kg/m(2) [p = 7.97 x 10(-21); 379 g in weight]). Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval [CI] 1.093-1.139, p = 3.37 x 10(-26)) in the whole population, but significantly (p(interaction) = 0.015) more in inactive individuals (odds ratio [OR] = 1.158 [95% CI 1.118-1.199; p = 1.93 x 10(-16)]) than in active individuals (OR = 1.095 (95% CI 1.068-1.123; p = 1

  9. Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample.

    Science.gov (United States)

    Michalek, Julia E; Kepa, Agnieszka; Vincent, John; Frissa, Souci; Goodwin, Laura; Hotopf, Matthew; Hatch, Stephani L; Breen, Gerome; Powell, Timothy R

    2017-04-15

    Previous studies have revealed increased biological ageing amongst major depressive disorder (MDD) patients, as assayed by shorter leukocyte telomere lengths (TL). Stressors such as childhood maltreatment are more common amongst MDD patients, and it has been suggested that this might contribute to shorter TL present amongst patients. However, to our knowledge, no study has yet tested for reverse causality, i.e. whether a genetic predisposition to shorter TL might predispose to MDD or an earlier onset of MDD. This study used a Mendelian randomisation design to investigate if shortened TL might increase risk for recurrent MDD in a relatively large UK sample (1628 MDD cases, 1140 controls). To achieve this, we used a subset of our sample, for which TL data was available, to identify a suitable instrumental variable. We performed single nucleotide polymorphism (SNP) genotyping on rs10936599, a SNP upstream of telomerase RNA component (TERC), and rs2736100, a SNP within telomerase reverse transcriptase (hTERT), and attempted to replicate findings which identified these SNPs as predictors of TL. After which, we performed regressions to test if genetic risk for shortened TL increased risk for MDD, childhood-onset MDD or childhood/adolescent-onset MDD. T-carriers of rs10936599 demonstrated shorter TL compared to CC-carriers (p≤0.05; 3% of variance explained) and was subsequently used as our instrumental variable. We found that the T-allele of rs10936599 predicted increased risk for childhood-onset MDD relative to controls (p≤0.05), and increased risk for childhood-onset MDD relative to adult-onset MDD cases (p≤0.001), but rs10936599 did not predict adult-onset MDD risk. Limitations include a relatively small sample of early-onset cases, and the fact that age-of-onset was ascertained by retrospective recall. Genetic predisposition to advanced biological ageing, as assayed using rs10936599, predicted a small, but significant, increased risk for childhood

  10. The altruism of Dona Benigna in Benito Perez Galdós’s Misericordia Religious Morality, Cultural Predisposition or Genetic Inheritance

    Directory of Open Access Journals (Sweden)

    Adel Fartakh,

    2014-06-01

    Full Text Available In the novel Misericordia (2004 by Benito Perez Galdós there is a character, Doña Benigna, who has developed an altruistic behavior in favor of other characters. What is certain is that the origin of this cooperative behavior is unclear. We would think that it emanates either from an acquired moral religious education, or from a cultural predisposition or a genetic inheritance. The moral development of the individual is one of the foundations for the birth of man as free individual during this period of Spanish history. Benito Perez Galdós’s narrative raises a debate about the issue of morality as solidarity action in this critical period of Spain’s evolution.

  11. Genetic Predisposition to Polycystic Ovary Syndrome, Postpartum Weight Reduction, and Glycemic Changes: A Longitudinal Study in Women With Prior Gestational Diabetes.

    Science.gov (United States)

    Wang, Tiange; Leng, Junhong; Li, Nan; Martins de Carvalho, Aline; Huang, Tao; Zheng, Yan; Li, Weiqin; Liu, Huikun; Wang, Leishen; Hu, Gang; Qi, Lu

    2015-12-01

    Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women and a major female-specific risk factor of obesity, impaired glucose tolerance, and diabetes. We examined whether the genetic variation predisposing to PCOS affected glycemic changes in women with prior gestational diabetes mellitus (GDM) and whether such an effect was modified by changes in body adiposity, especially during and after pregnancy. This is a longitudinal study in Tianjin, China. We genotyped 7 genome-wide association study-identified PCOS single nucleotide polymorphisms and assessed gestational weight gain and changes in glycemic traits and weight at 1 to 5 years postpartum in 1133 women with prior GDM. The main outcome measure was postpartum glycemic changes. The PCOS genetic risk score significantly interacted with postpartum weight reduction on changes in fasting glucose and 2-h glucose (P for interaction = .032 and .007; respectively) after multivariable adjustment. In women with postpartum weight reduction of ≥ 5 kg/y, the genetic risk score was associated with decreased fasting and 2-h glucose, whereas an opposite genetic effect was found in women who lost less weight. The association between postpartum weight reduction and glycemic improvement was more significant among women with a higher genetic risk score. In a large cohort of Chinese women with a history of GDM, our data for the first time indicate that the genetic predisposition to PCOS may interact with postpartum weight reduction on long-term glycemic changes, emphasizing the importance of postpartum weight management in prevention of diabetes in this subgroup of women.

  12. Maternal care affects EEG properties of spike-wave seizures (including pre- and post ictal periods) in adult WAG/Rij rats with genetic predisposition to absence epilepsy.

    Science.gov (United States)

    Sitnikova, Evgenia; Rutskova, Elizaveta M; Raevsky, Vladimir V

    2016-10-01

    WAG/Rij rats have a genetic predisposition to absence epilepsy and develop spontaneous spike-wave discharges in EEG during late ontogenesis (SWD, EEG manifestation of absence epilepsy). Changes in an environment during early postnatal ontogenesis can influence the genetically predetermined absence epilepsy. Here we examined the effect of maternal environment during weaning period on the EEG manifestation of absence epilepsy in adulthood. Experiments were performed in the offspring of WAG/Rij and Wistar rats. The newborn pups were fostered to dams of the same (in-fostering) or another strain (cross-fostering). Age-matched control WAG/Rij and Wistar rats were reared by their biological mothers. Absence seizures were uncommon in Wistar and were not aggravated in both in- and cross-fostered groups. In WAG/Rij rats, fewer SWD were found in the cross-fostered as compared to the in-fostered group. The cross-fostered WAG/Rij rats showed higher percentage of short-lasting SWD with duration <2s. The mean frequency of EEG at the beginning of SWD in the cross-fostered WAG/Rij rats was lower than in control (8.82 vs 9.25Hz), but it was higher in a period of 1.5s before and after SWD. It was concluded that a healthier maternal environment is able to alleviate genetically predetermined absence seizures in adulthood through changes in EEG rhythmic activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Is there a genetic predisposition for Turkish patients with sarcoidosis in the 329-bp region containing the BTNL2 rs2076530 polymorphism?

    Science.gov (United States)

    Ozdemir, Muhsin; Saydam, Faruk; Kurt, Emel; Değirmenci, Irfan; Tuncel, Tunç; Cilingir, Oğuz; Güneş, Hasan Veysi; Artan, Sevilhan

    2014-01-01

    Sarcoidosis is a complex, multifactorial immune disorder with unknown etiology. A single nucleotide polymorphism (G→A, rs2076530) in the butyrophilin-like 2 (BTNL2) gene results in a truncating protein formation. It has been previously reported that this variation may be a risk factor for sarcoidosis in certain ethnic groups. This study was conducted to determine whether there is any genetic predisposition for the BTNL2 rs2076530 polymorphism in the 329-bp region in Turkish patients with sarcoidosis. DNA samples were obtained from volunteers including 53 Turkish patients with sarcoidosis and 52 healthy controls. Analysis of the 329-bp region was carried out by polymerase chain reaction and sequencing of genomic DNA. We did not find any genetic variation except the rs2076530 polymorphism in the 329-bp region. The AA genotype was associated with an increased risk of sarcoidosis in a recessive model [P = 0.027, OR 2.56 (95% CI 1.02-6.49)], but it did not include a risk for sarcoidosis in a dominant model (P = 0.885). Our results emphasize the recessive characteristic of the rs2076530 polymorphism in Turkish patients with sarcoidosis. The lack of any genetic variation except rs2076530 in the 329-bp region is another significant finding for Turkish patients.

  14. Dietary ascorbic acid and subsequent change in body weight and waist circumference: associations may depend on genetic predisposition to obesity - a prospective study of three independent cohorts

    Science.gov (United States)

    2014-01-01

    Background Cross-sectional data suggests that a low level of plasma ascorbic acid positively associates with both Body Mass Index (BMI) and Waist Circumference (WC). This leads to questions about a possible relationship between dietary intake of ascorbic acid and subsequent changes in anthropometry, and whether such associations may depend on genetic predisposition to obesity. Hence, we examined whether dietary ascorbic acid, possibly in interaction with the genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHR), associates with subsequent annual changes in weight (∆BW) and waist circumference (∆WC). Methods A total of 7,569 participants’ from MONICA, the Diet Cancer and Health study and the INTER99 study were included in the study. We combined 50 obesity associated single nucleotide polymorphisms (SNPs) in four genetic scores: a score of all SNPs and a score for each of the traits (BMI, WC and WHR) with which the SNPs associate. Linear regression was used to examine the association between ascorbic acid intake and ΔBW or ΔWC. SNP-score × ascorbic acid interactions were examined by adding product terms to the models. Results We found no significant associations between dietary ascorbic acid and ∆BW or ∆WC. Regarding SNP-score × ascorbic acid interactions, each additional risk allele of the 14 WHR associated SNPs associated with a ∆WC of 0.039 cm/year (P = 0.02, 95% CI: 0.005 to 0.073) per 100 mg/day higher ascorbic acid intake. However, the association to ∆WC only remained borderline significant after adjustment for ∆BW. Conclusion In general, our study does not support an association between dietary ascorbic acid and ∆BW or ∆WC, but a diet with a high content of ascorbic acid may be weakly associated to higher WC gain among people who are genetically predisposed to a high WHR. However, given the quite limited association any public health relevance is questionable. PMID:24886192

  15. Dietary ascorbic acid and subsequent change in body weight and waist circumference: associations may depend on genetic predisposition to obesity--a prospective study of three independent cohorts.

    Science.gov (United States)

    Larsen, Sofus C; Angquist, Lars; Ahluwalia, Tarunveer Singh; Skaaby, Tea; Roswall, Nina; Tjønneland, Anne; Halkjær, Jytte; Overvad, Kim; Pedersen, Oluf; Hansen, Torben; Linneberg, Allan; Husemoen, Lise Lotte N; Toft, Ulla; Heitmann, Berit L; Sørensen, Thorkild I A

    2014-05-03

    Cross-sectional data suggests that a low level of plasma ascorbic acid positively associates with both Body Mass Index (BMI) and Waist Circumference (WC). This leads to questions about a possible relationship between dietary intake of ascorbic acid and subsequent changes in anthropometry, and whether such associations may depend on genetic predisposition to obesity. Hence, we examined whether dietary ascorbic acid, possibly in interaction with the genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHR), associates with subsequent annual changes in weight (∆BW) and waist circumference (∆WC). A total of 7,569 participants' from MONICA, the Diet Cancer and Health study and the INTER99 study were included in the study. We combined 50 obesity associated single nucleotide polymorphisms (SNPs) in four genetic scores: a score of all SNPs and a score for each of the traits (BMI, WC and WHR) with which the SNPs associate. Linear regression was used to examine the association between ascorbic acid intake and ΔBW or ΔWC. SNP-score × ascorbic acid interactions were examined by adding product terms to the models. We found no significant associations between dietary ascorbic acid and ∆BW or ∆WC. Regarding SNP-score × ascorbic acid interactions, each additional risk allele of the 14 WHR associated SNPs associated with a ∆WC of 0.039 cm/year (P = 0.02, 95% CI: 0.005 to 0.073) per 100 mg/day higher ascorbic acid intake. However, the association to ∆WC only remained borderline significant after adjustment for ∆BW. In general, our study does not support an association between dietary ascorbic acid and ∆BW or ∆WC, but a diet with a high content of ascorbic acid may be weakly associated to higher WC gain among people who are genetically predisposed to a high WHR. However, given the quite limited association any public health relevance is questionable.

  16. Radiation sensitivity and genetic predisposition seen from a clinical viewpoint; Strahlenempfindlichkeit und genetische Praedisposition aus klinischer Sicht

    Energy Technology Data Exchange (ETDEWEB)

    Budach, W. [Tuebingen Univ. (Germany). Radiologische Klinik, Abt. Strahlentherapie

    2001-07-01

    This contribution gives a short overview of the current state of knowledge concerning genetically related changes in radiation sensitivity. [German] In den Ausfuehrungen wird ein kurzer Ueberblick ueber derzeit bekannte genetisch bedingte Veraenderungen der Strahlenempfindlichkeit gegeben. (orig.)

  17. HLA-C, DRB1 and DQB1 alleles involved in genetic predisposition to psoriasis vulgaris in the Slovak population

    OpenAIRE

    Shawkatov?, Ivana; Javor, Juraj; P?rnick?, Zuzana; Kozub, Peter; ?il?nkov?, M?ria; Frey, Peter; Feren??k, Stanislav; Buc, Milan

    2012-01-01

    Psoriasis vulgaris is a complex chronic skin disease with immunological and genetic background. The most important predisposing genetic factors in psoriasis are genes of the human leukocyte antigen (HLA) region. Accumulative evidence has shown that several HLA alleles are closely associated with psoriasis; however, they tend to vary in different racial and ethnic backgrounds. One hundred forty-seven unrelated Slovak patients with psoriasis vulgaris (average age at onset 28???14?years) were ge...

  18. Genetic resources of teak (Tectona grandis Linn. f.)—strong genetic structure among natural populations

    DEFF Research Database (Denmark)

    Hansen, Ole Kim; Changtragoon, Suchitra; Ponoy, Bundit

    2015-01-01

    Twenty-nine provenances of teak (Tectona grandis Linn. f.) representing the full natural distribution range of the species were genotyped with microsatellite DNA markers to analyse genetic diversity and population genetic structure. Provenances originating from the semi-moist east coast of India...... of genetic diversity supports the hypothesis that teak has its centre of origin in India, from where it spread eastwards. The analysis of molecular variance (AMOVA) gave an overall highly significant F st value of 0.227—population pairwise F st values were in the range 0.01–0.48. Applying the G......″st differentiation parameter, the estimated overall differentiation was 0.632, implying a strong genetic structure among populations. A neighbour-joining (NJ) tree, using the pairwise population matrix of G″st values as input, contained three distinct groups: (1) the eight provenances from Thailand and Laos, (2...

  19. The Impact of Physical Activity and Dietary Measures on the Biochemical and Anthropometric Parameters in Obese Children. Is There Any Genetic Predisposition?

    Science.gov (United States)

    Zlatohlávek, Lukáš; Hubáček, Jaroslav Alois; Vrablík, Michal; Pejšová, Hana; Lánská, Věra; Češka, Richard

    2015-11-01

    The aim of the study was to monitor the importance of laboratory, anthropometric and genetic determination of the presence of risk factors for atherosclerosis, obesity, dyslipidemia and components of the metabolic syndrome in obese children and the response to dietary and regimen interventions in obese children. As a part of the study, 353 paediatric patients (46% boys, 54% girls) with obesity and dyslipidemia, aged 8-16 years, participated in a one-month lifestyle intervention programme. The programme involved a reduction of energy intake and supervised exercise programme consisting of 5 exercise units per day, each 50 minutes long. Standard biochemical methods were applied, including Lp-PLA2, as were anthropometric measurements and genetic analyses. During the reduction programme for the children there was a statistically significant decrease in all anthropometric indicators of bodyweight (pgenetic predisposition for obesity, as well as individuals with a better response to regimen interventions which could, among other things, be determined by the FTO and MC4R genotypes. Copyright© by the National Institute of Public Health, Prague 2015.

  20. The Genetic Predisposition Score of Seven Obesity-Related Single Nucleotide Polymorphisms Is Associated with Better Metabolic Outcomes after Roux-en-Y Gastric Bypass.

    Science.gov (United States)

    Nicoletti, Carolina Ferreira; Pinhel, Marcela A Souza; de Oliveira, Bruno Affonso Parenti; Marchini, Julio Sergio; Salgado Junior, Wilson; Silva Junior, Wilson Araujo; Nonino, Carla Barbosa

    2016-01-01

    Genetic variants associated with obesity have cumulative effects on obesity risk and related phenotypes. This study aimed to estimate the contribution of a genetic predisposition score (GPS) calculated from 7 obesity-related polymorphisms to the improvement of biochemical parameters 1 year after Roux-en-Y gastric bypass (RYGB). Obese patients (n = 150; aged 47.2 ± 10.5 years) were enrolled and weight, body mass index (BMI), and biochemical parameters (glycemia and lipid profile) were evaluated preoperatively and 1 year after RYGB. A GPS was calculated with the polymorphisms rs1801282 of PPARG2, rs4994 of ADRB3, rs1800592 of UCP1, rs659366 and rs669339 of UCP2, rs7121 of GNAS1, and rs5443 of GNB3. We observed that 66.3% of the patients has a GPS >5. During the preoperative period, the GPS showed a significant association with weight (β = -0.163; p = 0.020), BMI (β = -0.169; p = 0.038), and glucose concentrations (β = -0.177; p = 0.036). After sex and age adjustment, a higher GPS was associated with a greater reduction in glycemia (β = -0.158; p = 0.048), triglycerides (β = -0.256; p = 0.002), and total cholesterol (β = -0.172; p = 0.038) concentrations 1 year after surgery. Our data elucidated that a higher GPS provides a greater metabolic benefit of RYGB. © 2016 S. Karger AG, Basel.

  1. A pedigree-based proxy measure of genetic predisposition of drinking and alcohol use among female sex workers in China: a cross-sectional study.

    Science.gov (United States)

    Zhang, Chen; Li, Xiaoming; Liu, Yu; Qiao, Shan; Su, Shaobing; Zhang, Liying; Zhou, Yuejiao

    2017-02-01

    Scientific evidence has suggested that genetic factors accounted for more than half of the vulnerability of developing alcohol use problems. However, collecting genetic data poses a significant challenge for most population-based behavioral studies. The aim of this study was to assess the utilities of a pedigree-based proxy measure of genetic predisposition of drinking (GPD) and its effect on alcohol use behaviors as well as its interactions with personal and environmental factors. In the current study, cross-sectional data were collected from 700 female sex workers (FSW) in Guangxi, China. Participants provided information on a pedigree-based proxy measure of GPD and their alcohol use behaviors. Chi-square and independent t-test was applied for examining the bivariate associations between GPD and alcohol use behaviors; multivariate and ordinal regression models were used to examine the effect of GPD on alcohol use. This study found that women with a higher composite score of GPD tended to have a higher risk of alcohol use problem compared to their counterparts (p < .05). GPD was a significant predictor of alcohol use problems (p < .05), especially among women who had mental health issues or lack of health cares. The pedigree-based measure provided a useful proxy of GPD among participants. Both FSW's mental health and health care access interact with GPD and affect their drinking patterns. By understanding the genetic basis of alcohol use, we can develop scalable and efficacious interventions that will take into consideration the individual risk profile and environmental influences.

  2. Genetic predisposition to preeclampsia is conferred by fetal DNA variants near FLT1, a gene involved in the regulation of angiogenesis.

    Science.gov (United States)

    Gray, Kathryn J; Saxena, Richa; Karumanchi, S Ananth

    2018-02-01

    Preeclampsia risk is influenced by both the mother's genetic background and the genetics of her fetus; however, the specific genes responsible for conferring preeclampsia risk have largely remained elusive. Evidence that preeclampsia has a genetic predisposition was first detailed in the early 1960s, and overall preeclampsia heritability is estimated at ∼55%. Many traditional gene discovery approaches have been used to investigate the specific genes that contribute to preeclampsia risk, but these have largely not been successful or reproducible. Over the past decade, genome-wide association studies have allowed for significant advances in the understanding of the genetic basis of many common diseases. Genome-wide association studies are predicated on the idea that the genetic basis of many common diseases are complex and polygenic with many variants, each with modest effects that contribute to disease risk. Using this approach in preeclampsia, a large genome-wide association study recently identified and replicated the first robust fetal genomic region associated with excess risk. A screen of >7 million genetic variants in 2658 offspring from preeclamptic women and 308,292 population controls identified a single association signal close to the Fms-like tyrosine kinase 1 gene, on chromosome 13. Fms-like tyrosine kinase 1 encodes soluble Fms-like tyrosine kinase 1, a splice variant of the vascular endothelial growth factor receptor that exerts antiangiogenic activity by inhibiting signaling of proangiogenic factors. The Fms-like tyrosine kinase 1 pathway is central in preeclampsia pathogenesis because excess circulating soluble Fms-like tyrosine kinase 1 in the maternal plasma leads to the hallmark clinical features of preeclampsia, including hypertension and proteinuria. The success of this landmark fetal preeclampsia genome-wide association study suggests that well-powered, larger maternal and fetal genome-wide association study will be fruitful in identifying

  3. Genetic predisposition to obesity affects behavioural traits including food reward and anxiety-like behaviour in rats

    NARCIS (Netherlands)

    Vogel, Heike; Kraemer, Maria; Rabasa, Cristina; Askevik, Kaisa; Adan, Roger A.H.; Dickson, Suzanne L.

    2017-01-01

    Here we sought to define behavioural traits linked to anxiety, reward, and exploration in different strains of rats commonly used in obesity research. We hypothesized that genetic variance may contribute not only to their metabolic phenotype (that is well documented) but also to the expression of

  4. The association of genetic predisposition to depressive symptoms with non-suicidal and suicidal self-injuries

    NARCIS (Netherlands)

    Maciejewski, D.F.; Renteria, M.E.; Abdellaoui, A.; Medland, S.E.; Few, L.R.; Gordon, S.D.; Madden, P.A.F.; Montgomery, G.W.; Trull, T.J.; Heath, A.C.; Statham, D.J.; Martin, N.G.; Zietsch, B.P.; Verweij, K.J.H.

    2017-01-01

    Non-suicidal and suicidal self-injury are very destructive, yet surprisingly common behaviours. Depressed mood is a major risk factor for non-suicidal self-injury (NSSI), suicidal ideation and suicide attempts. We conducted a genetic risk prediction study to examine the polygenic overlap of

  5. The Association of Genetic Predisposition to Depressive Symptoms with Non-suicidal and Suicidal Self-Injuries

    NARCIS (Netherlands)

    Maciejewski, Dominique F; Renteria, Miguel E; Abdellaoui, Abdel; Medland, Sarah E; Few, Lauren R; Gordon, Scott D; Madden, Pamela A F; Montgomery, Grant W; Trull, Timothy J; Heath, Andrew C; Statham, Dixie J; Martin, Nicholas G; Zietsch, Brendan P; Verweij, Karin J. H.

    Non-suicidal and suicidal self-injury are very destructive, yet surprisingly common behaviours. Depressed mood is a major risk factor for non-suicidal self-injury (NSSI), suicidal ideation and suicide attempts. We conducted a genetic risk prediction study to examine the polygenic overlap of

  6. Improved prediction of genetic predisposition to psychiatric disorders using genomic feature best linear unbiased prediction models

    DEFF Research Database (Denmark)

    Rohde, Palle Duun; Demontis, Ditte; Børglum, Anders

    variance into components capturing the variance by a genomic feature (e.g. GO term) and the remaining genomic variance by differential weighting of the genetic variants within the two groups. Previously we have demonstrated (on pigs and fruit flies) increased predictive ability when the genomic feature...

  7. Can unknown predisposition in familial breast cancer be family-specific?

    Science.gov (United States)

    Lynch, Henry; Wen, Hongxiu; Kim, Yeong C; Snyder, Carrie; Kinarsky, Yulia; Chen, Pei Xian; Xiao, Fengxia; Goldgar, David; Cowan, Kenneth H; Wang, San Ming

    2013-01-01

    Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1-, BRCA2-, p53-, and PTEN-negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family-specific. As such, it will be difficult to detect them by applying population-based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown. © 2013 Wiley Periodicals, Inc.

  8. Strong evidence for a genetic contribution to late-onset Alzheimer's disease mortality: a population-based study.

    Directory of Open Access Journals (Sweden)

    John S K Kauwe

    Full Text Available Alzheimer's disease (AD is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date.We assessed the familiality of AD in The Utah Population Database (UPDB, a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF between AD individuals and randomly selected controls and estimated the Relative Risk (RR for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.

  9. Postirradiation sarcoma in retinoblastoma. Induction or predisposition

    International Nuclear Information System (INIS)

    Schwarz, M.B.; Burgess, L.P.; Fee, W.E. Jr.; Donaldson, S.S.

    1988-01-01

    An alarmingly high rate of postirradiation sarcomas following treatment for retinoblastoma has been described in the literature. We present four new cases and report 57 others from the English literature. Osteogenic sarcoma was the predominant histologic type (58%), followed by fibrosarcoma (21%) and various other sarcomas (21%). The average latency period between irradiation and development of the second primary (sarcoma) was 12.4 years. Irrespective of irradiation, a genetic linkage between retinoblastoma and osteogenic sarcoma on the 13q14 chromosome is recognized. Through a pleiotropic effect of this same chromosome, a predisposition for other sarcomas may exist as well. Finally, a strong role for radiation induction is proposed for all of these postirradiation sarcomas. This is based on the increased number of sarcomas arising in the field of prior irradiation (sites uncharacteristic of spontaneously occurring primary sarcomas) and the prolonged latency periods.13 references

  10. Human Leukocyte Antigen-B27: The Genetic Predisposition Leading to Reactive Arthritis during Induction Phase Chemotherapy for Acute Myeloid Leukemia

    Science.gov (United States)

    Bartakke, Sandip P; Sampagar, Abhilasha Ashok; Bafna, Vibha Sanjay; Patel, Putun

    2017-01-01

    We report a case of reactive arthritis (ReA) during induction phase chemotherapy of a 15-year-old male patient with acute myeloid leukemia (AML) M4 with inv(16), most probably due to a genetic predisposition of being human leukocyte antigen b27 (HLA-B27) positive. The episode of ReA recurred during consolidation therapy; however, the patient was asymptomatic after the completion of treatment. The link between HLA-B27 and a large family of inflammatory rheumatic diseases is a well-established fact, but interestingly, there is also a molecular link between HLA-B27 and hematological malignancies. This case brings to our notice, the common immunological, molecular, and microbiological link between AML, HLA-B27, and ReA. It also emphasizes the fact that clinicians should have a high index of suspicion of HLA-B27 positivity, if a case of AML develops arthritis during chemotherapy, since early introduction of immunosuppressive medications for arthritis may reduce morbidity and prevent delay in the administration of further chemotherapy cycles. PMID:29200696

  11. Plasma Taurine, Diabetes Genetic Predisposition, and Changes of Insulin Sensitivity in Response to Weight-Loss Diets.

    Science.gov (United States)

    Zheng, Yan; Ceglarek, Uta; Huang, Tao; Wang, Tiange; Heianza, Yoriko; Ma, Wenjie; Bray, George A; Thiery, Joachim; Sacks, Frank M; Qi, Lu

    2016-10-01

    Taurine metabolism disturbance is closely linked to obesity, insulin resistance, and diabetes. Previous evidence suggested that the preventative effects of taurine on diabetes might be through regulating the expression levels of diabetes-related genes. We estimated whether blood taurine levels modified the overall genetic susceptibility to diabetes on improvement of insulin sensitivity in a randomized dietary trial. We genotyped 31 diabetes-associated variants to calculate a genetic risk score (GRS) and measured plasma taurine levels and glycemic traits among participants from the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial. Seven-hundred eleven overweight or obese participants (age 30-70 y; 60% females) had genetic variants genotyped and blood taurine levels measured. Participants went on 2-year weight-loss diets, which were different in macronutrient composition. Improvements in glycemic traits were measured. We found that baseline taurine levels significantly modified the effects of diabetes GRS on changes in fasting glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) during the 2-year diet intervention (P-interaction = .04, .01, .002, respectively), regardless of weight loss. High baseline taurine levels were associated with a less reduction in both glucose and HOMA-IR among the participants with the lowest tertile of diabetes GRS (both P = .02), and with a greater reduction in both insulin and HOMA-IR among those with the highest tertile of diabetes GRS (both P = .04). Our data suggest that blood taurine levels might differentially modulate the effects of diabetes-related genes on improvement of insulin sensitivity among overweight/obese patients on weight-loss diets.

  12. Plasma Taurine, Diabetes Genetic Predisposition, and Changes of Insulin Sensitivity in Response to Weight-Loss Diets

    Science.gov (United States)

    Zheng, Yan; Ceglarek, Uta; Huang, Tao; Wang, Tiange; Heianza, Yoriko; Ma, Wenjie; Bray, George A.; Thiery, Joachim; Sacks, Frank M.

    2016-01-01

    Context: Taurine metabolism disturbance is closely linked to obesity, insulin resistance, and diabetes. Previous evidence suggested that the preventative effects of taurine on diabetes might be through regulating the expression levels of diabetes-related genes. Objective: We estimated whether blood taurine levels modified the overall genetic susceptibility to diabetes on improvement of insulin sensitivity in a randomized dietary trial. Design and Setting: We genotyped 31 diabetes-associated variants to calculate a genetic risk score (GRS) and measured plasma taurine levels and glycemic traits among participants from the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial. Participants: Seven-hundred eleven overweight or obese participants (age 30–70 y; 60% females) had genetic variants genotyped and blood taurine levels measured. Intervention: Participants went on 2-year weight-loss diets, which were different in macronutrient composition. Main Outcome Measure: Improvements in glycemic traits were measured. Results: We found that baseline taurine levels significantly modified the effects of diabetes GRS on changes in fasting glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) during the 2-year diet intervention (P-interaction = .04, .01, .002, respectively), regardless of weight loss. High baseline taurine levels were associated with a less reduction in both glucose and HOMA-IR among the participants with the lowest tertile of diabetes GRS (both P = .02), and with a greater reduction in both insulin and HOMA-IR among those with the highest tertile of diabetes GRS (both P = .04). Conclusions: Our data suggest that blood taurine levels might differentially modulate the effects of diabetes-related genes on improvement of insulin sensitivity among overweight/obese patients on weight-loss diets. PMID:27466884

  13. The Association of Genetic Predisposition to Depressive Symptoms with Non-suicidal and Suicidal Self-Injuries.

    Science.gov (United States)

    Maciejewski, Dominique F; Renteria, Miguel E; Abdellaoui, Abdel; Medland, Sarah E; Few, Lauren R; Gordon, Scott D; Madden, Pamela A F; Montgomery, Grant; Trull, Timothy J; Heath, Andrew C; Statham, Dixie J; Martin, Nicholas G; Zietsch, Brendan P; Verweij, Karin J H

    2017-01-01

    Non-suicidal and suicidal self-injury are very destructive, yet surprisingly common behaviours. Depressed mood is a major risk factor for non-suicidal self-injury (NSSI), suicidal ideation and suicide attempts. We conducted a genetic risk prediction study to examine the polygenic overlap of depressive symptoms with lifetime NSSI, suicidal ideation, and suicide attempts in a sample of 6237 Australian adult twins and their family members (3740 females, mean age = 42.4 years). Polygenic risk scores for depressive symptoms significantly predicted suicidal ideation, and some predictive ability was found for suicide attempts; the polygenic risk scores explained a significant amount of variance in suicidal ideation (lowest p = 0.008, explained variance ranging from 0.10 to 0.16 %) and, less consistently, in suicide attempts (lowest p = 0.04, explained variance ranging from 0.12 to 0.23 %). Polygenic risk scores did not significantly predict NSSI. Results highlight that individuals genetically predisposed to depression are also more likely to experience suicidal ideation/behaviour, whereas we found no evidence that this is also the case for NSSI.

  14. Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease.

    Science.gov (United States)

    Basso, P J; Fonseca, M T C; Bonfá, G; Alves, V B F; Sales-Campos, H; Nardini, V; Cardoso, C R B

    2014-09-01

    Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

  15. The journey from genetic predisposition to medication overuse headache to its acquisition as sequela of chronic migraine.

    Science.gov (United States)

    Martelletti, Paolo

    2018-01-10

    Migraine remains one of the biggest clinical case to be solved among the non-communicable diseases, second to low back pain for disability caused as reported by the Global Burden of Disease Study 2016. Despite this, its genetics roots are still unknown. Its evolution in chronic forms hits 2-4% of the population and causes a form so far defined Medication Overuse Headache (MOH), whose pathophysiological basis have not been explained by many dedicated studies. The Global Burden of Disease Study 2016 has not recognized MOH as independent entity, but as a sequela of Chronic Migraine. This concept, already reported in previous studies, has been confirmed by the efficacy of OnabotulinumtoxinA in Chronic Migraine independently from the presence of MOH. The consistency of the current definitions of both Medication Overuse Headache and Chronic Migraine itself might be re-read on the basis of new evidences.

  16. Protective effect of compression socks in a marathon runner with a genetic predisposition to thrombophilia due to Factor V Leiden.

    Science.gov (United States)

    Zaleski, Amanda L; Pescatello, Linda S; Thompson, Paul D; Taylor, Beth A

    2015-07-01

    The present case study is an analysis of the effect of compression socks on hemostatic activation following a marathon in a female endurance athlete found to be heterozygous for the coagulation factor V (F5 1691 G>A [Arg>Gln rs6025/560]) risk allele that predisposes one to a genetically inherited disorder of blood clotting, Factor V Leiden. Markers for coagulation and fibrinolysis were obtained 24 h prior to (PRE), immediately after (FINISH) and 24 h after (POST) completion of two marathons: the first in which the runner was not wearing compression socks, and the second in which the runner wore compression socks throughout the race. Compression socks worn during a marathon appeared to lower the overall impact on hemostasis as well as clot formation in this particular athlete as evidenced by lower t-PA (-56%), TAT (-63%) and D-dimer (-30%). Hemostatic activation may be lower with the use of compression socks, and thus may be effective for preserving hemostasis in endurance athletes at risk.

  17. Genetic predisposition to low bone mass is paralleled by an enhanced sensitivity to signals anabolic to the skeleton

    Science.gov (United States)

    Judex, Stefan; Donahue, Leah-Rae; Rubin, Clinton

    2002-01-01

    The structure of the adult skeleton is determined, in large part, by its genome. Whether genetic variations may influence the effectiveness of interventions to combat skeletal diseases remains unknown. The differential response of trabecular bone to an anabolic (low-level mechanical vibration) and a catabolic (disuse) mechanical stimulus were evaluated in three strains of adult mice. In low bone-mineral-density C57BL/6J mice, the low-level mechanical signal caused significantly larger bone formation rates (BFR) in the proximal tibia, but the removal of functional weight bearing did not significantly alter BFR. In mid-density BALB/cByJ mice, mechanical stimulation also increased BFR, whereas disuse significantly decreased BFR. In contrast, neither anabolic nor catabolic mechanical signals influenced any index of bone formation in high-density C3H/HeJ mice. Together, data from this study indicate that the sensitivity of trabecular tissue to both anabolic and catabolic stimuli is influenced by the genome. Extrapolated to humans, these results may explain in part why prophylaxes for low bone mass are not universally effective, yet also indicate that there may be a genotypic indication of people who are at reduced risk of suffering from bone loss.

  18. A Strong Case for Viral Genetic Factors in HIV Virulence

    Directory of Open Access Journals (Sweden)

    Joshua T. Herbeck

    2011-03-01

    Full Text Available HIV infections show great variation in the rate of progression to disease, and the role of viral genetic factors in this variation had remained poorly characterized until recently. Now a series of four studies [1–4] published within a year has filled this important gap and has demonstrated a robust effect of the viral genotype on HIV virulence.

  19. Comparative expression profiling of E. coli and S. aureus inoculated primary mammary gland cells sampled from cows with different genetic predispositions for somatic cell score

    Directory of Open Access Journals (Sweden)

    Ponsuksili Siriluck

    2011-06-01

    Full Text Available Abstract Background During the past ten years many quantitative trait loci (QTL affecting mastitis incidence and mastitis related traits like somatic cell score (SCS were identified in cattle. However, little is known about the molecular architecture of QTL affecting mastitis susceptibility and the underlying physiological mechanisms and genes causing mastitis susceptibility. Here, a genome-wide expression analysis was conducted to analyze molecular mechanisms of mastitis susceptibility that are affected by a specific QTL for SCS on Bos taurus autosome 18 (BTA18. Thereby, some first insights were sought into the genetically determined mechanisms of mammary gland epithelial cells influencing the course of infection. Methods Primary bovine mammary gland epithelial cells (pbMEC were sampled from the udder parenchyma of cows selected for high and low mastitis susceptibility by applying a marker-assisted selection strategy considering QTL and molecular marker information of a confirmed QTL for SCS in the telomeric region of BTA18. The cells were cultured and subsequently inoculated with heat-inactivated mastitis pathogens Escherichia coli and Staphylococcus aureus, respectively. After 1, 6 and 24 h, the cells were harvested and analyzed using the microarray expression chip technology to identify differences in mRNA expression profiles attributed to genetic predisposition, inoculation and cell culture. Results Comparative analysis of co-expression profiles clearly showed a faster and stronger response after pathogen challenge in pbMEC from less susceptible animals that inherited the favorable QTL allele 'Q' than in pbMEC from more susceptible animals that inherited the unfavorable QTL allele 'q'. Furthermore, the results highlighted RELB as a functional and positional candidate gene and related non-canonical Nf-kappaB signaling as a functional mechanism affected by the QTL. However, in both groups, inoculation resulted in up-regulation of genes

  20. Limited potential of genetic predisposition scores to predict muscle mass and strength performance in Flemish Caucasians between 19 and 73 years of age.

    Science.gov (United States)

    Charlier, Ruben; Caspers, Maarten; Knaeps, Sara; Mertens, Evelien; Lambrechts, Diether; Lefevre, Johan; Thomis, Martine

    2017-03-01

    Since both muscle mass and strength performance are polygenic in nature, the current study compared four genetic predisposition scores (GPS) in their ability to predict these phenotypes. Data were gathered within the framework of the first-generation Flemish Policy Research Centre "Sport, Physical Activity and Health" (2002-2004). Results are based on muscle characteristics data of 565 Flemish Caucasians (19-73 yr, 365 men). Skeletal muscle mass was determined from bioelectrical impedance. The Biodex dynamometer was used to measure isometric (PT static120° ) and isokinetic strength (PT dynamic60° and PT dynamic240° ), ballistic movement speed (S 20% ), and muscular endurance (Work) of the knee extensors. Genotyping was done for 153 gene variants, selected on the basis of a literature search and the expression quantitative trait loci of selected genes. Four GPS were designed: a total GPS (based on the sum of all 153 variants, each favorable allele = score 1), a data-driven and weighted GPS [respectively, the sum of favorable alleles of those variants with significant b-coefficients in stepwise regression (GPS dd ), and the sum of these variants weighted with their respective partial r 2 (GPS w )], and an elastic net GPS (based on the variants that were selected by an elastic net regularization; GPS en ). It was found that four different models for a GPS were able to significantly predict up to ~7% of the variance in strength performance. GPS en made the best prediction of SMM and Work. However, this was not the case for the remaining strength performance parameters, where best predictions were made by GPS dd and GPS w . Copyright © 2017 the American Physiological Society.

  1. Dietary management and genetic predisposition

    DEFF Research Database (Denmark)

    Jensen, Hanne Holbæk; Larsen, Lesli Hingstrup

    2013-01-01

    Today, dietary recommendations are based on recommended daily intake for the general population, and only a few subgroups are considered for additional dietary advice. Nutrigenetics aim to optimize health and prevent disease. Particularly for lifestyle disease, such as obesity, which has increase...

  2. Genetic predisposition to testicular cancer

    NARCIS (Netherlands)

    Lutke Holzik, Martijn Frederik

    2007-01-01

    Alhoewel zaadbalkanker een zeldzame ziekte is, is het toch de meest voorkomende vorm van kanker bij mannen tussen de 15 en 40 jaar. De ziekte is tegenwoordig goed te behandelen en de 10 jaars overleving is ongeveer 90%. Het hebben van een familielid met zaadbalkanker is de sterkste risicofactor voor

  3. Genetic Testing

    Science.gov (United States)

    ... risk factor for the development of celiac disease, genetic predisposition. Without this factor, it is impossible that the ... with antibody testing in the future. When the genetic predisposition for celiac disease was detected (on Chromosome 6) ...

  4. Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece

    Science.gov (United States)

    Objective: To determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether t...

  5. Chronic pain, depression and cardiovascular disease linked through a shared genetic predisposition: Analysis of a family-based cohort and twin study.

    Science.gov (United States)

    van Hecke, Oliver; Hocking, Lynne J; Torrance, Nicola; Campbell, Archie; Padmanabhan, Sandosh; Porteous, David J; McIntosh, Andrew M; Burri, Andrea V; Tanaka, Haruka; Williams, Frances M K; Smith, Blair H

    2017-01-01

    were obtained when the outcomes and predictors were reversed and similar effects seen among sibling pairs; depression in one sibling predicted chronic pain in the other (OR 1·34 [1·05-1·71]), angina predicted chronic pain in the other (OR 2·19 [1·63-2·95]), and depression, angina (OR 1·98 [1·49-2·65]). Individuals with chronic pain and angina showed almost four-fold greater odds of depression compared with those manifesting neither trait (OR 3·78 [2·99-4·78]); angina showed seven-fold increased odds in the presence of chronic pain and depression (OR 7·76 [6·05-9·95]) and chronic pain nine-fold in the presence of depression and angina (OR 9·43 [6·85-12·98]). In TwinsUK, the relationship between CWP and depression has been published (R = 0.34, pgenetic predisposition, shared between the two traits (2·2% [95% CI 0·06-0·23]). We found an increased co-occurrence of chronic pain, depression and cardiovascular disease in two independent cohorts (general population-based cohort, twins cohort) suggesting a shared genetic contribution. Adjustment for known environmental influences, particularly those relating to socio-economic status (Generation Scotland: age, gender, deprivation, smoking, education; Twins UK: age,BMI) did not explain the relationship observed between chronic pain, depression and cardiovascular disease. Our findings from two independent cohorts challenge the concept of traditional disease boundaries and warrant further investigation of shared biological mechanisms.

  6. Host microsatellite alleles in malaria predisposition?

    Directory of Open Access Journals (Sweden)

    Trivedi Rajni

    2005-10-01

    Full Text Available Abstract Background Malaria is a serious, sometimes fatal, disease caused by Plasmodium infection of human red blood cells. The host-parasite co-evolutionary processes are well understood by the association of coding variations such as G6PD, Duffy blood group receptor, HLA, and beta-globin gene variants with malaria resistance. The profound genetic diversity in host is attributed to polymorphic microsatellites loci. The microsatellite alleles in bacterial species are known to have aided their survival in fatal environmental conditions. The fascinating question is whether microsatellites are genomic cushion in the human genome to combat disease stress and has cause-effect relationships with infections. Presentation of the hypothesis It is hypothesized that repeat units or alleles of microsatellites TH01 and D5S818, located in close proximity to beta-globin gene and immune regulatory region in human play a role in malaria predisposition. Association of alleles at aforesaid microsatellites with malaria infection was analysed. To overrule the false association in unrecognized population stratification, structure analysis and AMOVA were performed among the sampled groups. Testing of hypothesis Associations of microsatellite alleles with malaria infection were verified using recombination rate, Chi-square, and powerful likelihood tests. Further investigation of population genetic structure, and AMOVA was done to rule out the confounding effects of population stratification in interpretation of association studies. Implication of the hypothesis Lower recombination rate (θ between microsatellites and genes implicated in host fitness; positive association between alleles -13 (D5S818, 9 (TH01 and strong susceptibility to Plasmodium falciparum; and alleles-12 (D5S818 and 6 (TH01 rendering resistance to human host were evident. The interesting fact emerging from the study was that while predisposition to malaria was a prehistoric attribute, among TH01

  7. Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.

    Science.gov (United States)

    Lotta, Luca A; Scott, Robert A; Sharp, Stephen J; Burgess, Stephen; Luan, Jian'an; Tillin, Therese; Schmidt, Amand F; Imamura, Fumiaki; Stewart, Isobel D; Perry, John R B; Marney, Luke; Koulman, Albert; Karoly, Edward D; Forouhi, Nita G; Sjögren, Rasmus J O; Näslund, Erik; Zierath, Juleen R; Krook, Anna; Savage, David B; Griffin, Julian L; Chaturvedi, Nishi; Hingorani, Aroon D; Khaw, Kay-Tee; Barroso, Inês; McCarthy, Mark I; O'Rahilly, Stephen; Wareham, Nicholas J; Langenberg, Claudia

    2016-11-01

    Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.

  8. Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.

    Directory of Open Access Journals (Sweden)

    Luca A Lotta

    2016-11-01

    Full Text Available Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8. The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25, encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8 for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6 for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6 for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are

  9. Trapped in the extinction vortex? Strong genetic effects in a declining vertebrate population

    Directory of Open Access Journals (Sweden)

    Larsson Mikael

    2010-02-01

    Full Text Available Abstract Background Inbreeding and loss of genetic diversity are expected to increase the extinction risk of small populations, but detailed tests in natural populations are scarce. We combine long-term population and fitness data with those from two types of molecular markers to examine the role of genetic effects in a declining metapopulation of southern dunlins Calidris alpina schinzii, an endangered shorebird. Results The decline is associated with increased pairings between related individuals, including close inbreeding (as revealed by both field observations of parentage and molecular markers. Furthermore, reduced genetic diversity seems to affect individual fitness at several life stages. Higher genetic similarity between mates correlates negatively with the pair's hatching success. Moreover, offspring produced by related parents are more homozygous and suffer from increased mortality during embryonic development and possibly also after hatching. Conclusions Our results demonstrate strong genetic effects in a rapidly declining population, emphasizing the importance of genetic factors for the persistence of small populations.

  10. Computing strong metric dimension of some special classes of graphs by genetic algorithms

    Directory of Open Access Journals (Sweden)

    Kratica Jozef

    2008-01-01

    Full Text Available In this paper we consider the NP-hard problem of determining the strong metric dimension of graphs. The problem is solved by a genetic algorithm that uses binary encoding and standard genetic operators adapted to the problem. This represents the first attempt to solve this problem heuristically. We report experimental results for the two special classes of ORLIB test instances: crew scheduling and graph coloring.

  11. A strong genetic footprint of the re-introduction history of Alpine ibex (Capra ibex ibex).

    Science.gov (United States)

    Biebach, Iris; Keller, Lukas F

    2009-12-01

    A population's neutral genetic variation is a composite of its size, degree of isolation and demographic history. Bottlenecks and founder events increase genetic drift, leading to the loss of genetic variation and increased genetic differentiation among populations. Gene flow has the opposite effects. Thus, gene flow can override the genetic patterns caused by founder events. Using 37 microsatellite loci, we investigated the effects of serial bottlenecks on genetic variation and differentiation among 42 Alpine ibex populations in Switzerland with known re-introduction histories. We detected a strong footprint of re-introduction events on contemporary genetic structure, with re-introduction history explaining a substantial part of the genetic differentiation among populations. As a result of the translocation of a considerable number of individuals from the sole formerly surviving population in northern Italy, most of the genetic variation of the ancestral population is now present in the combined re-introduced Swiss populations. However, re-introductions split up the genetic variation among populations, such that each contemporary Swiss population showed lower genetic variation than the ancestral population. As expected, serial bottlenecks had different effects on the expected heterozygosity (He) and standardized number of alleles (sNa). While loss of sNa was higher in the first bottlenecks than in subsequent ones, He declined to a similar degree with each bottleneck. Thus, genetic drift was detected with each bottleneck, even when no loss of sNa was observed. Overall, more than a hundred years after the beginning of this successful re-introduction programme, re-introduction history was the main determinant of today's genetic structure.

  12. Contribution of KIR genes, HLA class I ligands, and KIR/HLA class I ligand combinations on the genetic predisposition to celiac disease and coexisting celiac disease and type 1 diabetes mellitus.

    Science.gov (United States)

    Akar, H Haluk; Patiroglu, Turkan; Sevinc, Eylem; Aslan, Duran; Okdemir, Deniz; Kurtoglu, Selim

    2015-09-01

    There are some common genetic features between celiac disease (CD) and diabetes mellitus type 1 (DM). However, the genetic risk factors have not been fully clarified for CD and the co-occurrence of CD and DM. KIR (killer immunoglobulin-like receptor) genes regulate the cytolitic activity of NK-cells and T lymphocytes. The aim of this study is to evaluate the contribution of KIR genes, KIR ligands, and combinations of KIR/ KIR ligands on the genetic predisposition to CD and co-occurrence of CD and DM. Forty six patients with CD (n = 46), 20 patients with CD+DM (n = 20), and 60 healthy controls (n = 60) were included in this study. KIR genes and KIR ligands were investigated with PCR-SSOP and PCR-SSP in all subjects, respectively. This study showed that while the telomeric KIR genes (2DS5 and 3DS1), and combinations of 3DS1+HLA-BBw4-Thrand 3DS1+HLA-BBw4-Iso- (p KIR genes, C1 ligand, and combinations of 3DS1+HLA-BBw4-Thr- and 3DS1+HLA-BBw4-Iso- (p = 0.002, p = 0.004, p = 0.036, p KIR genes, KIR ligands, and KIR/KIR ligand interactions may be responsible for a predisposition to CD and the coexistence of CD and DM. For development of coexisting CD and DM, the 2DS5 and 3DS1 genes, C1 ligand, and combinations of 3DS1+HLA-BBw4-Thr- and 3DS1+HLA-BBw4-Iso- were found to be risk factors.

  13. Genetic polymorphisms of NOS2 and predisposition to fracture non-union: A case control study based on Han Chinese population.

    Science.gov (United States)

    Huang, Wei; Zhang, Kun; Zhu, Yangjun; Wang, Zhan; Li, Zijun; Zhang, Jun

    2018-01-01

    A non-union, especially atrophic non-unions, is a permanent failure of healing following a fracture and can be difficult to treat. Approximately 5-10% of fractures will result in a non-union during the healing process. non-unions can be classified into two types: atrophic non-union which is often due to impaired bone healing with a potential biological mechanism, and hypertrophic non-union which is due to inadequate fixation after fracture. Genetic variations also play an important role in the fracture healing response. Previous studies based on animal models have indicated that NOS2 might be greatly involved in the bone fracture healing process. In this case-control study, 346 nonunion patients were compared to 883 patients with normal fracture healing to investigate the potential genetic association between NOS2 and the fracture healing process using study subjects of Chinese Han ancestry. Twenty-seven single nucleotide polymorphisms (SNPs) covering NOS2 were genotyped in our study subjects and analyzed. In addition to the single marker-based analysis, we performed a gene-by-environment analysis to examine the potential interactions between genetic polymorphisms and some environmental factors. SNP rs2297514 showed significant association with the fracture healing process after adjusting for age and gender (OR = 1.38, P = 0.0005). Our results indicated that the T allele of rs2297514 significantly increased the risk of a non-union during the fracture healing process by 38% compared to the C allele. Further stratification analyses conducted for this SNP using data from subgroups classified by different sites of fracture indicated that significance could only be observed in the tibial diaphysis subgroup (N = 428, OR = 1.77, P = 0.0007) but not other groups including femur diaphysis, humeral shaft, ulnar shaft, and femur neck. Gene-by-environment interaction analyses of the three environmental factors showed no significant results. In this study, rs2297514 was

  14. Existe-t-il une predisposition genetique aux addictions ?

    OpenAIRE

    CASTERMANS, Emilie; GAILLEZ, Stephanie; BOURS, Vincent

    2013-01-01

    Is free will the rule in front of drugs, alcohol or gambling? Would interindividual genetic variations influence our behaviour to such a point that addiction susceptibility would be enhanced or decreased? Addiction predisposition is a complex trait, involving numerous predisposition genes and also environment. Heritability of this trait is 50%, meaning a similar contribution of genes and environment in the setting of this trait. Some genes of the dopaminergic system and some others specific f...

  15. Identification of Prostate Cancer Predisposition Genes on the Y Chromosome

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH -15 -1-0638 TITLE: Identification of Prostate Cancer Predisposition Genes on the Y Chromosome PRINCIPAL INVESTIGATOR...SUBTITLE 5a. CONTRACT NUMBER Identification of Prostate Cancer Predisposition Genes on the Y Chromosome 5b. GRANT NUMBER Chromosome 5c. PROGRAM...difficult. We hypothesize the existence of Y chromosome genes/variants related to increased risk, and propose multiple genetic analyses to efficiently

  16. Radiation-induced breast cancer: Influence of age at exposure, latency period, age, and genetic predisposition; Strahleninduziertes Mammakarzinom: Einfluss von Alter bei Exposition, Latenzzeit, erreichtem Lebensalter und genetischer Praedisposition

    Energy Technology Data Exchange (ETDEWEB)

    Kuni, H. [Klinische Nuklearmedizin, Marburg Univ. (Germany)

    2001-07-01

    Radiation induced breast cancer: Influence of age at exposure, time since exposure, attained age and genetic predisposition. The amount of undesirable effects of screening with mammography was estimated from mortality studies after radiation exposure. Newer incidence studies demonstrate, however, an underestimation of the health detriment by mortality studies, in particular with increasing age at exposure, which amounts about five- to sixfold after an exposure in an age of 45-50y. The multidimensional analysis of the discrete values of incidence after radiation exposure respecting age at exposure, time since exposure and attained age instead of calculating a steady function simply depending from age at exposure results in an increasing relative and absolute risk of cancer incidence (and mortality) with growing age after an exposure at an age above 40y. Some genes seems to be correlated with an predisposition of breast cancer. In women carrying BRCA-1 the radiosensitivity for induction of breast cancer may exceed the risk in the normal population by about two orders of magnitude. The resulting doubling dose amounts in the order of the natural and medical radiation exposure. At least in part the genetic predisposition is associated with an early onset of the cancer after an additional radiation exposure. This kind of health detriment was not considered in the former discussion of radiation hazards. (orig.) [German] Das Ausmass unerwuenschter Folgen eines Mammographie-Screenings war bisher aus Mortalitaetsstatistiken nach einer Strahlenbelastung abgeleitet worden. Neuere Inzidenzstatistiken zeigen, dass besonders mit zunehmendem Lebensalter die Mortalitaetsstatistiken die Gefaehrdung durch ein strahleninduziertes Mammakarzinom erheblich unterschaetzen, nach einer Strahlenbelastung im Alter um 45-50 Jahre um etwa das Fuenf- bis Siebenfache. Werden zur Beschreibung der strahleninduzierten Inzidinz aus den Statistiken keine kontinuierlichen mathematischen Funktionen

  17. Familial Predisposition for Salivary Gland Cancer in Finland

    Directory of Open Access Journals (Sweden)

    Katri Aro

    2014-01-01

    Full Text Available Background Salivary gland cancer (SGC accounts for 3–5% of head and neck malignancies, and register-based studies estimate the familial proportion to be 0.15%. Objective We studied familial predisposition for SGC in the genetically distinct Finnish population. Patients and Methods We sent a patient questionnaire to 161 Finnish SGC patients, 86 of whom responded. Results A total of 76% of the patients reported having one or more relatives with cancer, 30% two or more, and 9% three or more but only one patient reported having a relative with SGC. Tracing the birthplaces of the SGC patients’ grandparents showed no regional clustering suggestive of a founder effect. Conclusions Lack of familial SGC patients and the absence of a founder effect strongly suggest that familial predisposition for SGC is insignificant in the Finnish population. Various histological subtypes and the rarity of these neoplasms make it impossible to draw conclusions about site-specific association between SGC and other malignancies.

  18. Predisposition to Obesity

    DEFF Research Database (Denmark)

    Olsen, Nanna Julie; Mortensen, Erik Lykke; Heitmann, Berit Lilienthal

    2012-01-01

    predisposed to future obesity. The purpose of this paper is to review interventions on obesity prevention published during the past year, and to examine if interventions targeting predisposed groups or individuals seem more efficient in preventing obesity than studies targeting general populations. Among 15......Obesity prevention should remain a priority, even if there is some suggestion that the epidemic may presently have reached a stable level. However, previous interventions have not been effective in preventing overweight and obesity, and at the same time studies suggest that some subgroups are more...... identified studies, 7 targeted predisposed children or adolescents. More of the studies targeting predisposed individuals were able to show significant effects than the studies targeting general populations. Most studies targeting predisposed defined the predisposition based on ethnicity or socioeconomic...

  19. International Szent-Györgyi Prize for Progress in Cancer Research: basic and translational research recognition : Mary-Claire King received the 2016 Prize for her pioneering research that demonstrated the first evidence of genetic predisposition to breast cancer.

    Science.gov (United States)

    Hartmann, Hali; Zhao, Jie; Ba, Sujuan

    2017-11-21

    The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award sponsored by the National Foundation for Cancer Research (NFCR)-a leading cancer research charitable organization in the United States that supports innovative cancer research globally with the ultimate goal to cure cancer. The coveted Szent-Györgyi Prize annually honors a scientist whose seminal discovery or body of work has resulted in, or led toward, notable contributions to cancer prevention, diagnosis, or treatment; and the discovery has had a high direct impact of saving people's lives. In addition, the prize promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. In 2016, NFCR's Szent-Györgyi Prize Selection Committee was unanimous in its decision to recognize an icon in human disease genetics, Dr. Mary-Claire King, for her pioneering research that demonstrated the first evidence of genetic predisposition to breast cancer. Her proof of existence of BRCA1 gene and its location has made genetic screening for breast and ovarian cancers possible, saving lives of many people who are at high risk with inherited BRCA1 mutations.

  20. Hereditary Predispositions to Myelodysplastic Syndrome

    Directory of Open Access Journals (Sweden)

    Sarah A. Bannon

    2016-05-01

    Full Text Available Myelodysplastic syndromes (MDS are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral cytopenias. Familial forms of MDS have traditionally been considered rare, especially in adults; however, the increasing availability of somatic and germline genetic analyses has identified multiple susceptibility loci. Bone marrow failure syndromes have been well-described in the pediatric setting, e.g., Fanconi anemia (FA, dyskeratosis congenita (DC, Diamond–Blackfan anemia (DBA, and Shwachman–Diamond syndrome (SBS, hallmarked by clinically-recognizable phenotypes (e.g., radial ray anomalies in FA and significantly increased risks for MDS and/or acute myeloid leukemia (AML in the setting of bone marrow failure. However, additional families with multiple cases of MDS or AML have long been reported in the medical literature with little known regarding potential hereditary etiologies. Over the last decade, genomic investigation of such families has revealed multiple genes conferring inherited risks for MDS and/or AML as the primary malignancy, including RUNX1, ANKRD26, DDX41, ETV6, GATA2, and SRP72. As these syndromes are increasingly appreciated in even apparently de novo presentations of MDS, it is important for hematologists/oncologists to become familiar with these newly-described syndromes. Herein, we provide a review of familial MDS syndromes and practical aspects of management in patients with predisposition syndromes.

  1. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies

    DEFF Research Database (Denmark)

    Lal, Dennis; Ruppert, Ann-Kathrin; Trucks, Holger

    2015-01-01

    Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (...%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative...... a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes....

  2. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology.

    Science.gov (United States)

    Ripperger, Tim; Bielack, Stefan S; Borkhardt, Arndt; Brecht, Ines B; Burkhardt, Birgit; Calaminus, Gabriele; Debatin, Klaus-Michael; Deubzer, Hedwig; Dirksen, Uta; Eckert, Cornelia; Eggert, Angelika; Erlacher, Miriam; Fleischhack, Gudrun; Frühwald, Michael C; Gnekow, Astrid; Goehring, Gudrun; Graf, Norbert; Hanenberg, Helmut; Hauer, Julia; Hero, Barbara; Hettmer, Simone; von Hoff, Katja; Horstmann, Martin; Hoyer, Juliane; Illig, Thomas; Kaatsch, Peter; Kappler, Roland; Kerl, Kornelius; Klingebiel, Thomas; Kontny, Udo; Kordes, Uwe; Körholz, Dieter; Koscielniak, Ewa; Kramm, Christof M; Kuhlen, Michaela; Kulozik, Andreas E; Lamottke, Britta; Leuschner, Ivo; Lohmann, Dietmar R; Meinhardt, Andrea; Metzler, Markus; Meyer, Lüder H; Moser, Olga; Nathrath, Michaela; Niemeyer, Charlotte M; Nustede, Rainer; Pajtler, Kristian W; Paret, Claudia; Rasche, Mareike; Reinhardt, Dirk; Rieß, Olaf; Russo, Alexandra; Rutkowski, Stefan; Schlegelberger, Brigitte; Schneider, Dominik; Schneppenheim, Reinhard; Schrappe, Martin; Schroeder, Christopher; von Schweinitz, Dietrich; Simon, Thorsten; Sparber-Sauer, Monika; Spix, Claudia; Stanulla, Martin; Steinemann, Doris; Strahm, Brigitte; Temming, Petra; Thomay, Kathrin; von Bueren, Andre O; Vorwerk, Peter; Witt, Olaf; Wlodarski, Marcin; Wössmann, Willy; Zenker, Martin; Zimmermann, Stefanie; Pfister, Stefan M; Kratz, Christian P

    2017-04-01

    Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected. © 2017 Wiley Periodicals, Inc.

  3. Significance of genetic predisposition and genomic instability for individual sensitivity to radiation. Implications for radiation protection; Bedeutung der genetischen Praedisposition und der genomischen Instabilitaet fuer die individuelle Strahlenempfindlichkeit. Konsequenzen fuer den Strahlenschutz

    Energy Technology Data Exchange (ETDEWEB)

    Heller, H. (ed.)

    2001-07-01

    At its closed-door meeting on 20/21 January 2000 the Radiation Protection Committee dedicated much of its attention to the significance of genetic predisposition and genetic instability for individual radiation sensitivity and to the implication of this for radiation protection. The statements and contributions to the closing plenary discussion touched on many aspects of ethics, personal rights, occupational medicine and insurance issues relating to this subject, all of which extend far beyond the purely technical issues of radiation protection. The present volume contains the lecture manuscripts of the meeting as well as a summarising assessment by the Radiation Protection Committee. [German] Der Strahlenschutzkommission war es ein besonderes Anliegen, sich im Rahmen ihrer Klausurtagung am 20./21. Januar 2000 mit der Bedeutung der genetischen Praedisposition und der genetischen Instabilitaet fuer die individuelle Strahlenempfindlichkeit sowie mit den damit moeglicherweise verbundenen Auswirkungen auf den Strahlenschutz intensiv auseinanderzusetzen. Die vielfaeltigen ethischen, persoenlichkeitsrechtlichen, arbeitsmedizinischen und versicherungsrelevanten Aspekte dieser Thematik, die weit ueber rein fachliche Fragen des Strahlenschutzes hinausgehen, kamen waehrend des abschliessenden Podiumsgespraeches in Stellungnahmen und Diskussionsbeitraegen zur Sprache. Der vorliegende Band beinhaltet die Vortragsmanuskripte dieser Veranstaltung sowie eine zusammenfassende Bewertung durch die Strahlenschutzkommission. (orig.)

  4. Total and regional fat distribution is strongly influenced by genetic factors in young and elderly twins

    DEFF Research Database (Denmark)

    Malis, Charlotte; Rasmussen, Eva L; Poulsen, Pernille

    2005-01-01

    OBJECTIVE: Indirect estimates of obesity such as BMI seem to be strongly influenced by genetic factors in twins. Precise measurements of total and regional fat as determined by direct techniques such as DXA scan have only been applied in a few twin studies. The aim of the present study was to est......OBJECTIVE: Indirect estimates of obesity such as BMI seem to be strongly influenced by genetic factors in twins. Precise measurements of total and regional fat as determined by direct techniques such as DXA scan have only been applied in a few twin studies. The aim of the present study...... was to estimate the heritability (h(2)) of total and regional fat distribution in young and elderly Danish twins. RESEARCH METHODS AND PROCEDURES: Monozygotic (108) and dizygotic (88) twins in two age groups (25 to 32 and 58 to 66 years) underwent anthropometric measurements and DXA scans. Intraclass correlations...... genetic component (h(2)) of total (h(2)(young) = 0.83, h(2)(elderly) = 0.86) and regional fat percentages (trunk, h(2)(young) = 0.82, h(2)(elderly) = 0.85; lower body, h(2)(young) = 0.83, h(2)(elderly) = 0.81; and trunk/lower body, h(2)(young) = 0.83, h(2)(elderly) = 0.71) in both the young and elderly...

  5. Exposure to low-dose radiation and the risk of breast cancer among women with a familial or genetic predisposition : a meta-analysis

    NARCIS (Netherlands)

    Jansen-van der Weide, Marijke C.; Greuter, Marcel J. W.; Jansen, Liesbeth; Oosterwijk, Jan C.; Pijnappel, Ruud M.; de Bock, Geertruida H.

    2010-01-01

    Women with familial or genetic aggregation of breast cancer are offered screening outside the population screening programme. However, the possible benefit of mammography screening could be reduced due to the risk of radiation-induced tumours. A systematic search was conducted addressing the

  6. Additive influence of genetic predisposition and conventional risk factors in the incidence of coronary heart disease: a population-based study in Greece

    Science.gov (United States)

    An additive genetic risk score (GRS) for coronary heart disease (CHD) has previously been associated with incident CHD in the population-based Greek European Prospective Investigation into Cancer and nutrition (EPIC) cohort. In this study, we explore GRS-‘environment’ joint actions on CHD for severa...

  7. Bone Strength Estimated by Micro-Finite Element Analysis (µFEA) Is Heritable and Shares Genetic Predisposition With Areal BMD: The Framingham Study.

    Science.gov (United States)

    Karasik, David; Demissie, Serkalem; Lu, Darlene; Broe, Kerry E; Boyd, Steven K; Liu, Ching-Ti; Hsu, Yi-Hsiang; Bouxsein, Mary L; Kiel, Douglas P

    2017-11-01

    Genetic factors contribute to the risk of bone fractures, partly because of effects on bone strength. High-resolution peripheral quantitative computed tomography (HR-pQCT) estimates bone strength using micro-finite element analysis (µFEA). The goal of this study was to investigate if the bone failure load estimated by HR-pQCT-based µFEA is heritable and to what extent it shares genetic regulation with areal bone mineral density (aBMD). Bone microarchitecture was measured by HR-pQCT at the ultradistal tibia and ultradistal radius in adults from the Framingham Heart Study (n = 1087, mean age 72 years; 57% women). Radial and tibial failure load in compression were estimated by µFEA. Femoral neck (FN) and ultradistal forearm (UD) aBMD were measured by dual-energy X-ray absorptiometry (DXA). Heritability (h 2 ) of failure load and aBMD and genetic correlations between them was estimated adjusting for covariates (age and sex). Failure load values at the non-weight-bearing ultradistal radius and at the weight-bearing ultradistal tibia were highly correlated (r = 0.906; p analysis, there was a high phenotypic and genetic correlation between covariate-adjusted failure load at the radius and UD aBMD (ρ P  = 0.826, ρ G  = 0.954, respectively), whereas environmental correlations were lower (ρ E  = 0.696), all highly significant (p micro-finite element analysis is heritable and shares some genetic composition with areal BMD, regardless of the skeletal site. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

  8. Low genetic diversity and strong population structure shaped by anthropogenic habitat fragmentation in a critically endangered primate, Trachypithecus leucocephalus.

    Science.gov (United States)

    Wang, W; Qiao, Y; Li, S; Pan, W; Yao, M

    2017-06-01

    Habitat fragmentation may strongly impact population genetic structure and reduce the genetic diversity and viability of small and isolated populations. The white-headed langur (Trachypithecus leucocephalus) is a critically endangered primate species living in a highly fragmented and human-modified habitat in southern China. We examined the population genetic structure and genetic diversity of the species and investigated the environmental and anthropogenic factors that may have shaped its population structure. We used 214 unique multi-locus genotypes from 41 social groups across the main distribution area of T. leucocephalus, and found strong genetic structure and significant genetic differentiation among local populations. Our landscape genetic analyses using a causal modelling framework suggest that a large habitat gap and geographical distance represent the primary landscape elements shaping genetic structure, yet high levels of genetic differentiation also exist between patches separated by a small habitat gap or road. This is the first comprehensive study that has evaluated the population genetic structure and diversity of T. leucocephalus using nuclear markers. Our results indicate strong negative impacts of anthropogenic land modifications and habitat fragmentation on primate genetic connectivity between forest patches. Our analyses suggest that two management units of the species could be defined, and indicate that habitat continuity should be enforced and restored to reduce genetic isolation and enhance population viability.

  9. Computer simulation of heterogeneous single nucleotide polymorphisms in the catalase gene indicates structural changes in the enzyme active site, NADPH-binding and tetramerization domains: a genetic predisposition for an altered catalase in patients with vitiligo?

    Science.gov (United States)

    Wood, John M; Gibbons, Nicholas C J; Chavan, Bhaven; Schallreuter, Karin U

    2008-04-01

    Patients with vitiligo have low levels/activities of catalase in their lesional and non-lesional epidermis as well as in their epidermal melanocytes under in vitro conditions while the levels of catalase mRNA are unaltered. This defect leads to a build-up of hydrogen peroxide (H(2)O(2)) in the 10(-3) m range in the epidermis of these patients. In this context, it was realized that 10(-3) m H(2)O(2) deactivates catalase. Along this line, it was also suspected that catalase in patients with vitiligo possesses a special sensitivity to this reactive oxygen species (ROS), and indeed several heterozygous single nucleotide polymorphisms (SNPs) have been documented in the cat gene of these patients. Based on the 3D structure of human catalase monomer, we have modelled the influence of three selected SNPs on the enzyme active site, on the NADPH- as well as the tetramerization-binding domains. Our results show that these SNPs severely alter catalase structurally, which in turn should make the enzyme more susceptible to ROS compared with wild-type enzyme. Taken together, the work presented herein together with the earlier results on SNPs in the cat gene suggests a genetic predisposition for an altered catalase in patients with vitiligo.

  10. Focusing light through strongly scattering media using genetic algorithm with SBR discriminant

    Science.gov (United States)

    Zhang, Bin; Zhang, Zhenfeng; Feng, Qi; Liu, Zhipeng; Lin, Chengyou; Ding, Yingchun

    2018-02-01

    In this paper, we have experimentally demonstrated light focusing through strongly scattering media by performing binary amplitude optimization with a genetic algorithm. In the experiments, we control 160 000 mirrors of digital micromirror device to modulate and optimize the light transmission paths in the strongly scattering media. We replace the universal target-position-intensity (TPI) discriminant with signal-to-background ratio (SBR) discriminant in genetic algorithm. With 400 incident segments, a relative enhancement value of 17.5% with a ground glass diffuser is achieved, which is higher than the theoretical value of 1/(2π )≈ 15.9 % for binary amplitude optimization. According to our repetitive experiments, we conclude that, with the same segment number, the enhancement for the SBR discriminant is always higher than that for the TPI discriminant, which results from the background-weakening effect of SBR discriminant. In addition, with the SBR discriminant, the diameters of the focus can be changed ranging from 7 to 70 μm at arbitrary positions. Besides, multiple foci with high enhancement are obtained. Our work provides a meaningful reference for the study of binary amplitude optimization in the wavefront shaping field.

  11. Strong incidence of Pseudomonas aeruginosa on bacterial rrs and ITS genetic structures of cystic fibrosis sputa.

    Directory of Open Access Journals (Sweden)

    Laurence Pages-Monteiro

    Full Text Available Cystic fibrosis (CF lungs harbor a complex community of interacting microbes, including pathogens like Pseudomonas aeruginosa. Meta-taxogenomic analysis based on V5-V6 rrs PCR products of 52 P. aeruginosa-positive (Pp and 52 P. aeruginosa-negative (Pn pooled DNA extracts from CF sputa suggested positive associations between P. aeruginosa and Stenotrophomonas and Prevotella, but negative ones with Haemophilus, Neisseria and Burkholderia. Internal Transcribed Spacer analyses (RISA from individual DNA extracts identified three significant genetic structures within the CF cohorts, and indicated an impact of P. aeruginosa. RISA clusters Ip and IIIp contained CF sputa with a P. aeruginosa prevalence above 93%, and of 24.2% in cluster IIp. Clusters Ip and IIIp showed lower RISA genetic diversity and richness than IIp. Highly similar cluster IIp RISA profiles were obtained from two patients harboring isolates of a same P. aeruginosa clone, suggesting convergent evolution in the structure of their microbiota. CF patients of cluster IIp had received significantly less antibiotics than patients of clusters Ip and IIIp but harbored the most resistant P. aeruginosa strains. Patients of cluster IIIp were older than those of Ip. The effects of P. aeruginosa on the RISA structures could not be fully dissociated from the above two confounding factors but several trends in these datasets support the conclusion of a strong incidence of P. aeruginosa on the genetic structure of CF lung microbiota.

  12. Breast cancer predisposition syndromes.

    Science.gov (United States)

    Hemel, Deborah; Domchek, Susan M

    2010-10-01

    A small, but important, percentage of breast cancer cases is caused by the inheritance of a single copy of a mutated gene. BRCA1 and BRCA2 are the genes most commonly associated with inherited breast cancer; however, mutations in TP53 and PTEN cause Li-Fraumeni syndrome and Cowden syndrome, respectively, both of which are associated with high lifetime risks of breast cancer. Advances in the field of breast cancer genetics have led to an improved understanding of detection and prevention strategies. More recently, strategies to target the underlying genetic defects in BRCA1- and BRCA2-associated breast and ovarian cancers are emerging and may have implications for certain types of sporadic breast cancer. Copyright 2010 Elsevier Inc. All rights reserved.

  13. Estimation of BDNF gene polymorphism and predisposition to dependence development for selected psychoactive compounds: genetic aspects of addiction with the selected drugs, amphetamine, tetrahydrocannabinol and opiates.

    Science.gov (United States)

    Biskupska, J; Borowiak, K S; Karlin-Grazewicz, K; Janus, T; Waloszczyk, P; Potocka-Banas, B; Machoy-Mokrzynska, A; Ossowski, A; Ciechanowicz, A

    2013-03-01

    The etiology of drug addiction, a central nervous system (CNS) disease, is not fully known. This complex problem is believed to be connected with concurrently affecting genetic, psychological and environmental factors. The development of addiction is connected with CNS reinforcement system and dopaminergic neurotransmission. Molecular processes are postulated to be of universal character and allow to presume a similar mechanism of dependence for both ethanol and other substances. Therefore, elements of dopaminergic transmission become excellent candidates for the examination of genetic influence on the development of addiction. A relationship between alcoholic disease and the presence of TaqIA1 and DRD2 alleles permits to initiate another investigation of gene-coding DRD2 dopamine receptor. The latest results indicate the importance of brain-derived neurotrophic factor (BDNF) in the regulation of dopaminergic route. The purpose of this research was to reveal the relationship between the Val66Met BDNF gene polymorphism and dependence of psychoactive agent. The examinations were performed with the Local Research Ethics Committee approval and patient's consent. The study group consisted of 100 patients (88 men and 12 women) aged 18-52 years, qualified for research program according to the International Classification of Diseases, Tenth Revision (ICD-10) requirements, medical examination and detailed questionnaire.

  14. Population genetics inference for longitudinally-sampled mutants under strong selection.

    Science.gov (United States)

    Lacerda, Miguel; Seoighe, Cathal

    2014-11-01

    Longitudinal allele frequency data are becoming increasingly prevalent. Such samples permit statistical inference of the population genetics parameters that influence the fate of mutant variants. To infer these parameters by maximum likelihood, the mutant frequency is often assumed to evolve according to the Wright-Fisher model. For computational reasons, this discrete model is commonly approximated by a diffusion process that requires the assumption that the forces of natural selection and mutation are weak. This assumption is not always appropriate. For example, mutations that impart drug resistance in pathogens may evolve under strong selective pressure. Here, we present an alternative approximation to the mutant-frequency distribution that does not make any assumptions about the magnitude of selection or mutation and is much more computationally efficient than the standard diffusion approximation. Simulation studies are used to compare the performance of our method to that of the Wright-Fisher and Gaussian diffusion approximations. For large populations, our method is found to provide a much better approximation to the mutant-frequency distribution when selection is strong, while all three methods perform comparably when selection is weak. Importantly, maximum-likelihood estimates of the selection coefficient are severely attenuated when selection is strong under the two diffusion models, but not when our method is used. This is further demonstrated with an application to mutant-frequency data from an experimental study of bacteriophage evolution. We therefore recommend our method for estimating the selection coefficient when the effective population size is too large to utilize the discrete Wright-Fisher model. Copyright © 2014 by the Genetics Society of America.

  15. Disentangling the Importance of Psychological Predispositions and Social Constructions in the Organization of American Political Ideology.

    Science.gov (United States)

    Verhulst, Brad; Hatemi, Peter K; Eaves, Lindon J

    2012-06-01

    Ideological preferences within the American electorate are contingent on both the environmental conditions that provide the content of the contemporary political debate and internal predispositions that motivate people to hold liberal or conservative policy preferences. In this article we apply Jost, Federico, and Napier's (2009) top-down/bottom-up theory of political attitude formation to a genetically informative population sample. In doing so, we further develop the theory by operationalizing the top-down pathway to be a function of the social environment and the bottom-up pathway as a latent set of genetic factors. By merging insights from psychology, behavioral genetics, and political science, we find strong support for the top-down/bottom-up framework that segregates the two independent pathways in the formation of political attitudes and identifies a different pattern of relationships between political attitudes at each level of analysis.

  16. Exposure to low-dose radiation and the risk of breast cancer among women with a familial or genetic predisposition: a meta-analysis

    Energy Technology Data Exchange (ETDEWEB)

    Jansen-van der Weide, Marijke C. [University Medical Center Groningen, University of Groningen, Department of Radiology, Hanzeplein 1, PO Box 30.001, Groningen (Netherlands); University Medical Center Groningen, University of Groningen, Department of Epidemiology, Groningen (Netherlands); Greuter, Marcel J.W.; Pijnappel, Ruud M. [University Medical Center Groningen, University of Groningen, Department of Radiology, Hanzeplein 1, PO Box 30.001, Groningen (Netherlands); Jansen, Liesbeth [University Medical Center Groningen, University of Groningen, Department of Surgery, Groningen (Netherlands); Oosterwijk, Jan C. [University Medical Center Groningen, University of Groningen, Department of Clinical Genetics, Groningen (Netherlands); Bock, Geertruida H. de [University Medical Center Groningen, University of Groningen, Department of Epidemiology, Groningen (Netherlands)

    2010-11-15

    Women with familial or genetic aggregation of breast cancer are offered screening outside the population screening programme. However, the possible benefit of mammography screening could be reduced due to the risk of radiation-induced tumours. A systematic search was conducted addressing the question of how low-dose radiation exposure affects breast cancer risk among high-risk women. A systematic search was conducted for articles addressing breast cancer, mammography screening, radiation and high-risk women. Effects of low-dose radiation on breast cancer risk were presented in terms of pooled odds ratios (OR). Of 127 articles found, 7 were selected for the meta-analysis. Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9- 1.8). Exposure before age 20 (OR = 2.0, 95% CI: 1.3-3.1) or a mean of {>=}5 exposures (OR = 1.8, 95% CI: 1.1-3.0) was significantly associated with a higher radiation-induced breast cancer risk. Low-dose radiation increases breast cancer risk among high-risk women. When using low-dose radiation among high-risk women, a careful approach is needed, by means of reducing repeated exposure, avoidance of exposure at a younger age and using non-ionising screening techniques. (orig.)

  17. Exposure to low-dose radiation and the risk of breast cancer among women with a familial or genetic predisposition: a meta-analysis

    International Nuclear Information System (INIS)

    Jansen-van der Weide, Marijke C.; Greuter, Marcel J.W.; Pijnappel, Ruud M.; Jansen, Liesbeth; Oosterwijk, Jan C.; Bock, Geertruida H. de

    2010-01-01

    Women with familial or genetic aggregation of breast cancer are offered screening outside the population screening programme. However, the possible benefit of mammography screening could be reduced due to the risk of radiation-induced tumours. A systematic search was conducted addressing the question of how low-dose radiation exposure affects breast cancer risk among high-risk women. A systematic search was conducted for articles addressing breast cancer, mammography screening, radiation and high-risk women. Effects of low-dose radiation on breast cancer risk were presented in terms of pooled odds ratios (OR). Of 127 articles found, 7 were selected for the meta-analysis. Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9- 1.8). Exposure before age 20 (OR = 2.0, 95% CI: 1.3-3.1) or a mean of ≥5 exposures (OR = 1.8, 95% CI: 1.1-3.0) was significantly associated with a higher radiation-induced breast cancer risk. Low-dose radiation increases breast cancer risk among high-risk women. When using low-dose radiation among high-risk women, a careful approach is needed, by means of reducing repeated exposure, avoidance of exposure at a younger age and using non-ionising screening techniques. (orig.)

  18. Predictors associated with MRI surveillance screening in women with a personal history of unilateral breast cancer but without a genetic predisposition for future contralateral breast cancer.

    Science.gov (United States)

    Hegde, John V; Wang, Xiaoyan; Attai, Deanna J; DiNome, Maggie L; Kusske, Amy; Hoyt, Anne C; Hurvitz, Sara A; Weidhaas, Joanne B; Steinberg, Michael L; McCloskey, Susan A

    2017-11-01

    For women with a personal history of breast cancer (PHBC), no validated mechanisms exist to calculate future contralateral breast cancer (CBC) risk. The Manchester risk stratification guidelines were developed to evaluate CBC risk in women with a PHBC, primarily for surgical decision making. This tool may be informative for the use of MRI screening, as CBC risk is an assumed consideration for high-risk surveillance. Three hundred twenty-two women with a PHBC were treated with unilateral surgery within our multidisciplinary breast clinic. We calculated lifetime CBC risk using the Manchester tool, which incorporates age at diagnosis, family history, genetic mutation status, estrogen receptor positivity, and endocrine therapy use. Univariate and multivariate logistic regression analyses (UVA/MVA) were performed, evaluating whether CBC risk predicted MRI surveillance. For women with invasive disease undergoing MRI surveillance, 66% had low, 23% above-average, and 11% moderate/high risk for CBC. On MVA, previous mammography-occult breast cancer [odds ratio (OR) 18.95, p breast tissue (OR 3.69, p = 0.0007), mastectomy versus lumpectomy (OR 3.12, p = 0.0041), and CBC risk (OR 3.17 for every 10% increase, p = 0.0002) were associated with MRI surveillance. No pathologic factors increasing ipsilateral breast cancer recurrence were significant on MVA. Although CBC risk predicted MRI surveillance, 89% with invasive disease undergoing MRI had breast cancer detectability (dense breasts and/or previous mammography-occult disease) predominate decision making. Pathologic factors important for determining ipsilateral recurrence risk, aside from age, were not associated with MRI surveillance.

  19. MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

    Science.gov (United States)

    Trifa, Adrian P; Bănescu, Claudia; Bojan, Anca S; Voina, Cristian M; Popa, Ștefana; Vișan, Simona; Ciubean, Alina D; Tripon, Florin; Dima, Delia; Popov, Viola M; Vesa, Ștefan C; Andreescu, Mihaela; Török-Vistai, Tünde; Mihăilă, Romeo G; Berbec, Nicoleta; Macarie, Ioan; Coliţă, Andrei; Iordache, Maria; Cătană, Alina C; Farcaș, Marius F; Tomuleasa, Ciprian; Vasile, Kinga; Truică, Cristina; Todincă, Adriana; Pop-Muntean, Lavinia; Manolache, Raluca; Bumbea, Horia; Vlădăreanu, Ana-Maria; Gaman, Mihaela; Ciufu, Cristina M; Popp, Radu A

    2018-01-01

    Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN. © 2017 Wiley Periodicals, Inc.

  20. Mature habitats associated with genetic divergence despite strong dispersal ability in an arthropod

    Directory of Open Access Journals (Sweden)

    Taylor Derek J

    2007-04-01

    Full Text Available Abstract Background Populations may be bound by contemporary gene flow, selective sweeps, and extinction-recolonization processes. Indeed, existing molecular estimates indicate that species with low levels of gene flow are rare. However, strong priority effects and local selective regimes may hinder gene flow (despite dispersal sending populations on independent evolutionary trajectories. In this scenario (the monopolization hypothesis, population differentiation will increase with time and genealogical evidence should yield ample private haplotypes. Cyclical parthenogens (e.g. rotifers and cladocerans such as Daphnia have an increased capacity for rapid local adaptation and priority effects because sexual reproduction is followed by multiple generations of clonal selection and massive egg bank formation. We aimed to better understand the history of population differentiation and ongoing gene flow in Daphnia rosea s.l., by comparing population and regional divergences in mature unglaciated areas and younger previously glaciated areas. We also examined the timing and paths of colonization of previously-glaciated areas to assess the dispersal limitations of D. rosea s.l. We used DNA sequence variation (84 populations and >400 individuals at the mitochondrial ND2 and nuclear HSP90 loci from Holarctic populations for our genetic analyses. Results The genetic evidence indicated pronounced historical structure. Holarctic mtDNA phylogenies of D. rosea s.l. revealed three geographically restricted and divergent clades: European, Siberian and Japanese/American. The Japanese/American clade showed marked population genetic structure (FST > 0.8 that was weakly associated with geographic distance, and a high proportion of private haplotypes. Populations from older unglaciated habitats (i.e., Japan showed higher DNA sequence divergences than populations from presumed younger habitats (i.e. non-Beringian North America with nDNA and with mtDNA. Mismatch

  1. Evidence of an Inherited Predisposition for Cervical Spondylotic Myelopathy

    Science.gov (United States)

    Patel, Alpesh A.; Spiker, William Ryan; Daubs, Michael; Brodke, Darrel S.; Cannon-Albright, Lisa A.

    2011-01-01

    Study Design A retrospective population based study cross referencing a genealogic database of over 2 million Utah residents with 10 years of clinical diagnosis data from a large tertiary hospital. Objective The objective of this study is to determine the presence or absence of an inherited predisposition to the development of cervical spondylotic myelopathy (CSM). Summary of Background Data A genetic predisposition for the development of cervical spondylosis has been discussed in the literature with low quality evidence. Families with a high incidence of disease or early onset disease in monozygotic twins have both been reported. However, these suggestions of an inherited predisposition for disease have never been rigorously studied. The purpose of this study is to determine a genetic predisposition among patients diagnosed with cervical spondylotic myelopathy. Methods The Utah Population Database (UPDB) combines health and genealogic data on over 2 million Utah residents. ICD-9 codes were used to identify 486 patients in the database with a diagnosis of cervical spondylosis with myelopathy (ICD9 code 721.1). The hypothesis of excessive familial clustering was tested using the Genealogical Index of Familiality (GIF) and Relative risks (RR) in relatives were estimated by comparing rates of disease in relatives with rates estimated in the relatives of 5 matched controls for each case. This methodology has been previously reported and validated for other disease conditions but not for cervical spondylotic myelopathy. Results The GIF analysis for patients with CSM showed significant excess relatedness for disease (pspondylosis with myelopathy. Level of Evidence III PMID:21252820

  2. Fragile X Syndrome: Genetic Predisposition to Psychopathology.

    Science.gov (United States)

    Bregman, Joel D.; And Others

    1988-01-01

    Psychiatric evaluation of 14 males (ages 3-27 years) with the fragile X syndrome found pervasive hyperactivity, impulsivity, and attentional deficits, and a significant degree of anxiety. However, diagnostic criteria for persistent pervasive developmental disorder and autism were not met. (Author/DB)

  3. Temporal genetic stability in natural populations of the waterflea Daphnia magna in response to strong selection pressure.

    Science.gov (United States)

    Orsini, Luisa; Marshall, Hollie; Cuenca Cambronero, Maria; Chaturvedi, Anurag; Thomas, Kelley W; Pfrender, Michael E; Spanier, Katina I; De Meester, Luc

    2016-12-01

    Studies monitoring changes in genetic diversity and composition through time allow a unique understanding of evolutionary dynamics and persistence of natural populations. However, such studies are often limited to species with short generation times that can be propagated in the laboratory or few exceptional cases in the wild. Species that produce dormant stages provide powerful models for the reconstruction of evolutionary dynamics in the natural environment. A remaining open question is to what extent dormant egg banks are an unbiased representation of populations and hence of the species' evolutionary potential, especially in the presence of strong environmental selection. We address this key question using the water flea Daphnia magna, which produces dormant stages that accumulate in biological archives over time. We assess temporal genetic stability in three biological archives, previously used in resurrection ecology studies showing adaptive evolutionary responses to rapid environmental change. We show that neutral genetic diversity does not decline with the age of the population and it is maintained in the presence of strong selection. In addition, by comparing temporal genetic stability in hatched and unhatched populations from the same biological archive, we show that dormant egg banks can be consulted to obtain a reliable measure of genetic diversity over time, at least in the multidecadal time frame studied here. The stability of neutral genetic diversity through time is likely mediated by the buffering effect of the resting egg bank. © 2016 John Wiley & Sons Ltd.

  4. Polygyny and strong genetic structuring within an isolated population of the wood ant Formica rufa

    Directory of Open Access Journals (Sweden)

    Wouter Dekoninck

    2014-12-01

    Full Text Available Social structuring of populations within some Formica species exhibits considerable variation going from monodomous and monogynous populations to polydomous, polygynous populations. The wood ant species Formica rufa appears to be mainly monodomous and monogynous throughout most of its distribution area in central and northern Europe. Only occasionally it was mentioned that F. rufa can have both polygynous and monogynous colonies in the same geographical region. We studied an isolated polydomous F. rufa population in a deciduous mixed forest in the north-west of Belgium. The level of polydomy within the colonies varied from monodomous to 11 nests per colony. Our genetic analysis of eight variable microsatellites suggest an oligo- to polygynous structure for at least the major part of the sampled nests. Relatedness amongst nest mate workers varies considerable within the population and colonies but confirms in general a polygynous structure. Additionally high genetic diversity (e.g. up to 8 out of 11 alleles per nest for the most variable locus and high within nest genetic variance (93% indicate that multiple queens contribute to the gene pool of workers of the same nest. Moreover significant genetic structuring among colonies indicates that gene flow between colonies is restricted and that exchange of workers between colonies is very limited. Finally we explain how possible factors as budding and the absence of Serviformica can explain the differences in genetic structure within this polygynous F. rufa population.

  5. Microsatellites reveal a strong subdivision of genetic structure in Chinese populations of the mite Tetranychus urticae Koch (Acari: Tetranychidae

    Directory of Open Access Journals (Sweden)

    Sun Jing-Tao

    2012-02-01

    Full Text Available Abstract Background Two colour forms of the two-spotted spider mite (Tetranychus urticae Koch coexist in China: a red (carmine form, which is considered to be native and a green form which is considered to be invasive. The population genetic diversity and population genetic structure of this organism were unclear in China, and there is a controversy over whether they constitute distinct species. To address these issues, we genotyped a total of 1,055 individuals from 18 red populations and 7 green populations in China using eight microsatellite loci. Results We identified 109 alleles. We found a highly significant genetic differentiation among the 25 populations (global FST = 0.506, global FST {ENA} = 0.473 and a low genetic diversity in each population. In addition, genetic diversity of the red form mites was found to be higher than the green form. Pearson correlations between statistics of variation (AR and HE and geographic coordinates (latitude and longitude showed that the genetic diversity of the red form was correlated with latitude. Using Bayesian clustering, we divided the Chinese mite populations into five clades which were well congruent with their geographic distributions. Conclusions Spider mites possess low levels of genetic diversity, limit gene flow between populations and significant and IBD (isolation by distance effect. These factors in turn contribute to the strong subdivision of genetic structure. In addition, population genetic structure results don't support the separation of the two forms of spider mite into two species. The morphological differences between the two forms of mites may be a result of epigenetic effects.

  6. Breed predisposition to canine gastric carcinoma

    DEFF Research Database (Denmark)

    Seim-Wikse, Tonje; Jörundsson, Einar; Nødtvedt, Ane

    2013-01-01

    Previous research has indicated a breed predisposition to gastric carcinoma in dogs. However, results to date are inconsistent since several studies have failed to prove such a predisposition. Better knowledge of breeds at risk could facilitate early detection of gastric carcinoma in dogs. The aim...

  7. Pubertal onset in girls is strongly influenced by genetic variation affecting FSH action

    DEFF Research Database (Denmark)

    Hagen, Casper P; Sørensen, Kaspar; Aksglaede, Lise

    2014-01-01

    Age at pubertal onset varies substantially in healthy girls. Although genetic factors are responsible for more than half of the phenotypic variation, only a small part has been attributed to specific genetic polymorphisms identified so far. Follicle-stimulating hormone (FSH) stimulates ovarian...... follicle maturation and estradiol synthesis which is responsible for breast development. We assessed the effect of three polymorphisms influencing FSH action on age at breast deveopment in a population-based cohort of 964 healthy girls. Girls homozygous for FSHR -29AA (reduced FSH receptor expression...

  8. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

    International Nuclear Information System (INIS)

    Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram; Kerr, Iain D.; Min, Jinrong

    2015-01-01

    The crystal structure of the human MLH1 N-terminus is reported at 2.30 Å resolution. The overall structure is described along with an analysis of two clinically important mutations. Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants

  9. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram [University of Toronto, 101 College Street, Toronto, ON M5G 1L7 (Canada); Kerr, Iain D., E-mail: ikerr@myriad.com [Myriad Genetic Laboratories Inc., 320 Wakara Way, Salt Lake City, UT 84108 (United States); Min, Jinrong, E-mail: ikerr@myriad.com [University of Toronto, 101 College Street, Toronto, ON M5G 1L7 (Canada); University of Toronto, Toronto, ON M5G 1L7 (Canada)

    2015-07-28

    The crystal structure of the human MLH1 N-terminus is reported at 2.30 Å resolution. The overall structure is described along with an analysis of two clinically important mutations. Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants.

  10. The Impact of Familial Predisposition to Obesity and Cardiovascular Disease on Childhood Obesity

    Science.gov (United States)

    Nielsen, Louise Aas; Nielsen, Tenna Ruest Haarmark; Holm, Jens-Christian

    2015-01-01

    The prevalence of childhood obesity has reached alarming rates world-wide. The aetiology seems to be an interplay between genetic and environmental factors, and a surrogate measure of this complex interaction is suggested as familial predisposition. Familial predisposition to obesity and related cardiovascular disease (CVD) complications constitute the presence of obesity and/or obesity-related complications in primarily blood-related family members. The approaches of its measurement and applicability vary, and the evidence especially of its influence on obesity and obesity treatment in childhood is limited. Studies have linked a familial predisposition of obesity, CVD (hypertension, dyslipidaemia and thromboembolic events), and type 2 diabetes mellitus to BMI as well as other adiposity measures in children, suggesting degrees of familial aggregation of metabolic derangements. A pattern of predispositions arising from mothers, parents or grandparents as being most influential have been found, but further comprehensive studies are needed in order to specify the exact implications of familial predisposition. In the scope of childhood obesity this article reviews the current literature regarding familial predisposition to obesity and obesity-related complications, and how these familial predispositions may impact obesity in the offspring. PMID:26465142

  11. Mitochondrial dysfunction in DDR-related cancer predisposition syndromes.

    Science.gov (United States)

    Lyakhovich, Alex; Graifer, Dmitry; Stefanovie, Barbora; Krejci, Lumir

    2016-04-01

    Given the key role of mitochondria in various cellular events, it is not surprising that mitochondrial dysfunction (MDF) is seen in many pathological conditions, in particular cancer. The mechanisms defining MDF are not clearly understood and may involve genetic defects, misbalance of reactive oxygen species (ROS), impaired autophagy (mitophagy), acquired mutations in mitochondrial or nuclear DNA and inability of cells to cope with the consequences. The importance of MDF arises from its detection in the syndromes with defective DNA damage response (DDR) and cancer predisposition. Here, we will focus on the dual role of these syndromes in cancer predisposition and MDF with specific emphasis on impaired autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Genetic epidemiology of coronary artery disease: an Asian Indian ...

    Indian Academy of Sciences (India)

    It is a matter of great interest to understand the role of genetic factors in ethnic populations that have a strong underlying predisposition to CAD such as the South Asian populations, particularly among Asian Indians living in India and abroad. Although, a number of isolated studies do implicate certain gene polymorphisms ...

  13. A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea.

    Science.gov (United States)

    Bergström, Anders; Oppenheimer, Stephen J; Mentzer, Alexander J; Auckland, Kathryn; Robson, Kathryn; Attenborough, Robert; Alpers, Michael P; Koki, George; Pomat, William; Siba, Peter; Xue, Yali; Sandhu, Manjinder S; Tyler-Smith, Chris

    2017-09-15

    New Guinea shows human occupation since ~50 thousand years ago (ka), independent adoption of plant cultivation ~10 ka, and great cultural and linguistic diversity today. We performed genome-wide single-nucleotide polymorphism genotyping on 381 individuals from 85 language groups in Papua New Guinea and find a sharp divide originating 10 to 20 ka between lowland and highland groups and a lack of non-New Guinean admixture in the latter. All highlanders share ancestry within the last 10 thousand years, with major population growth in the same period, suggesting population structure was reshaped following the Neolithic lifestyle transition. However, genetic differentiation between groups in Papua New Guinea is much stronger than in comparable regions in Eurasia, demonstrating that such a transition does not necessarily limit the genetic and linguistic diversity of human societies. Copyright © 2017, American Association for the Advancement of Science.

  14. A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea

    Science.gov (United States)

    Bergström, Anders; Oppenheimer, Stephen J; Mentzer, Alexander J; Auckland, Kathryn; Robson, Kathryn; Attenborough, Robert; Alpers, Michael P; Koki, George; Pomat, William; Siba, Peter; Xue, Yali; Sandhu, Manjinder S; Tyler-Smith, Chris

    2018-01-01

    New Guinea shows human occupation since ~50 thousand years ago (kya), independent adoption of plant cultivation ~10 kya, and great cultural and linguistic diversity today. We performed genome-wide SNP genotyping on 381 individuals from 85 language groups in Papua New Guinea (PNG) and find a sharp divide originating 10-20 kya between lowland and highland groups, and a lack of non-New Guinean admixture in the latter. All highlanders share ancestry within the last 10 kya, with major population growth in the same period, suggesting population structure was reshaped following the Neolithic lifestyle transition. However, genetic differentiation between groups in PNG is much stronger than in comparable regions in Eurasia, demonstrating that such a transition does not necessarily limit the genetic and linguistic diversity of human societies. PMID:28912245

  15. Candidate genes detected in transcriptome studies are strongly dependent on genetic background.

    Directory of Open Access Journals (Sweden)

    Pernille Sarup

    2011-01-01

    Full Text Available Whole genome transcriptomic studies can point to potential candidate genes for organismal traits. However, the importance of potential candidates is rarely followed up through functional studies and/or by comparing results across independent studies. We have analysed the overlap of candidate genes identified from studies of gene expression in Drosophila melanogaster using similar technical platforms. We found little overlap across studies between putative candidate genes for the same traits in the same sex. Instead there was a high degree of overlap between different traits and sexes within the same genetic backgrounds. Putative candidates found using transcriptomics therefore appear very sensitive to genetic background and this can mask or override effects of treatments. The functional importance of putative candidate genes emerging from transcriptome studies needs to be validated through additional experiments and in future studies we suggest a focus on the genes, networks and pathways affecting traits in a consistent manner across backgrounds.

  16. Winemaking and bioprocesses strongly shaped the genetic diversity of the ubiquitous yeast Torulaspora delbrueckii.

    Directory of Open Access Journals (Sweden)

    Warren Albertin

    Full Text Available The yeast Torulaspora delbrueckii is associated with several human activities including oenology, bakery, distillery, dairy industry, etc. In addition to its biotechnological applications, T. delbrueckii is frequently isolated in natural environments (plant, soil, insect. T. delbrueckii is thus a remarkable ubiquitous yeast species with both wild and anthropic habitats, and appears to be a perfect yeast model to search for evidence of human domestication. For that purpose, we developed eight microsatellite markers that were used for the genotyping of 110 strains from various substrates and geographical origins. Microsatellite analysis showed four genetic clusters: two groups contained most nature strains from Old World and Americas respectively, and two clusters were associated with winemaking and other bioprocesses. Analysis of molecular variance (AMOVA confirmed that human activities significantly shaped the genetic variability of T. delbrueckii species. Natural isolates are differentiated on the basis of geographical localisation, as expected for wild population. The domestication of T. delbrueckii probably dates back to the Roman Empire for winemaking (∼ 1900 years ago, and to the Neolithic era for bioprocesses (∼ 4000 years ago. Microsatellite analysis also provided valuable data regarding the life-cycle of the species, suggesting a mostly diploid homothallic life. In addition to population genetics and ecological studies, the microsatellite tool will be particularly useful for further biotechnological development of T. delbrueckii strains for winemaking and other bioprocesses.

  17. Winemaking and bioprocesses strongly shaped the genetic diversity of the ubiquitous yeast Torulaspora delbrueckii.

    Science.gov (United States)

    Albertin, Warren; Chasseriaud, Laura; Comte, Guillaume; Panfili, Aurélie; Delcamp, Adline; Salin, Franck; Marullo, Philippe; Bely, Marina

    2014-01-01

    The yeast Torulaspora delbrueckii is associated with several human activities including oenology, bakery, distillery, dairy industry, etc. In addition to its biotechnological applications, T. delbrueckii is frequently isolated in natural environments (plant, soil, insect). T. delbrueckii is thus a remarkable ubiquitous yeast species with both wild and anthropic habitats, and appears to be a perfect yeast model to search for evidence of human domestication. For that purpose, we developed eight microsatellite markers that were used for the genotyping of 110 strains from various substrates and geographical origins. Microsatellite analysis showed four genetic clusters: two groups contained most nature strains from Old World and Americas respectively, and two clusters were associated with winemaking and other bioprocesses. Analysis of molecular variance (AMOVA) confirmed that human activities significantly shaped the genetic variability of T. delbrueckii species. Natural isolates are differentiated on the basis of geographical localisation, as expected for wild population. The domestication of T. delbrueckii probably dates back to the Roman Empire for winemaking (∼ 1900 years ago), and to the Neolithic era for bioprocesses (∼ 4000 years ago). Microsatellite analysis also provided valuable data regarding the life-cycle of the species, suggesting a mostly diploid homothallic life. In addition to population genetics and ecological studies, the microsatellite tool will be particularly useful for further biotechnological development of T. delbrueckii strains for winemaking and other bioprocesses.

  18. Strongly enhanced colorectal cancer risk stratification by combining family history and genetic risk score

    Directory of Open Access Journals (Sweden)

    Weigl K

    2018-01-01

    Full Text Available Korbinian Weigl,1,2 Jenny Chang-Claude,3,4 Phillip Knebel,5 Li Hsu,6 Michael Hoffmeister,1 Hermann Brenner1,2,7 1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ, Heidelberg, 2German Cancer Consortium (DKTK, German Cancer Research Center (DKFZ, Heidelberg, 3Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ, Heidelberg, 4University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, 5Department for General, Visceral and Transplantation Surgery, University Heidelberg, Heidelberg, Germany; 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 7Division of Preventive Oncology, German Cancer Research Center (DKFZ and National Center for Tumor Diseases (NCT, Heidelberg, Germany Background and aim: Family history (FH and genetic risk scores (GRSs are increasingly used for risk stratification for colorectal cancer (CRC screening. However, they were mostly considered alternatively rather than jointly. The aim of this study was to assess the potential of individual and joint risk stratification for CRC by FH and GRS.Patients and methods: A GRS was built based on the number of risk alleles in 53 previously identified single-nucleotide polymorphisms among 2,363 patients with a first diagnosis of CRC and 2,198 controls in DACHS [colorectal cancer: chances for prevention through screening], a population-based case-control study in Germany. Associations between GRS and FH with CRC risk were quantified by multiple logistic regression.Results: A total of 316 cases (13.4% and 214 controls (9.7% had a first-degree relative (FDR with CRC (adjusted odds ratio [aOR] 1.86, 95% CI 1.52–2.29. A GRS in the highest decile was associated with a 3.0-fold increased risk of CRC (aOR 3.00, 95% CI 2.24–4.02 compared with the lowest decile. This association was tentatively more pronounced in older age groups. FH and GRS were essentially unrelated, and their

  19. Automatic Creation of Machine Learning Workflows with Strongly Typed Genetic Programming

    Czech Academy of Sciences Publication Activity Database

    Křen, T.; Pilát, M.; Neruda, Roman

    2017-01-01

    Roč. 26, č. 5 (2017), č. článku 1760020. ISSN 0218-2130 R&D Projects: GA ČR GA15-19877S Grant - others:GA MŠk(CZ) LM2015042 Institutional support: RVO:67985807 Keywords : genetic programming * machine learning workflows * asynchronous evolutionary algorithm Subject RIV: IN - Informatics, Computer Science OBOR OECD: Computer sciences, information science, bioinformathics (hardware development to be 2.2, social aspect to be 5.8) Impact factor: 0.778, year: 2016

  20. A Strong Impact of Genetic Background on Gut Microflora in Mice

    Directory of Open Access Journals (Sweden)

    R. Steven Esworthy

    2010-01-01

    Full Text Available Genetic background affects susceptibility to ileocolitis in mice deficient in two intracellular glutathione peroxidases, GPx1 and GPx2. The C57BL/6 (B6 GPx1/2 double-knockout (DKO mice have mild ileocolitis, and 129S1/Sv (129 DKO mice have severe inflammation. We used diet to modulate ileocolitis; a casein-based defined diet with AIN76A micronutrients (AIN attenuates inflammation compared to conventional LabDiets. Because luminal microbiota induce DKO ileocolitis, we assessed bacterial composition with automated ribosomal intergenic-spacer analysis (ARISA on cecal DNA. We found that mouse strain had the strongest impact on the composition of microbiota than diet and GPx genotypes. In comparing AIN and LabDiet, DKO mice were more resistant to change than the non-DKO or WT mice. However, supplementing yeast and inulin to AIN diet greatly altered microflora profiles in the DKO mice. From 129 DKO strictly, we found overgrowth of Escherichia coli. We conclude that genetic background predisposes mice to colonization of potentially pathogenic E. coli.

  1. Self-Conscious Shyness: Growth during Toddlerhood, Strong Role of Genetics, and No Prediction from Fearful Shyness.

    Science.gov (United States)

    Eggum-Wilkens, Natalie D; Lemery-Chalfant, Kathryn; Aksan, Nazan; Goldsmith, H Hill

    2015-01-01

    Fearful and self-conscious subtypes of shyness have received little attention in the empirical literature. Study aims included: 1) determining if fearful shyness predicted self-conscious shyness, 2) describing development of self-conscious shyness, and 3) examining genetic and environmental contributions to fearful and self-conscious shyness. Observed self-conscious shyness was examined at 19, 22, 25, and 28 months in same-sex twins (MZ = 102, DZ = 111, missing zygosity = 3 pairs). Self-conscious shyness increased across toddlerhood, but onset was earlier than predicted by theory. Fearful shyness (observed [6 and 12 months] and parents' reports [12 and 22 months]) was not predictive of self-conscious shyness. Independent genetic factors made strong contributions to parent-reported (but not observed) fearful shyness (additive genetic influence = .69 and .72 at 12 and 22 months, respectively) and self-conscious shyness (additive genetic influence = .90 for the growth model intercept). Results encourage future investigation of patterns of change and interrelations in shyness subtypes.

  2. Strong genetic structure corresponds to small-scale geographic breaks in the Australian alpine grasshopper Kosciuscola tristis.

    Science.gov (United States)

    Slatyer, Rachel A; Nash, Michael A; Miller, Adam D; Endo, Yoshinori; Umbers, Kate D L; Hoffmann, Ary A

    2014-10-02

    Mountain landscapes are topographically complex, creating discontinuous 'islands' of alpine and sub-alpine habitat with a dynamic history. Changing climatic conditions drive their expansion and contraction, leaving signatures on the genetic structure of their flora and fauna. Australia's high country covers a small, highly fragmented area. Although the area is thought to have experienced periods of relative continuity during Pleistocene glacial periods, small-scale studies suggest deep lineage divergence across low-elevation gaps. Using both DNA sequence data and microsatellite markers, we tested the hypothesis that genetic partitioning reflects observable geographic structuring across Australia's mainland high country, in the widespread alpine grasshopper Kosciuscola tristis (Sjösted). We found broadly congruent patterns of regional structure between the DNA sequence and microsatellite datasets, corresponding to strong divergence among isolated mountain regions. Small and isolated mountains in the south of the range were particularly distinct, with well-supported divergence corresponding to climate cycles during the late Pliocene and Pleistocene. We found mixed support, however, for divergence among other mountain regions. Interestingly, within areas of largely contiguous alpine and sub-alpine habitat around Mt Kosciuszko, microsatellite data suggested significant population structure, accompanied by a strong signature of isolation-by-distance. Consistent patterns of strong lineage divergence among different molecular datasets indicate genetic breaks between populations inhabiting geographically distinct mountain regions. Three primary phylogeographic groups were evident in the highly fragmented Victorian high country, while within-region structure detected with microsatellites may reflect more recent population isolation. Despite the small area of Australia's alpine and sub-alpine habitats, their low topographic relief and lack of extensive glaciation

  3. Human cancer predisposition and the implications for radiological protection

    International Nuclear Information System (INIS)

    Cox, R.

    1994-01-01

    It is well established from clinical, epidemiological and laboratory studies that specific human germ line mutation can predispose to spontaneously arising cancer. Some of the responsible genes have been characterized at the molecular level and evidence is rapidly accumulating on mechanistic aspects of the problem. A major outstanding issue is the extent to which genetically determined cancer predisposition in man interacts with exposures to environmental genotoxic agents such as ionizing radiation. This brief review considers the current position regarding the different forms and frequencies of cancer-predisposing mutations in the human population and provides an interim view of the possible implications for protection of man from ionizing radiation. (author)

  4. Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer.

    Science.gov (United States)

    Couch, Fergus J; Shimelis, Hermela; Hu, Chunling; Hart, Steven N; Polley, Eric C; Na, Jie; Hallberg, Emily; Moore, Raymond; Thomas, Abigail; Lilyquist, Jenna; Feng, Bingjian; McFarland, Rachel; Pesaran, Tina; Huether, Robert; LaDuca, Holly; Chao, Elizabeth C; Goldgar, David E; Dolinsky, Jill S

    2017-09-01

    Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined. To determine the risks of breast cancer associated with germline variants in cancer predisposition genes. A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016. Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes. The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer. This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among

  5. Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS) : Protocol for a prospective, observational, multicentre study

    NARCIS (Netherlands)

    Postema, Floor A M; Hopman, Saskia M J; De Borgie, Corianne A J M; Hammond, Peter; Hennekam, Raoul C.; Merks, Johannes H M; Aalfs, Cora M.; Anninga, Jakob K.; Berger, Lieke P V; Bleeker, Fonnet E.; De Bont, Eveline S J M; Dommering, Charlotte J.; Van Eijkelenburg, Natasha K A; Van Den Heuvel-Eibrink, Marry M.; Jongmans, Marjolijn C J; Kors, Wijnanda A.; Letteboer, Tom G W; Loeffen, Jan L C M; Olderode-Berends, Maran J W; Wagner, Anja

    2017-01-01

    Introduction: Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard

  6. Quantification of genetically modified soya using strong anion exchange chromatography and time-of-flight mass spectrometry.

    Science.gov (United States)

    Chang, Po-Chih; Reddy, P Muralidhar; Ho, Yen-Peng

    2014-09-01

    Stable-isotope dimethyl labeling was applied to the quantification of genetically modified (GM) soya. The herbicide-resistant gene-related protein 5-enolpyruvylshikimate-3-phosphate synthase (CP4 EPSPS) was labeled using a dimethyl labeling reagent, formaldehyde-H2 or -D2. The identification and quantification of CP4 EPSPS was performed using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The CP4 EPSPS protein was separated from high abundance proteins using strong anion exchange chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Then, the tryptic peptides from the samples and reference were labeled with formaldehyde-H2 and formaldehyde-D2, respectively. The two labeled pools were mixed and analyzed using MALDI-MS. The data showed a good correlation between the peak ratio of the H- and D-labeled peptides and the GM soya percentages at 0.5, 1, 3, and 5 %, with R (2) of 0.99. The labeling reagents are readily available. The labeling experiments and the detection procedures are simple. The approach is useful for the quantification of GM soya at a level as low as 0.5 %.

  7. Genetic evidence strongly support an essential role for PfPV1 in intra-erythrocytic growth of P. falciparum.

    Directory of Open Access Journals (Sweden)

    Trang Chu

    Full Text Available Upon invading the host erythrocyte, the human malaria parasite P. falciparum lives and replicates within a membrane bound compartment referred to as the parasitophorous vacuole. Recently, interest in this compartment and its protein content has grown, due to the important roles these play in parasite egress and protein traffic to the host cell. Surprisingly, the function of many proteins within this compartment has not been experimentally addressed. Here, we study the importance of one of these proteins, termed PfPV1, for intra-erythrocytic parasite survival. Despite numerous attempts to inactivate the gene encoding PfPV1, we were unable to recover deletion mutants. Control experiments verified that the pv1 gene locus was per se open for gene targeting experiments, allowing us to exclude technical limitations in our experimental strategy. Our data provide strong genetic evidence that PfPV1 is essential for survival of blood stage P. falciparum, and further highlight the importance of parasitophorous vacuole proteins in this part of the parasite's life cycle.

  8. Objectively Measured Physical Activity, Sedentary Behavior, and Genetic Predisposition to Obesity in U.S. Hispanics/Latinos: Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

    Science.gov (United States)

    Moon, Jee-Young; Wang, Tao; Sofer, Tamar; North, Kari E; Isasi, Carmen R; Cai, Jianwen; Gellman, Marc D; Moncrieft, Ashley E; Sotres-Alvarez, Daniela; Argos, Maria; Kaplan, Robert C; Qi, Qibin

    2017-12-01

    Studies using self-reported data suggest a gene-physical activity interaction on obesity, yet the influence of sedentary behavior, distinct from a lack of physical activity, on genetic associations with obesity remains unclear. We analyzed interactions of accelerometer-measured moderate to vigorous physical activity (MVPA) and time spent sedentary with genetic variants on obesity among 9,645 U.S. Hispanics/Latinos. An overall genetic risk score (GRS), a central nervous system (CNS)-related GRS, and a non-CNS-related GRS were calculated based on 97 BMI-associated single nucleotide polymorphisms (SNPs). Genetic association with BMI was stronger in individuals with lower MVPA (first tertile) versus higher MVPA (third tertile) (β = 0.78 kg/m 2 [SE, 0.10 kg/m 2 ] vs. 0.39 kg/m 2 [0.09 kg/m 2 ] per SD increment of GRS; P interaction = 0.005), and in those with more time spent sedentary (third tertile) versus less time spent sedentary (first tertile) (β = 0.73 kg/m 2 [SE, 0.10 kg/m 2 ] vs. 0.44 kg/m 2 [0.09 kg/m 2 ]; P interaction = 0.006). Similar significant interaction patterns were observed for obesity risk, body fat mass, fat percentage, fat mass index, and waist circumference, but not for fat-free mass. The CNS-related GRS, but not the non-CNS-related GRS, showed significant interactions with MVPA and sedentary behavior, with effects on BMI and other adiposity traits. Our data suggest that both increasing physical activity and reducing sedentary behavior may attenuate genetic associations with obesity, although the independence of these interaction effects needs to be investigated further. © 2017 by the American Diabetes Association.

  9. Genetic counselling and testing for inherited gene mutations in newly diagnosed patients with breast cancer: a review of the existing literature and a proposed research agenda

    OpenAIRE

    Meiser, Bettina; Tucker, Kathy; Friedlander, Michael; Barlow-Stewart, Kristine; Lobb, Elizabeth; Saunders, Christobel; Mitchell, Gillian

    2008-01-01

    Many women newly diagnosed with breast cancer and with a strong family history of breast cancer are referred to a family cancer service for genetic counselling and for consideration of genetic testing for germline mutations in cancer predisposition genes following completion of their cancer treatment. However, there is growing evidence that mutation status may influence treatment recommendations, and that there may be benefits in having 'treatment-focused genetic counselling and testing' avai...

  10. Alcohol consumption and its interaction with adiposity-associated genetic variants in relation to subsequent changes in waist circumference and body weight

    DEFF Research Database (Denmark)

    Rohde, Jeanett F.; Ängquist, Lars; Larsen, Sofus C.

    2017-01-01

    the association between alcohol intake recorded at baseline and subsequent annual changes in body weight (∆BW), waist circumference (ΔWC) and WC adjusted for BMI (ΔWCBMI), and to test for interaction with genetic predisposition scores based on single nucleotide polymorphisms (SNPs) associated with various forms...... interaction was observed among the men. CONCLUSION: Alcohol intake was associated with a decrease in BW and WC among men and women, and an increase in WCBMI among women only. We found no strong indication that these associations depend on a genetic predisposition to adiposity. TRIAL REGISTRATION: Registry......BACKGROUND: Studies have suggested a link between alcohol intake and adiposity. However, results from longitudinal studies have been inconsistent, and a possible interaction with genetic predisposition to adiposity measures has often not been taken into account. OBJECTIVE: To examine...

  11. The plant pathogen Pseudomonas syringae pv. tomato is genetically monomorphic and under strong selection to evade tomato immunity.

    Directory of Open Access Journals (Sweden)

    Rongman Cai

    2011-08-01

    Full Text Available Recently, genome sequencing of many isolates of genetically monomorphic bacterial human pathogens has given new insights into pathogen microevolution and phylogeography. Here, we report a genome-based micro-evolutionary study of a bacterial plant pathogen, Pseudomonas syringae pv. tomato. Only 267 mutations were identified between five sequenced isolates in 3,543,009 nt of analyzed genome sequence, which suggests a recent evolutionary origin of this pathogen. Further analysis with genome-derived markers of 89 world-wide isolates showed that several genotypes exist in North America and in Europe indicating frequent pathogen movement between these world regions. Genome-derived markers and molecular analyses of key pathogen loci important for virulence and motility both suggest ongoing adaptation to the tomato host. A mutational hotspot was found in the type III-secreted effector gene hopM1. These mutations abolish the cell death triggering activity of the full-length protein indicating strong selection for loss of function of this effector, which was previously considered a virulence factor. Two non-synonymous mutations in the flagellin-encoding gene fliC allowed identifying a new microbe associated molecular pattern (MAMP in a region distinct from the known MAMP flg22. Interestingly, the ancestral allele of this MAMP induces a stronger tomato immune response than the derived alleles. The ancestral allele has largely disappeared from today's Pto populations suggesting that flagellin-triggered immunity limits pathogen fitness even in highly virulent pathogens. An additional non-synonymous mutation was identified in flg22 in South American isolates. Therefore, MAMPs are more variable than expected differing even between otherwise almost identical isolates of the same pathogen strain.

  12. Seagrass radiation after Messinian salinity crisis reflected by strong genetic structuring and out-of-Africa scenario (Ruppiaceae.

    Directory of Open Access Journals (Sweden)

    Ludwig Triest

    Full Text Available Many aquatic plant and seagrass species are widespread and the origin of their continent-wide ranges might result from high gene flow levels. The response of species when extending northwards since the Last Glacial Maximum can be opposed to the structuring of their populations that survived glaciation cycles in southern regions. The peri-Mediterranean is a complex series of sea basins, coastlines, islands and river deltas with a unique history since the Messinian Crisis that potentially influenced allopatric processes of aquatic life. We tested whether vast ranges across Europe and the peri-Mediterranean of a global seagrass group (Ruppia species complexes can be explained by either overall high levels of gene flow or vicariance through linking population genetics, phylogeography and shallow phylogenetics. A multigene approach identified haplogroup lineages of two species complexes, of ancient and recent hybrids with most of the diversity residing in the South. High levels of connectivity over long distances were only observed at recently colonized northern ranges and in recently-filled seas following the last glaciation. A strong substructure in the southern Mediterranean explained an isolation-by-distance model across Europe. The oldest lineages of the southern Mediterranean Ruppia dated back to the period between the end of the Messinian and Late Pliocene. An imprint of ancient allopatric origin was left at basin level, including basal African lineages. Thus both vicariance in the South and high levels of connectivity in the North explained vast species ranges. Our findings highlight the need for interpreting global distributions of these seagrass and euryhaline species in the context of their origin and evolutionary significant units for setting up appropriate conservation strategies.

  13. Constant, cycling, hot and cold thermal environments: strong effects on mean viability but not on genetic estimates

    DEFF Research Database (Denmark)

    Ketola, Tarmo; Kellermann, Vanessa; Kristensen, Torsten Nygård

    2012-01-01

    and their fluctuations. How species will respond to these changes is uncertain, particularly as there is a lack of studies which compare genetic performances in constant vs. fluctuating environments. In this study, we used a nested full-sib/half-sib breeding design to examine how the genetic variances and heritabilities...

  14. Predisposición genética para el cáncer de mama: genes BRCA1 y BRCA2 Genetic predisposition for breast cancer: BRCA1 and BRCA2 genes

    Directory of Open Access Journals (Sweden)

    Steven A Narod

    2011-10-01

    Full Text Available El descubrimiento de los genes BRCA1 y BRCA2 ha llevado a la introducción de pruebas genéticas cada vez más sofisticadas para medir el riesgo de cáncer de mama de origen hereditario, entre otras cosas. En el presente artículo exploramos los criterios a seguir para realizar pruebas para estos genes, así como las implicaciones en el tratamiento para los pacientes en caso de identificarlos.The discovery of genes BRCA1 and BRCA2 has led to the introduction of genetic tests more complex every time for the evaluation ofthehereditarycancerrisk,amongothers.In the present paper we explore the criteria to decide when to run the testing for the genes, as well as the implications for the treatment of patients who are identified with them.

  15. A rapid, strong, and convergent genetic response to urban habitat fragmentation in four divergent and widespread vertebrates

    Science.gov (United States)

    Delaney, Kathleen Semple; Riley, Seth P.D.; Fisher, Robert N.

    2010-01-01

    Background: Urbanization is a major cause of habitat fragmentation worldwide. Ecological and conservation theory predicts many potential impacts of habitat fragmentation on natural populations, including genetic impacts. Habitat fragmentation by urbanization causes populations of animals and plants to be isolated in patches of suitable habitat that are surrounded by non-native vegetation or severely altered vegetation, asphalt, concrete, and human structures. This can lead to genetic divergence between patches and in turn to decreased genetic diversity within patches through genetic drift and inbreeding. Methodology/Principal Findings: We examined population genetic patterns using microsatellites in four common vertebrate species, three lizards and one bird, in highly fragmented urban southern California. Despite significant phylogenetic, ecological, and mobility differences between these species, all four showed similar and significant reductions in gene flow over relatively short geographic and temporal scales. For all four species, the greatest genetic divergence was found where development was oldest and most intensive. All four animals also showed significant reduction in gene flow associated with intervening roads and freeways, the degree of patch isolation, and the time since isolation. Conclusions/Significance: Despite wide acceptance of the idea in principle, evidence of significant population genetic changes associated with fragmentation at small spatial and temporal scales has been rare, even in smaller terrestrial vertebrates, and especially for birds. Given the striking pattern of similar and rapid effects across four common and widespread species, including a volant bird, intense urbanization may represent the most severe form of fragmentation, with minimal effective movement through the urban matrix.

  16. A rapid, strong, and convergent genetic response to urban habitat fragmentation in four divergent and widespread vertebrates.

    Directory of Open Access Journals (Sweden)

    Kathleen Semple Delaney

    2010-09-01

    Full Text Available Urbanization is a major cause of habitat fragmentation worldwide. Ecological and conservation theory predicts many potential impacts of habitat fragmentation on natural populations, including genetic impacts. Habitat fragmentation by urbanization causes populations of animals and plants to be isolated in patches of suitable habitat that are surrounded by non-native vegetation or severely altered vegetation, asphalt, concrete, and human structures. This can lead to genetic divergence between patches and in turn to decreased genetic diversity within patches through genetic drift and inbreeding.We examined population genetic patterns using microsatellites in four common vertebrate species, three lizards and one bird, in highly fragmented urban southern California. Despite significant phylogenetic, ecological, and mobility differences between these species, all four showed similar and significant reductions in gene flow over relatively short geographic and temporal scales. For all four species, the greatest genetic divergence was found where development was oldest and most intensive. All four animals also showed significant reduction in gene flow associated with intervening roads and freeways, the degree of patch isolation, and the time since isolation.Despite wide acceptance of the idea in principle, evidence of significant population genetic changes associated with fragmentation at small spatial and temporal scales has been rare, even in smaller terrestrial vertebrates, and especially for birds. Given the striking pattern of similar and rapid effects across four common and widespread species, including a volant bird, intense urbanization may represent the most severe form of fragmentation, with minimal effective movement through the urban matrix.

  17. A rapid, strong, and convergent genetic response to urban habitat fragmentation in four divergent and widespread vertebrates.

    Science.gov (United States)

    Delaney, Kathleen Semple; Riley, Seth P D; Fisher, Robert N

    2010-09-16

    Urbanization is a major cause of habitat fragmentation worldwide. Ecological and conservation theory predicts many potential impacts of habitat fragmentation on natural populations, including genetic impacts. Habitat fragmentation by urbanization causes populations of animals and plants to be isolated in patches of suitable habitat that are surrounded by non-native vegetation or severely altered vegetation, asphalt, concrete, and human structures. This can lead to genetic divergence between patches and in turn to decreased genetic diversity within patches through genetic drift and inbreeding. We examined population genetic patterns using microsatellites in four common vertebrate species, three lizards and one bird, in highly fragmented urban southern California. Despite significant phylogenetic, ecological, and mobility differences between these species, all four showed similar and significant reductions in gene flow over relatively short geographic and temporal scales. For all four species, the greatest genetic divergence was found where development was oldest and most intensive. All four animals also showed significant reduction in gene flow associated with intervening roads and freeways, the degree of patch isolation, and the time since isolation. Despite wide acceptance of the idea in principle, evidence of significant population genetic changes associated with fragmentation at small spatial and temporal scales has been rare, even in smaller terrestrial vertebrates, and especially for birds. Given the striking pattern of similar and rapid effects across four common and widespread species, including a volant bird, intense urbanization may represent the most severe form of fragmentation, with minimal effective movement through the urban matrix.

  18. Familial predisposition to anterior cruciate ligament injury

    Directory of Open Access Journals (Sweden)

    Kenichi Goshima

    2014-04-01

    Full Text Available Although several risk factors for anterior cruciate ligament (ACL injury have been evaluated in the literature, there are few reports on familial predisposition. This study investigated the familial predisposition to ACL injury. The study included 350 patients who underwent ACL reconstruction between January 2005 and September 2008. All patients were surveyed by telephone or a written questionnaire about family history (FH of ACL injury, sports played by family members, and mechanisms of injury. We also compared age, sex, height, weight, body mass index, Tegner activity score, general joint laxity, and tibial slope between an FH group (with FH and a control group (without FH. In addition, we compared the incidence of ACL graft rupture and contralateral ACL rupture 2 years after primary surgery. Complete information was obtained from 316 patients, 38 (12.0% of whom had FH of ACL injury. Two families had three members with ACL injuries. Of the 40 family members with ACL injuries, 38 (95% had noncontact injuries and 34 (85% shared a similar mechanism of injury with the related patient. No significant differences were identified between the two groups, except that tibial slope was significantly greater in the FH group than in the control group. Although the incidence of repeat ACL injury was greater in the FH group (23.7% than in the control group (16.4%, there was no significant difference. Our results indicated a high probability of familial predisposition to many of the identified risk factors for ACL injury. In addition, patients with FH of ACL injury might be at high risk for initial and repeat ACL injuries. Therefore, prevention programs should be implemented for patients with FH of ACL injury in order to decrease the risk of these injuries.

  19. Le diabete de type 1: de la predisposition genetique a un contexte environnemental hypothetique.

    OpenAIRE

    Phlips, J.-C.; Radermecker, Régis

    2012-01-01

    Type 1 diabetes is an autoimmune disease that results in a progressive (complete in most cases) destruction of insulin-secreting beta cells from Langerhans islets. Even if the autoimmune process becomes to be well known, no one is yet sure what specifically prompts the autoimmune response that destroys the body's ability to produce insulin. Etiology of this complex disease combines a genetic predisposition and still (almost) unknown environmental factors that trigger autoimmuninty specificall...

  20. Chromosomal radiosensitivity, cancer predisposition and response to radiotherapy

    International Nuclear Information System (INIS)

    Scott, D.

    2000-01-01

    Aim: This paper briefly summarizes the research on this topic, undertaken in the Department of Cancer Genetics, Paterson Institute for Cancer Research, Manchester, England, over the previous 6 years. We have investigated the possible role of radiosensitivity as a marker of cancer predisposition and response to radiotherapy in the general population. Results: We found that 42% (57/135) of breast cancer patients exhibit chromosomal radiosensitivity when lymphocytes are irradiated in the G 2 phase of the cell cycle, compared with 6% (6/105) of healthy controls. These figures are much higher than the estimated frequencies of carriers of the ataxia-telangiectasia gene (heterozygotes) amongst breast cancer patients ( 2 sensitivity by studying relatives of breast cancer cases. The pattern of inheritance is relatively simple and attributable to 1 or 2 genes segregating in each family. In a prospective study of 123 breast cancer patients, 9 (7%) had severe acute reactions to radiotherapy and their mean G 2 sensitivity was significantly greater (p=0.001) than that of the remaining patients. In 16 patients with adverse acute reactions we found no mutations of the ataxia-telangiectasia gene (ATM). Using another chromosomal assay (micronucleus induction in G 0 lymphocytes) we found that the mean radiosensitivity of patients with severe late reactions was higher than that of normal reactors. For example, 8 patients with severe fibrosis were more sensitive (p=0.055) than 39 patients with a normal response. However, the discriminatory power of these chromosomal assays is too low for them to be used alone in a clinical setting. Conclusion: Our results provide good evidence that genes other than ATM, that confer chromosomal radiosensitivity, are involved in low penetrance predisposition to breast cancer in a high proportion of cases and contribute to adverse reactions after radiotherapy. (orig.) [de

  1. Influence of the larval phase on connectivity: strong differences in the genetic structure of brooders and broadcasters in the Ophioderma longicauda species complex.

    Science.gov (United States)

    Weber, A A-T; Mérigot, B; Valière, S; Chenuil, A

    2015-12-01

    Closely related species with divergent life history traits are excellent models to infer the role of such traits in genetic diversity and connectivity. Ophioderma longicauda is a brittle star species complex composed of different genetic clusters, including brooders and broadcasters. These species diverged very recently and some of them are sympatric and ecologically syntopic, making them particularly suitable to study the consequences of their trait differences. At the scale of the geographic distribution of the broadcasters (Mediterranean Sea and northeastern Atlantic), we sequenced the mitochondrial marker COI and genotyped an intron (i51) for 788 individuals. In addition, we sequenced 10 nuclear loci newly developed from transcriptome sequences, for six sympatric populations of brooders and broadcasters from Greece. At the large scale, we found a high genetic structure within the brooders (COI: 0.07 lecithotrophic larval stage allows on average a 50-fold increase in migration rates, a 280-fold increase in effective size and a threefold to fourfold increase in genetic diversity. Our work, investigating complementary genetic markers on sympatric and syntopic taxa, highlights the strong impact of the larval phase on connectivity and genetic diversity. © 2015 John Wiley & Sons Ltd.

  2. No Genetic Diversity at Molecular Markers and Strong Phenotypic Plasticity in Populations of Ranunculus nodiflorus, an Endangered Plant Species in France

    Science.gov (United States)

    Noel, Florence; Machon, Nathalie; Porcher, Emmanuelle

    2007-01-01

    Background and Aims Although conservation biology has long focused on population dynamics and genetics, phenotypic plasticity is likely to play a significant role in population viability. Here, an investigation is made into the relative contribution of genetic diversity and phenotypic plasticity to the phenotypic variation in natural populations of Ranunculus nodiflorus, a rare annual plant inhabiting temporary puddles in the Fontainebleau forest (Paris region, France) and exhibiting metapopulation dynamics. Methods The genetic diversity and phenotypic plasticity of quantitative traits (morphological and fitness components) were measured in five populations, using a combination of field measurements, common garden experiments and genotyping at microsatellite loci. Key Results It is shown that populations exhibit almost undetectable genetic diversity at molecular markers, and that the variation in quantitative traits observed among populations is due to a high level of phenotypic plasticity. Despite the lack of genetic diversity, the natural population of R. nodiflorus exhibits large population sizes and does not appear threatened by extinction; this may be attributable to large phenotypic plasticity, enabling the production of numerous seeds under a wide range of environmental conditions. Conclusions Efficient conservation of the populations can only be based on habitat management, to favour the maintenance of microenvironmental variation and the resulting strong phenotypic plasticity. In contrast, classical actions aiming to improve genetic diversity are useless in the present case. PMID:17468109

  3. Why Are High Altitude Natives So Strong at High Altitude? Nature vs. Nurture: Genetic Factors vs. Growth and Development.

    Science.gov (United States)

    Brutsaert, Tom

    Among high-altitude natives there is evidence of a general hypoxia tolerance leading to enhanced performance and/or increased capacity in several important domains. These domains likely include an enhanced physical work capacity, an enhanced reproductive capacity, and an ability to resist several common pathologies of chronic high-altitude exposure. The "strength" of the high-altitude native in this regard may have both a developmental and a genetic basis, although there is better evidence for the former (developmental effects) than for the latter. For example, early-life hypoxia exposure clearly results in lung growth and remodeling leading to an increased O2 diffusing capacity in adulthood. Genetic research has yet to reveal a population genetic basis for enhanced capacity in high-altitude natives, but several traits are clearly under genetic control in Andean and Tibetan populations e.g., resting and exercise arterial O2 saturation (SaO2). This chapter reviews the effects of nature and nurture on traits that are relevant to the process of gas exchange, including pulmonary volumes and diffusion capacity, the maximal oxygen consumption (VO2max), the SaO2, and the alveolar-arterial oxygen partial pressure difference (A-aDO2) during exercise.

  4. Strong genetic structure among coral populations within a conservation priority region, the Bird's Head Seascape (Papua, Indonesia

    Directory of Open Access Journals (Sweden)

    Craig John Starger

    2015-11-01

    Full Text Available Marine Protected Areas (MPAs are widely considered to be one of the best strategies available for protecting species diversity and ecosystem processes in marine environments. While data on connectivity and genetic structure of marine populations are critical to designing appropriately sized and spaced networks of MPAs, such data are rarely available. This study examines genetic structure in reef-building corals from Papua and West Papua, Indonesia, one of the most biodiverse and least disturbed coral reef regions in the world. We focused on two common reef-building corals, Pocillopora damicornis (Linnaeus 1758 and Seriatopora hystrix (family: Pocilloporidae, from three regions under different management regimes: Teluk Cenderawasih, Raja Ampat, and southwest Papua. Analyses of molecular variance, assignment tests, and genetical bandwidth mapping based on microsatellite variation revealed significant genetic structure in both species, although there were no clear regional filters to gene flow among regions. Overall, P. damicornis populations were less structured (FST = 0.139, p < 0.00001 than S. hystrix (FST = 0.357, p < 0.00001. Despite occurring in one of the most pristine marine habitats in Indonesia, populations of both species showed evidence of recent declines. Furthermore, exclusion of individual populations from connectivity analyses resulted in marked increases in self-recruitment. Maintaining connectivity within and among regions of Eastern Indonesia will require coral conservation on the local scales and regional networks of MPAs. 

  5. Strong population genetic structuring in an annual fish, Nothobranchius furzeri, suggests multiple savannah refugia in southern Mozambique

    Czech Academy of Sciences Publication Activity Database

    Bartáková, V.; Reichard, M.; Janko, Karel; Polačik, M.; Blažek, R.; Reichwald, K.; Cellerino, A.; Bryja, J.

    2013-01-01

    Roč. 13, č. 196 (2013), s. 1-15 ISSN 1471-2148 Institutional support: RVO:67985904 Keywords : temporary pool * pyhlogeography * population genetics Subject RIV: EG - Zoology Impact factor: 3.407, year: 2013 http://www.biomedcentral.com/1471-2148/13/196

  6. Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC).

    Science.gov (United States)

    DiNardo, Courtney D; Bannon, Sarah A; Routbort, Mark; Franklin, Anna; Mork, Maureen; Armanios, Mary; Mace, Emily M; Orange, Jordan S; Jeff-Eke, Meselle; Churpek, Jane E; Takahashi, Koichi; Jorgensen, Jeffrey L; Garcia-Manero, Guillermo; Kornblau, Steve; Bertuch, Alison; Cheung, Hannah; Bhalla, Kapil; Futreal, Andrew; Godley, Lucy A; Patel, Keyur P

    2016-07-01

    Although multiple predispositions to hematologic malignancies exist, evaluations for hereditary cancer syndromes (HCS) are underperformed by most hematologist/oncologists. Criteria for initiating HCS evaluation are poorly defined, and results of genetic testing for hereditary hematologic malignancies have not been systematically reported. From April 2014 to August 2015, 67 patients were referred to the Hereditary Hematologic Malignancy Clinic (HHMC). Referral reasons included (1) bone marrow failure or myelodysplastic syndrome in patients ≤ 50 years, (2) evaluation for germ-line inheritance of identified RUNX1, GATA2, or CEBPA mutations on targeted next-generation sequencing panels, and (3) strong personal and/or family history of malignancy. Cultured skin fibroblasts were utilized for germ-line DNA in all patients with hematologic malignancy. Eight patients (12%) were clinically diagnosed with a HCS: 4 patients with RUNX1-related familial platelet disorder (FPD)/acute myeloid leukemia (AML), and 1 patient each with dyskeratosis congenita, Fanconi anemia, germ-line DDX41, and Li-Fraumeni syndrome (LFS). Two patients with concern for FPD/AML and LFS, respectively, had RUNX1 and TP53 variants of unknown significance. Additionally, 4 patients with prior HCS diagnosis (1 LFS, 3 FPD/AML) were referred for further evaluation and surveillance. In this HHMC-referred hematologic malignancy cohort, HCS was confirmed in 12 patients (18%). HCS identification provides insight for improved and individualized treatment, as well as screening/surveillance opportunities for family members. The HHMC has facilitated HCS diagnosis; with increased clinical awareness of hematologic malignancy predisposition syndromes, more patients who may benefit from evaluation can be identified. Mutation panels intended for prognostication may provide increased clinical suspicion for germ-line testing. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Population Genetics of the São Tomé Caecilian (Gymnophiona: Dermophiidae: Schistometopum thomense) Reveals Strong Geographic Structuring

    Science.gov (United States)

    Stoelting, Ricka E.; Measey, G. John; Drewes, Robert C.

    2014-01-01

    Islands provide exciting opportunities for exploring ecological and evolutionary mechanisms. The oceanic island of São Tomé in the Gulf of Guinea exhibits high diversity of fauna including the endemic caecilian amphibian, Schistometopum thomense. Variation in pigmentation, morphology and size of this taxon over its c. 45 km island range is extreme, motivating a number of taxonomic, ecological, and evolutionary hypotheses to explain the observed diversity. We conducted a population genetic study of S. thomense using partial sequences of two mitochondrial DNA genes (ND4 and 16S), together with morphological examination, to address competing hypotheses of taxonomic or clinal variation. Using Bayesian phylogenetic analysis and Spatial Analysis of Molecular Variance, we found evidence of four geographic clades, whose range and approximated age (c. 253 Kya – 27 Kya) are consistent with the spread and age of recent volcanic flows. These clades explained 90% of variation in ND4 (φCT = 0.892), and diverged by 4.3% minimum pairwise distance at the deepest node. Most notably, using Mismatch Distributions and Mantel Tests, we identified a zone of population admixture that dissected the island. In the northern clade, we found evidence of recent population expansion (Fu's Fs = −13.08 and Tajima's D = −1.80) and limited dispersal (Mantel correlation coefficient = 0.36, p = 0.01). Color assignment to clades was not absolute. Paired with multinomial regression of chromatic data, our analyses suggested that the genetic groups and a latitudinal gradient together describe variation in color of S. thomense. We propose that volcanism and limited dispersal ability are the likely proximal causes of the observed genetic structure. This is the first population genetic study of any caecilian and demonstrates that these animals have deep genetic divisions over very small areas in accordance with previous speculations of low dispersal abilities. PMID:25171066

  8. Self-Conscious Shyness: Growth during Toddlerhood, Strong Role of Genetics, and No Prediction from Fearful Shyness

    OpenAIRE

    Eggum-Wilkens, Natalie D.; Lemery-Chalfant, Kathryn; Aksan, Nazan; Goldsmith, H. Hill

    2014-01-01

    Fearful and self-conscious subtypes of shyness have received little attention in the empirical literature. Study aims included: 1) determining if fearful shyness predicted self-conscious shyness, 2) describing development of self-conscious shyness, and 3) examining genetic and environmental contributions to fearful and self-conscious shyness. Observed self-conscious shyness was examined at 19, 22, 25, and 28 months in same-sex twins (MZ = 102, DZ = 111, missing zygosity = 3 pairs). Self-consc...

  9. Strong population genetic structuring in an annual fish, Nothobranchius furzeri, suggests multiple savannah refugia in southern Mozambique

    Czech Academy of Sciences Publication Activity Database

    Bartáková, Veronika; Reichard, Martin; Janko, Karel; Polačik, Matej; Blažek, Radim; Reichwald, K.; Cellerino, A.; Bryja, Josef

    2013-01-01

    Roč. 13, č. 196 (2013), s. 196 ISSN 1471-2148 R&D Projects: GA ČR GA206/09/0815; GA ČR GBP505/12/G112 Institutional support: RVO:68081766 Keywords : Temporary pool * Phylogeography * Population genetics * Cyprinodontiformes * Senescence * Pluvials * Pleistocene climate changes * Dispersal * Founder effect * Killifish Subject RIV: EG - Zoology Impact factor: 3.407, year: 2013 http://www.biomedcentral.com/1471-2148/13/196

  10. Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood.

    Science.gov (United States)

    Abel, Laurent; Plancoulaine, Sabine; Jouanguy, Emmanuelle; Zhang, Shen-Ying; Mahfoufi, Nora; Nicolas, Nathalie; Sancho-Shimizu, Vanessa; Alcaïs, Alexandre; Guo, Yiqi; Cardon, Annabelle; Boucherit, Soraya; Obach, Dorothée; Clozel, Thomas; Lorenzo, Lazaro; Amsallem, Daniel; Berquin, Patrick; Blanc, Thierry; Bost-Bru, Cécile; Chabrier, Stéphane; Chabrol, Brigitte; Cheuret, Emmanuel; Dulac, Olivier; Evrard, Philippe; Héron, Bénédicte; Lazaro, Leila; Mancini, Josette; Pedespan, Jean-Michel; Rivier, François; Vallée, Louis; Lebon, Pierre; Rozenberg, Flore; Casanova, Jean-Laurent; Tardieu, Marc

    2010-10-01

    To test the hypothesis that predisposition to childhood herpes simplex virus (HSV) type 1 encephalitis (HSE) may be determined in part by human genetic factors. A genetic epidemiologic survey of childhood HSE (onset at age 3 months to 15 years) over a 20-year period (1985-2004) was conducted throughout France (comprising 29 university hospital neuropediatric centers). A total of 85 children fulfilled the diagnostic criteria for inclusion. Family and personal histories were obtained by face-to-face interview for 51 patients. No familial cases of HSE were identified in our survey; however, a high proportion (20%) of the children interviewed had a relevant family history: parental consanguinity (12% of patients), early-onset herpetic keratitis in a first-degree relative (6%), or both (2%). The narrow window of high susceptibility to HSE before age 3 years (62% of patients) further indicates that predisposition to HSE is tightly age-dependent. This survey suggests that childhood HSE, although sporadic, may result from Mendelian predisposition (from autosomal recessive susceptibility in particular), at least in some children. There likely is incomplete penetrance, however, which may reflect, at least in part, the impact of age at the time of HSV-1 infection. Copyright (c) 2010 Mosby, Inc. All rights reserved.

  11. Strong genetic influence on a UK nationwide test of educational achievement at the end of compulsory education at age 16.

    Science.gov (United States)

    Shakeshaft, Nicholas G; Trzaskowski, Maciej; McMillan, Andrew; Rimfeld, Kaili; Krapohl, Eva; Haworth, Claire M A; Dale, Philip S; Plomin, Robert

    2013-01-01

    We have previously shown that individual differences in educational achievement are highly heritable in the early and middle school years in the UK. The objective of the present study was to investigate whether similarly high heritability is found at the end of compulsory education (age 16) for the UK-wide examination, called the General Certificate of Secondary Education (GCSE). In a national twin sample of 11,117 16-year-olds, heritability was substantial for overall GCSE performance for compulsory core subjects (58%) as well as for each of them individually: English (52%), mathematics (55%) and science (58%). In contrast, the overall effects of shared environment, which includes all family and school influences shared by members of twin pairs growing up in the same family and attending the same school, accounts for about 36% of the variance of mean GCSE scores. The significance of these findings is that individual differences in educational achievement at the end of compulsory education are not primarily an index of the quality of teachers or schools: much more of the variance of GCSE scores can be attributed to genetics than to school or family environment. We suggest a model of education that recognizes the important role of genetics. Rather than a passive model of schooling as instruction (instruere, 'to build in'), we propose an active model of education (educare, 'to bring out') in which children create their own educational experiences in part on the basis of their genetic propensities, which supports the trend towards personalized learning.

  12. Analyses of historical and current populations of black grouse in Central Europe reveal strong effects of genetic drift and loss of genetic diversity

    NARCIS (Netherlands)

    Segelbacher, G.; Strand, T.M.; Quintela, M.; Axelsson, T.; Jansman, H.A.H.; Koelewijn, H.P.; Hoglund, J.

    2014-01-01

    Black grouse (Tetrao tetrix) in Central Europe have undergone a severe contraction of their range in recent decades with only a few small isolated remaining populations. Here we compare genetic diversity of two contemporary isolated populations (Sallandse Heuvelrug, Netherlands and Luneburger Heide,

  13. Genetic Susceptibility to Prostate Cancer in the Netherlands

    National Research Council Canada - National Science Library

    Ostrer, Harry

    2004-01-01

    Studies of the genetics of populations that were historically endogamous for reasons of geography, religion, or language have contributed substantially to our understanding about hereditary predisposition to cancer...

  14. Genetic Susceptibility to Prostate Cancer in the Netherlands

    National Research Council Canada - National Science Library

    Ostrer, Harry

    2001-01-01

    Studies of the genetics of populations that were historically endogamous for reasons of geography, religion, or language have contributed substantially to our understanding about hereditary predisposition to cancer...

  15. Genetic Susceptibility to Prostate Cancer in the Netherlands

    National Research Council Canada - National Science Library

    Ostrer, Harry

    2002-01-01

    Studies of the genetics of populations that were historically endogamous for reasons of geography, religion, or language have contributed substantially to our understanding about hereditary predisposition to cancer...

  16. Genetic Susceptibility to Prostate Cancer in the Netherlands

    National Research Council Canada - National Science Library

    Ostrer, Harry

    2003-01-01

    Studies of the genetics of populations that were historically endogamous for reasons of geography, religion, or language have contributed substantially to our understanding about hereditary predisposition to cancer...

  17. Genetic structure of the date palm (Phoenix dactylifera) in the Old World reveals a strong differentiation between eastern and western populations.

    Science.gov (United States)

    Zehdi-Azouzi, Salwa; Cherif, Emira; Moussouni, Souhila; Gros-Balthazard, Muriel; Abbas Naqvi, Summar; Ludeña, Bertha; Castillo, Karina; Chabrillange, Nathalie; Bouguedoura, Nadia; Bennaceur, Malika; Si-Dehbi, Farida; Abdoulkader, Sabira; Daher, Abdourahman; Terral, Jean-Frederic; Santoni, Sylvain; Ballardini, Marco; Mercuri, Antonio; Ben Salah, Mohamed; Kadri, Karim; Othmani, Ahmed; Littardi, Claudio; Salhi-Hannachi, Amel; Pintaud, Jean-Christophe; Aberlenc-Bertossi, Frédérique

    2015-07-01

    Date palms (Phoenix dactylifera, Arecaceae) are of great economic and ecological value to the oasis agriculture of arid and semi-arid areas. However, despite the availability of a large date palm germplasm spreading from the Atlantic shores to Southern Asia, improvement of the species is being hampered by a lack of information on global genetic diversity and population structure. In order to contribute to the varietal improvement of date palms and to provide new insights on the influence of geographic origins and human activity on the genetic structure of the date palm, this study analysed the diversity of the species. Genetic diversity levels and population genetic structure were investigated through the genotyping of a collection of 295 date palm accessions ranging from Mauritania to Pakistan using a set of 18 simple sequence repeat (SSR) markers and a plastid minisatellite. Using a Bayesian clustering approach, the date palm genotypes can be structured into two different gene pools: the first, termed the Eastern pool, consists of accessions from Asia and Djibouti, whilst the second, termed the Western pool, consists of accessions from Africa. These results confirm the existence of two ancient gene pools that have contributed to the current date palm diversity. The presence of admixed genotypes is also noted, which points at gene flows between eastern and western origins, mostly from east to west, following a human-mediated diffusion of the species. This study assesses the distribution and level of genetic diversity of accessible date palm resources, provides new insights on the geographic origins and genetic history of the cultivated component of this species, and confirms the existence of at least two domestication origins. Furthermore, the strong genetic structure clearly established here is a prerequisite for any breeding programme exploiting the effective polymorphism related to each gene pool. © The Author 2015. Published by Oxford University Press on

  18. Study of some genetic predisposition in pulmonary embolism

    Directory of Open Access Journals (Sweden)

    Gehan Elassal

    2014-10-01

    Conclusion: Gene mutation especially factor V Leiden mutation is very important to be considered in young patients presented with venous thrombo-embolism, patients with thrombosis in unusual sites or patients with recurrent thrombo-embolic manifestations.

  19. Genetics Home Reference: BAP1 tumor predisposition syndrome

    Science.gov (United States)

    ... syndrome University of Michigan Kellogg Eye Center: Uveal Melanoma (Eye Cancer) Patient Support and Advocacy Resources (4 links) American Cancer Society Melanoma Research Foundation Ocular Melanoma Foundation Skin Cancer Foundation ...

  20. Genetic predisposition to schizophrenia associated with increased use of cannabis

    NARCIS (Netherlands)

    Power, R.A.; Verweij, K.J.H.; Zuhair, M.; Montgomery, G.W.; Henders, A.K.; Heath, A.C.; Madden, P.A.F.; Medland, S.E.; Wray, N.R.; Martin, N.G.

    2014-01-01

    Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric

  1. Genetic predisposition to schizophrenia associated with increased use of cannabis.

    NARCIS (Netherlands)

    Power, R.A.; Verweij, C.J.H.; Zuhair, M.; Montgomery, G.W.; Henders, A.K.; Heath, A.C.; Madden, P.A.F.; Medland, S.E.; Wray, N.R.; Martin, N.G.

    2014-01-01

    Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric

  2. Populations genetically rifting within a complex geological system: The case of strong structure and low genetic diversity in the migratory freshwater catfish, Bagrus docmak, in East Africa

    OpenAIRE

    Basiita, Rose Komugisha; Zenger, Kyall Richard; Jerry, Dean Robert

    2017-01-01

    Abstract The complex geological history of East Africa has been a driving factor in the rapid evolution of teleost biodiversity. While there is some understanding of how macroevolutionary drivers have shaped teleost speciation in East Africa, there is a paucity of research into how the same biogeographical factors have affected microevolutionary processes within lakes and rivers. To address this deficiency, population genetic diversity, demography, and structure were investigated in a widely ...

  3. Genetics Home Reference: Denys-Drash syndrome

    Science.gov (United States)

    ... Conditions Diagnosis & Management Resources Genetic Testing (1 link) Genetic Testing Registry: Drash syndrome Other Diagnosis and Management Resources (2 links) GeneReview: Wilms Tumor Predisposition MedlinePlus Encyclopedia: Nephrotic Syndrome General Information from MedlinePlus ( ...

  4. Low Genetic Diversity and Strong Geographical Structure of the Critically Endangered White-Headed Langur (Trachypithecus leucocephalus) Inferred from Mitochondrial DNA Control Region Sequences.

    Science.gov (United States)

    Wang, Weiran; Qiao, Yu; Pan, Wenshi; Yao, Meng

    2015-01-01

    Many Asian colobine monkey species are suffering from habitat destruction and population size decline. There is a great need to understand their genetic diversity, population structure and demographic history for effective species conservation. The white-headed langur (Trachypithecus leucocephalus) is a Critically Endangered colobine species endemic to the limestone karst forests in southwestern China. We analyzed the mitochondrial DNA (mtDNA) control region sequences of 390 fecal samples from 40 social groups across the main distribution areas, which represented one-third of the total extant population. Only nine haplotypes and 10 polymorphic sites were identified, indicating remarkably low genetic diversity in the species. Using a subset of 77 samples from different individuals, we evaluated genetic variation, population structure, and population demographic history. We found very low values of haplotype diversity (h = 0.570 ± 0.056) and nucleotide diversity (π = 0.00323 ± 0.00044) in the hypervariable region I (HVRI) of the mtDNA control region. Distribution of haplotypes displayed marked geographical pattern, with one population (Chongzuo, CZ) showing a complete lack of genetic diversity (having only one haplotype), whereas the other population (Fusui, FS) having all nine haplotypes. We detected strong population genetic structure among habit patches (ΦST = 0.375, P population size and modest population expansion in the last 2,000 years. Our results indicate different genetic diversity and possibly distinct population history for different local populations, and suggest that CZ and FS should be considered as one evolutionarily significant unit (ESU) and two management units (MUs) pending further investigation using nuclear markers.

  5. Single nucleotide polymorphism rs1800872 in the promoter region of the IL10 gene is associated with predisposition to chronic hepatitis C in Russian population.

    Science.gov (United States)

    Barkhash, Andrey V; Kochneva, Galina V; Chub, Elena V; Romaschenko, Aida G

    2018-03-01

    Previously, we studied an association of two IL28B gene single nucleotide polymorphisms (SNPs) and three IL10 gene SNPs with predisposition to tick-borne encephalitis in a Russian population. In this study, a possible involvement of these SNPs in the development of predisposition to chronic hepatitis C (caused by structurally similar, related virus from the Flaviviridae family) was investigated in the same population. Only the IL10 promoter rs1800872 SNP was associated with predisposition to chronic hepatitis C. This SNP seems to be a common genetic marker of predisposition to two diseases caused by hepatitis C and tick-borne encephalitis viruses in Russian population. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  6. Population genomic analysis suggests strong influence of river network on spatial distribution of genetic variation in invasive saltcedar across the southwestern United States

    Science.gov (United States)

    Lee, Soo-Rang; Jo, Yeong-Seok; Park, Chan-Ho; Friedman, Jonathan M.; Olson, Matthew S.

    2018-01-01

    Understanding the complex influences of landscape and anthropogenic elements that shape the population genetic structure of invasive species provides insight into patterns of colonization and spread. The application of landscape genomics techniques to these questions may offer detailed, previously undocumented insights into factors influencing species invasions. We investigated the spatial pattern of genetic variation and the influences of landscape factors on population similarity in an invasive riparian shrub, saltcedar (Tamarix L.) by analysing 1,997 genomewide SNP markers for 259 individuals from 25 populations collected throughout the southwestern United States. Our results revealed a broad-scale spatial genetic differentiation of saltcedar populations between the Colorado and Rio Grande river basins and identified potential barriers to population similarity along both river systems. River pathways most strongly contributed to population similarity. In contrast, low temperature and dams likely served as barriers to population similarity. We hypothesize that large-scale geographic patterns in genetic diversity resulted from a combination of early introductions from distinct populations, the subsequent influence of natural selection, dispersal barriers and founder effects during range expansion.

  7. Impact of strong selection for the PrP major gene on genetic variability of four French sheep breeds (Open Access publication

    Directory of Open Access Journals (Sweden)

    Pantano Thais

    2008-11-01

    Full Text Available Abstract Effective selection on the PrP gene has been implemented since October 2001 in all French sheep breeds. After four years, the ARR "resistant" allele frequency increased by about 35% in young males. The aim of this study was to evaluate the impact of this strong selection on genetic variability. It is focussed on four French sheep breeds and based on the comparison of two groups of 94 animals within each breed: the first group of animals was born before the selection began, and the second, 3–4 years later. Genetic variability was assessed using genealogical and molecular data (29 microsatellite markers. The expected loss of genetic variability on the PrP gene was confirmed. Moreover, among the five markers located in the PrP region, only the three closest ones were affected. The evolution of the number of alleles, heterozygote deficiency within population, expected heterozygosity and the Reynolds distances agreed with the criteria from pedigree and pointed out that neutral genetic variability was not much affected. This trend depended on breed, i.e. on their initial states (population size, PrP frequencies and on the selection strategies for improving scrapie resistance while carrying out selection for production traits.

  8. So Far Away, Yet So Close: Strong Genetic Structure in Homonota uruguayensis (Squamata, Phyllodactylidae), a Species with Restricted Geographic Distribution in the Brazilian and Uruguayan Pampas

    Science.gov (United States)

    Felappi, Jéssica F.; Vieira, Renata C.; Fagundes, Nelson J. R.; Verrastro, Laura V.

    2015-01-01

    The Pampas is a biologically rich South American biome, but is poorly represented in phylogeographic studies. While the Pleistocene glacial cycles may have affected the evolutionary history of species distributed in forested biomes, little is known about their effects on the habitats that remained stable through glacial cycles. The South American Pampas have been covered by grasslands during both glacial and interglacial periods and therefore represent an interesting system to test whether the genetic structure in such environments is less pronounced. In this study, we sampled Pampean populations of Homonota uruguayensis from Southern Brazil and Uruguay to assess the tempo and mode of population divergence, using both morphological measurements and molecular markers. Our results indicate that, in spite of its narrow geographic distribution, populations of H. uruguayensis show high levels of genetic structure. We found four major well-supported mtDNA clades with strong geographic associations. Estimates of their divergence times fell between 3.16 and 1.82 million years before the present. Populations from the central portion of the species distribution, on the border between Uruguay and Brazil, have high genetic diversity and may have undergone a population expansion approximately 250,000 years before the present. The high degree of genetic structure is reflected in the analyses of morphological characters, and most individuals could be correctly assigned to their parental population based on morphology alone. Finally, we discuss the biogeographic and conservation implications of these findings. PMID:25692471

  9. So far away, yet so close: strong genetic structure in Homonota uruguayensis (Squamata, Phyllodactylidae, a species with restricted geographic distribution in the Brazilian and Uruguayan Pampas.

    Directory of Open Access Journals (Sweden)

    Jéssica F Felappi

    Full Text Available The Pampas is a biologically rich South American biome, but is poorly represented in phylogeographic studies. While the Pleistocene glacial cycles may have affected the evolutionary history of species distributed in forested biomes, little is known about their effects on the habitats that remained stable through glacial cycles. The South American Pampas have been covered by grasslands during both glacial and interglacial periods and therefore represent an interesting system to test whether the genetic structure in such environments is less pronounced. In this study, we sampled Pampean populations of Homonota uruguayensis from Southern Brazil and Uruguay to assess the tempo and mode of population divergence, using both morphological measurements and molecular markers. Our results indicate that, in spite of its narrow geographic distribution, populations of H. uruguayensis show high levels of genetic structure. We found four major well-supported mtDNA clades with strong geographic associations. Estimates of their divergence times fell between 3.16 and 1.82 million years before the present. Populations from the central portion of the species distribution, on the border between Uruguay and Brazil, have high genetic diversity and may have undergone a population expansion approximately 250,000 years before the present. The high degree of genetic structure is reflected in the analyses of morphological characters, and most individuals could be correctly assigned to their parental population based on morphology alone. Finally, we discuss the biogeographic and conservation implications of these findings.

  10. Female alcoholism: Gender differences as victimogenic predispositions

    Directory of Open Access Journals (Sweden)

    Konstantinović-Vilić Slobodanka

    2014-01-01

    Full Text Available The subject matter of this paper is an analysis of stereotypical social reactions to women’s alcoholism in the micro and macro social and cultural environment. The social stigma and blame that female alcohol abusers are exposed to have become part of deeply rooted gender-related labels. In a broader social context, they lead to discrimination and social exclusion. In the contemporary society, female alcoholism is turning into a growing social and health problem and because of that it is essential to make the social environment more sensitive to the issue of female alcoholism in order to eliminate the causes of female alcoholism and fully support women’s medical treatment,. It would have a preventive effect in suppressing female alcoholism and it would significantly reduce victimization of women who are, in such circumstances, much more vulnerable and exposed to physical and sexual violence. The aim of this paper is to point out to the basic phenomenological and etiological feature of female alcoholism, prejudices and stereotypical attitudes they are exposed to, social and cultural implications of female alcoholism, which is perceived as a predisposition for women’s victimization and exposure to violence, so as to promote a different social approach to female alcoholism and advocate for instituting social and educational policy based on the concept of gender equality and support of social control measures.

  11. Myeloid Neoplasms with Germline Predisposition: A New Provisional Entity Within the World Health Organization Classification.

    Science.gov (United States)

    Czuchlewski, David R; Peterson, LoAnn C

    2016-03-01

    The forthcoming update of the World Health Organization (WHO) classification of hematopoietic neoplasms will feature "Myeloid Neoplasms with Germline Predisposition" as a new provisional diagnostic entity. This designation will be applied to some cases of acute myeloid leukemia and myelodysplastic syndrome arising in the setting of constitutional mutations that render patients susceptible to the development of myeloid malignancies. For the diagnostic pathologist, recognizing these cases and confirming the diagnosis will demand a sophisticated grasp of clinical genetics and molecular techniques. This article presents a concise review of this new provisional WHO entity, including strategies for clinical practice. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. An overview of the role of prophylactic surgery in the management of individuals with a hereditary cancer predisposition.

    Science.gov (United States)

    Oseni, Tawakalitu; Jatoi, Ismail

    2008-08-01

    Genetic testing for cancer susceptibility has been implemented widely in recent years, with the hope that it eventually will lead to a reduction in cancer-related mortality. Asymptomatic individuals who have a genetic predisposition for cancer can be identified, and many may benefit from early intervention. Not all of these individuals will develop cancer, however, and the penetrance varies among individuals with different mutations. Surveillance, chemoprevention, and prophylactic surgery are accepted options for managing individuals who have a genetic predisposition for cancer. Yet, there are no randomized prospective trials that have assessed the impact of these interventions specifically in mutation carriers. The decision to undergo prophylactic surgery therefore should be made after all other management options are considered, and the patient is informed of the potential risks and benefits of surgery. This article provides an overview of the role of prophylactic surgery for managing patients who have a genetic predisposition for cancer. It specifically discusses the potential role of surgery in preventing breast, colon, thyroid, and gastric cancers. Additionally, it discusses the types of prophylactic surgical procedures that are performed commonly, and their expanding role in cancer prevention.

  13. Localization of genes modulating the predisposition to schizophrenia: a revision

    Directory of Open Access Journals (Sweden)

    E.Z. Lopes-Machado

    2000-09-01

    Full Text Available The genetics of schizophrenia or bipolar affective disorder has advanced greatly at the molecular level since the introduction of probes for the localization of specific genes. Research on gene candidates for susceptibility to schizophrenia can broadly be divided into two types, i.e., linkage studies, where a gene is found near a specific DNA marker on a specific chromosome, and association studies, when a condition is associated with a specific allele of a specific gene. This review covers a decade of publications in this area, from the 1988 works of Bassett et al. and Sherrington et al. on a gene localized on the long arm of chromosome 5 at the 5q11-13 loci, to the 1997 work of Lin et al. pointing to the 13q14.1-q32 loci of chromosome 13 and to the 1998 work of Wright et al. on an HLA DRB1 gene locus on chromosome 6 at 6p21-3. The most replicated loci were those in the long arm of chromosome 22 (22q12-q13.1 and on the short arm of chromosome 6 (6p24-22. In this critical review of the molecular genetic studies involved in the localization of genes which modulate the predisposition to schizophrenia the high variability in the results obtained by different workers suggests that multiple loci are involved in the predisposition to this illness.A genética da esquizofrenia (como também do distúrbio bipolar teve grande avanço a partir da descoberta, a nível de genética molecular, da técnica de localização de genes com uso de sondas de DNA (Botstein et al., 1980. Os estudos que procuram "genes candidatos" a exercerem algum papel na susceptibilidade à esquizofrenia são, basicamente, de dois tipos: de ligação ("linkage" e de associação. Quando, à luz da genética molecular, um gene é localizado próximo a um marcador de DNA específico no cromossomo, fala-se em estudo "de ligação". Por outro lado, quando a doença é associada a um alelo específico de um determinado gene, fala-se em estudo "de associação". Esta revisão cobriu uma d

  14. Strong genetic differentiation among east Atlantic populations of the sword razor shell ( Ensis siliqua) assessed with mtDNA and RAPD markers

    Science.gov (United States)

    Arias, Alberto; Fernández-Moreno, Mercedes; Fernández-Tajes, Juan; Gaspar, Miguel B.; Méndez, Josefina

    2011-03-01

    The sword razor shell Ensis siliqua (Linnaeus, 1758) is a bivalve with a high commercial value being appreciated in fresh and processed markets. However, the genetic studies carried out in populations of E. siliqua are scarce. In this work, the genetic variability and differentiation of the sword razor shell was assessed using PCR-RFLPs of a fragment of the 16S rRNA mitochondrial gene and random amplified polymorphic loci (RAPD) in nine localities from Ireland, Spain, and Portugal. In the 314 individuals examined for the mitochondrial fragment, 12 composite haplotypes were observed; meanwhile, a unique phenotype was observed for each of the 242 individuals analyzed with 61 RAPD loci. Two of the mitochondrial composite haplotypes accounted for the majority of individuals (89.81%) and showed a remarkably disjoint distribution between Irish and Iberian samples, with the exception of Aveiro which exhibited as the most frequent haplotype the same found in Ireland. The level of variability observed for each sample was generally correlated with both types of markers and the results obtained suggest the existence of a strong population differentiation between Irish and Iberian localities, except for the Portuguese sample from Aveiro which is surprisingly closer to Irish individuals, although it is probably highly differentiated.

  15. The Geographic Distribution of Saccharomyces cerevisiae Isolates within three Italian Neighboring Winemaking Regions Reveals Strong Differences in Yeast Abundance, Genetic Diversity and Industrial Strain Dissemination

    Directory of Open Access Journals (Sweden)

    Alessia Viel

    2017-08-01

    Full Text Available In recent years the interest for natural fermentations has been re-evaluated in terms of increasing the wine terroir and managing more sustainable winemaking practices. Therefore, the level of yeast genetic variability and the abundance of Saccharomyces cerevisiae native populations in vineyard are becoming more and more crucial at both ecological and technological level. Among the factors that can influence the strain diversity, the commercial starter release that accidentally occur in the environment around the winery, has to be considered. In this study we led a wide scale investigation of S. cerevisiae genetic diversity and population structure in the vineyards of three neighboring winemaking regions of Protected Appellation of Origin, in North-East of Italy. Combining mtDNA RFLP and microsatellite markers analyses we evaluated 634 grape samples collected over 3 years. We could detect major differences in the presence of S. cerevisiae yeasts, according to the winemaking region. The population structures revealed specificities of yeast microbiota at vineyard scale, with a relative Appellation of Origin area homogeneity, and transition zones suggesting a geographic differentiation. Surprisingly, we found a widespread industrial yeast dissemination that was very high in the areas where the native yeast abundance was low. Although geographical distance is a key element involved in strain distribution, the high presence of industrial strains in vineyard reduced the differences between populations. This finding indicates that industrial yeast diffusion it is a real emergency and their presence strongly interferes with the natural yeast microbiota.

  16. Genetics Home Reference: myasthenia gravis

    Science.gov (United States)

    ... GP, Tzartos SJ, Poulas K. Recent advances in genetic predisposition of myasthenia gravis. Biomed Res Int. 2013;2013:404053. doi: 10.1155/2013/404053. Epub 2013 Nov 5. Review. Citation on PubMed or Free article on PubMed ... from Genetics Home Reference Bulletins Genetics Home Reference Celebrates Its ...

  17. Genetics Home Reference: Dupuytren contracture

    Science.gov (United States)

    ... 60 develop the disorder. Studies suggest that a genetic predisposition to develop this disorder may have been spread through northern Europe and Britain by the Vikings. Dupuytren contracture is less common in ... information about a genetic condition can statistics provide? Why are some genetic ...

  18. Predisposition to insulin resistance and obesity due to staple consumption of rice: Amylose content versus germination status.

    Directory of Open Access Journals (Sweden)

    Bilyaminu Abubakar

    Full Text Available Type 2 diabetes is a metabolic disorder with established, well-defined precursors. Obesity and insulin resistance are amongst most important factors in predisposition to diabetes. Rice is a staple for about half the global population and its consumption has been strongly linked with diabetogenesis. We assert that tackling the prevalence of predisposing factors by modifying certain rice cultivars could reduce the global burden of obesity and insulin resistance, and by extension type 2 diabetes. Several rice cultivars with various properties were fed to nulliparous rats (five weeks old at the start of the experiment for 90 days. They were then returned to a diet of standard pellets and mated with males raised on a standard diet. The resulting pups and dams were investigated for obesity and insulin resistance markers. We found that germination did more to reduce predisposition to obesity and insulin resistance than high amylose content. The combined reducing effect of germination and high amylose content on predisposition to obesity and insulin resistance was greater than the sum of their independent effects. Polished (white rice with a low amylose content predisposed dams on a high-fat diet to markers of insulin resistance and obesity and this predisposition was inherited (in biochemical terms by their F1 offspring. Overall, the results suggest that harnessing the beneficial properties of germination and amylose in rice would reduce the burden of obesity and insulin resistance, which are known to be key risk factors for development of type 2 diabetes.

  19. Strong correlation between cross-amplification success and genetic distance across all members of 'True Salamanders' (Amphibia: Salamandridae) revealed by Salamandra salamandra-specific microsatellite loci.

    Science.gov (United States)

    Hendrix, Ralf; Susanne Hauswaldt, J; Veith, Michael; Steinfartz, Sebastian

    2010-11-01

    The unpredictable and low cross-amplification success of microsatellite loci tested for congeneric amphibian species has mainly been explained by the size and complexity of amphibian genomes, but also by taxonomy that is inconsistent with phylogenetic relationships among taxa. Here, we tested whether the cross-amplification success of nine new and 11 published microsatellite loci cloned for an amphibian source species, the fire salamander (Salamandra salamandra), correlated with the genetic distance across all members of True Salamanders (genera Chioglossa, Lyciasalamandra, Mertensiella and Salamandra that form a monophyletic clade within the family of Salamandridae) serving as target species. Cross-amplification success varied strongly among the species and showed a highly significant negative relationship with genetic distance and amplification success. Even though lineages of S. salamandra and Lyciasalamndra have separated more than 30 Ma, a within genus amplification success rate of 65% was achieved for species of Lyciasalamandra thus demonstrating that an efficient cross-species amplification of microsatellite loci in amphibians is feasible even across large evolutionary distances. A decrease in genome size, on the other hand, paralleled also a decrease in amplified loci and therefore contradicted previous results and expectations that amplification success should increase with a decrease in genome size. However, in line with other studies, our comprehensive dataset clearly shows that cross-amplification success of microsatellite loci is well explained by phylogenetic divergence between species. As taxonomic classifications on the species and genus level do not necessarily mirror phylogenetic divergence between species, the pure belonging of species to the same taxonomic units (i.e. species or genus) might be less useful to predict cross-amplification success of microsatellite loci between such species. © 2010 Blackwell Publishing Ltd.

  20. Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence

    Science.gov (United States)

    Liu, Xinyang; Hildebrandt, Andrea; Recio, Guillermo; Sommer, Werner; Cai, Xinxia; Wilhelm, Oliver

    2017-01-01

    Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio-emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O-Methyl-Transferase (COMT) Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event-related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN), when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account or not. These

  1. Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence

    Directory of Open Access Journals (Sweden)

    Xinyang Liu

    2017-08-01

    Full Text Available Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio-emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O-Methyl-Transferase (COMT Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event-related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN, when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account

  2. Biomarkers and genes predictive of disease predisposition and ...

    African Journals Online (AJOL)

    Biomarkers and genes predictive of disease predisposition and prognosis in rheumatoid arthritis. Rheumatoid arthritis is a debilitating disease which often progresses to relentlessly severe disease. Pieter W A Meyer, NHDip Med Tech, MTech, PhD. Medical Research Council Unit for Inflammation and Immunity, Department ...

  3. Content, Structure, and Usefulness of Juvenile Predisposition Psychological Evaluations

    Science.gov (United States)

    Morin, Samantha L.; Cruise, Keith R.; Hinz, Holly; Holloway, Evan D.; Chapman, John F.

    2015-01-01

    Background: There is a dearth of research regarding the content and structure of juvenile predisposition psychological evaluations. Limited research suggests that key mental health domains are insufficiently represented and judges use evaluator recommendations regarding legal outcomes more often than clinical outcomes. Studies have not addressed…

  4. Predisposition of Nigerian children with severe malaria to urinary ...

    African Journals Online (AJOL)

    The predisposition of children with severe malaria to urinary tract infection was investigated in a group of 112 clinically diagnosed and para sitologically confirmed severe malaria patients (test) and in another subset of 114 apparently physically healthy non-malaria infected subjects (control). Standard bacteriological and ...

  5. Divorce: An Unreliable Predictor of Children's Emotional Predispositions.

    Science.gov (United States)

    Bernard, Janine M.; Nesbitt, Sally

    1981-01-01

    Used the Children's Emotion Projection Instrument to investigate the emotional predispositions of children from divorce or disruption and children from intact families. Results indicated that children of divorce or disruption are not more hampered emotionally than children from intact families. Discusses implications for family therapists.…

  6. Family Size and Parental Education on Predisposition to Female ...

    African Journals Online (AJOL)

    This study investigated the influence of family size and parental education on predisposition to female trafficking in southern Nigeria. Stratified Random sampling procedure was used to select the 150 parents from various ethnic groups consisting of. Yoruba, Igbo, Bini, and Ibibio/Efik among others. A researcher-constructed ...

  7. Genetics Home Reference: DICER1 syndrome

    Science.gov (United States)

    ... Encyclopedia: Sertoli-Leydig Cell Tumor Health Topic: Cancer Genetic and Rare Diseases Information Center (1 link) DICER1-related pleuropulmonary blastoma cancer predisposition syndrome Additional NIH Resources (1 link) National Cancer ...

  8. Populations genetically rifting within a complex geological system: The case of strong structure and low genetic diversity in the migratory freshwater catfish,Bagrus docmak,in East Africa.

    Science.gov (United States)

    Basiita, Rose Komugisha; Zenger, Kyall Richard; Jerry, Dean Robert

    2017-08-01

    The complex geological history of East Africa has been a driving factor in the rapid evolution of teleost biodiversity. While there is some understanding of how macroevolutionary drivers have shaped teleost speciation in East Africa, there is a paucity of research into how the same biogeographical factors have affected microevolutionary processes within lakes and rivers. To address this deficiency, population genetic diversity, demography, and structure were investigated in a widely distributed and migratory (potamodromous) African teleost species, Ssemutundu ( Bagrus docmak ). Samples were acquired from five geographical locations in East Africa within two major drainage basins; the Albertine Rift and Lake Victoria Basin. Individuals ( N  = 175) were genotyped at 12 microsatellite loci and 93 individuals sequenced at the mitochondrial DNA control region. Results suggested populations from Lakes Edward and Victoria had undergone a severe historic bottleneck resulting in very low nucleotide diversity (π = 0.004 and 0.006, respectively) and negatively significant Fu values (-3.769 and -5.049; p  < .05). Heterozygosity deficiencies and restricted effective population size ( N eLD ) suggested contemporary exposure of these populations to stress, consistent with reports of the species decline in the East African Region. High genetic structuring between drainages was detected at both historical (ɸ ST  = 0.62 for mtDNA; p  < .001) and contemporary (microsatellite F ST  = 0.460; p  < .001) levels. Patterns of low genetic diversity and strong population structure revealed are consistent with speciation patterns that have been linked to the complex biogeography of East Africa, suggesting that these biogeographical features have operated as both macro- and micro-evolutionary forces in the formation of the East African teleost fauna.

  9. Management of women with a hereditary predisposition for breast cancer.

    Science.gov (United States)

    Jatoi, Ismail; Benson, John R

    2016-10-01

    Women with a hereditary breast cancer predisposition have three management options: screening, chemoprevention (risk-reducing medication) and risk-reducing surgery. However, no randomized trials have addressed the effect of these strategies in mutation carriers. In the general population, randomized trials failed to demonstrate a benefit for screening in premenopausal women. Moreover, although chemoprevention reduces breast cancer incidence in high-risk populations, this benefit is potentially confined to estrogen receptor-positive tumors. Finally, observational studies suggest that prophylactic mastectomy and even prophylactic salpingo-ophorectomy reduces breast cancer risk in BRCA mutation carriers, but there are systematic biases associated with such studies. Therefore, women with a hereditary predisposition for breast cancer should be informed of the three risk-reducing strategies, and that their benefits are not fully understood.

  10. Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing.

    Science.gov (United States)

    Ng, P S; Wen, W X; Fadlullah, M Z H; Yoon, S Y; Lee, S Y; Thong, M K; Yip, C H; Mohd Taib, N A; Teo, S H

    2016-10-01

    Although an association between protein-truncating variants and breast cancer risk has been established for 11 genes, only alterations in BRCA1, BRCA2, TP53 and PALB2 have been reported in Asian populations. Given that the age of onset of breast cancer is lower in Asians, it is estimated that inherited predisposition to breast cancer may be more significant. To determine the potential utility of panel testing, we investigated the prevalence of germline alterations in 11 established and 4 likely breast cancer genes in a cross-sectional hospital-based cohort of 108 moderate to high-risk breast cancer patients using targeted next generation sequencing. Twenty patients (19%) were identified to carry deleterious mutations, of whom 13 (12%) were in the BRCA1 or BRCA2, 6 (6%) were in five other known breast cancer predisposition genes and 1 patient had a mutation in both BRCA2 and BARD1. Our study shows that BRCA1 and BRCA2 account for the majority of genetic predisposition to breast cancer in our cohort of Asian women. Although mutations in other known breast cancer genes are found, the functional significance and breast cancer risk have not yet been determined, thus limiting the clinical utility of panel testing in Asian populations. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Effect of deregulation of Sonic Hedgehog pathway on responses to DNA damage and cancer predisposition

    International Nuclear Information System (INIS)

    Charazac, Aurelie

    2015-01-01

    The Gorlin syndrome is a rare genetic disorder characterized by several developmental abnormalities. Due to mutations in PTCH1, a key player of the sonic hedgehog signaling pathway, clinical manifestations also includes hyper-radiosensitivity and an increased predisposition to the development of basal cell carcinomas. Given the implication of DNA repair system defects in hyper-radiosensitivity pathologies, we decided to study the effect of PTCH1 mutations on the DNA damage response in order to better understand the cellular and molecular mechanisms leading to Gorlin's phenotype.This study demonstrate a global failure of the DNA damage repair systems in Gorlin fibroblasts with respect to controls. It highlights in particular the collapse of the base excision repair pathway (BER) responsible for the repair of oxidative DNA damage. (author) [fr

  12. River predisposition to ice jams: a simplified geospatial model

    Directory of Open Access Journals (Sweden)

    S. De Munck

    2017-07-01

    Full Text Available Floods resulting from river ice jams pose a great risk to many riverside municipalities in Canada. The location of an ice jam is mainly influenced by channel morphology. The goal of this work was therefore to develop a simplified geospatial model to estimate the predisposition of a river channel to ice jams. Rather than predicting the timing of river ice breakup, the main question here was to predict where the broken ice is susceptible to jam based on the river's geomorphological characteristics. Thus, six parameters referred to potential causes for ice jams in the literature were initially selected: presence of an island, narrowing of the channel, high sinuosity, presence of a bridge, confluence of rivers, and slope break. A GIS-based tool was used to generate the aforementioned factors over regular-spaced segments along the entire channel using available geospatial data. An ice jam predisposition index (IJPI was calculated by combining the weighted optimal factors. Three Canadian rivers (province of Québec were chosen as test sites. The resulting maps were assessed from historical observations and local knowledge. Results show that 77 % of the observed ice jam sites on record occurred in river sections that the model considered as having high or medium predisposition. This leaves 23 % of false negative errors (missed occurrence. Between 7 and 11 % of the highly predisposed river sections did not have an ice jam on record (false-positive cases. Results, limitations, and potential improvements are discussed.

  13. A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

    Science.gov (United States)

    Carmona, F. David; Mackie, Sarah L.; Martín, Jose-Ezequiel; Taylor, John C.; Vaglio, Augusto; Eyre, Stephen; Bossini-Castillo, Lara; Castañeda, Santos; Cid, Maria C.; Hernández-Rodríguez, José; Prieto-González, Sergio; Solans, Roser; Ramentol-Sintas, Marc; González-Escribano, M. Francisca; Ortiz-Fernández, Lourdes; Morado, Inmaculada C.; Narváez, Javier; Miranda-Filloy, José A.; Martínez-Berriochoa, Agustín; Unzurrunzaga, Ainhoa; Hidalgo-Conde, Ana; Madroñero-Vuelta, Ana B.; Fernández-Nebro, Antonio; Ordóñez-Cañizares, M. Carmen; Escalante, Begoña; Marí-Alfonso, Begoña; Sopeña, Bernardo; Magro, César; Raya, Enrique; Grau, Elena; Román, José A.; de Miguel, Eugenio; López-Longo, F. Javier; Martínez, Lina; Gómez-Vaquero, Carmen; Fernández-Gutiérrez, Benjamín; Rodríguez-Rodríguez, Luis; Díaz-López, J. Bernardino; Caminal-Montero, Luis; Martínez-Zapico, Aleida; Monfort, Jordi; Tío, Laura; Sánchez-Martín, Julio; Alegre-Sancho, Juan J.; Sáez-Comet, Luis; Pérez-Conesa, Mercedes; Corbera-Bellalta, Marc; García-Villanueva, M. Jesús; Fernández-Contreras, M. Encarnación; Sanchez-Pernaute, Olga; Blanco, Ricardo; Ortego-Centeno, Norberto; Ríos-Fernández, Raquel; Callejas, José L.; Fanlo-Mateo, Patricia; Martínez-Taboada, Víctor M.; Beretta, Lorenzo; Lunardi, Claudio; Cimmino, Marco A.; Gianfreda, Davide; Santilli, Daniele; Ramirez, Giuseppe A.; Soriano, Alessandra; Muratore, Francesco; Pazzola, Giulia; Addimanda, Olga; Wijmenga, Cisca; Witte, Torsten; Schirmer, Jan H.; Moosig, Frank; Schönau, Verena; Franke, Andre; Palm, Øyvind; Molberg, Øyvind; Diamantopoulos, Andreas P.; Carette, Simon; Cuthbertson, David; Forbess, Lindsy J.; Hoffman, Gary S.; Khalidi, Nader A.; Koening, Curry L.; Langford, Carol A.; McAlear, Carol A.; Moreland, Larry; Monach, Paul A.; Pagnoux, Christian; Seo, Philip; Spiera, Robert; Sreih, Antoine G.; Warrington, Kenneth J.; Ytterberg, Steven R.; Gregersen, Peter K.; Pease, Colin T.; Gough, Andrew; Green, Michael; Hordon, Lesley; Jarrett, Stephen; Watts, Richard; Levy, Sarah; Patel, Yusuf; Kamath, Sanjeet; Dasgupta, Bhaskar; Worthington, Jane; Koeleman, Bobby P.C.; de Bakker, Paul I.W.; Barrett, Jennifer H.; Salvarani, Carlo; Merkel, Peter A.; González-Gay, Miguel A.; Morgan, Ann W.; Martín, Javier

    2015-01-01

    We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10−40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10−43) and HLA-DQα1 47 (p = 4.02 × 10−46), 56, and 76 (both p = 1.84 × 10−45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10−6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10−6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10−5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. PMID:25817017

  14. Genetics

    Science.gov (United States)

    ... Likelihood of getting certain diseases Mental abilities Natural talents An abnormal trait (anomaly) that is passed down ... one of them has a genetic disorder. Information Human beings have cells with 46 chromosomes . These consist ...

  15. PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors.

    Science.gov (United States)

    de Quervain, Dominique J-F; Kolassa, Iris-Tatjana; Ackermann, Sandra; Aerni, Amanda; Boesiger, Peter; Demougin, Philippe; Elbert, Thomas; Ertl, Verena; Gschwind, Leo; Hadziselimovic, Nils; Hanser, Edveena; Heck, Angela; Hieber, Petra; Huynh, Kim-Dung; Klarhöfer, Markus; Luechinger, Roger; Rasch, Björn; Scheffler, Klaus; Spalek, Klara; Stippich, Christoph; Vogler, Christian; Vukojevic, Vanja; Stetak, Attila; Papassotiropoulos, Andreas

    2012-05-29

    Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity--including aversive memory--in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.

  16. Strong genetic structure revealed by multilocus patterns of variation in Giardia duodenalis isolates of patients from Galicia (NW-Iberian Peninsula).

    Science.gov (United States)

    Gabín-García, Luis B; Bartolomé, Carolina; Abal-Fabeiro, José L; Méndez, Santiago; Llovo, José; Maside, Xulio

    2017-03-01

    We report a survey of genetic variation at three coding loci in Giardia duodenalis of assemblages A and B obtained from stool samples of patients from Santiago de Compostela (Galicia, NW-Iberian Peninsula). The mean pooled synonymous diversity for assemblage A was nearly five times lower than for assemblage B (0.77%±0.30% and 4.14%±1.65%, respectively). Synonymous variation in both assemblages was in mutation-drift equilibrium and an excess of low-frequency nonsynonymous variants suggested the action of purifying selection at the three loci. Differences between isolates contributed to 40% and 60% of total genetic variance in assemblages A and B, respectively, which revealed a significant genetic structure. These results, together with the lack of evidence for recombination, support that (i) Giardia assemblages A and B are in demographic equilibrium and behave as two genetically isolated populations, (ii) infections are initiated by a reduced number of individuals, which may be genetically diverse and even belong to different assemblages, and (iii) parasites reproduce clonally within the host. However, the observation of invariant loci in some isolates means that mechanisms for the homogenization of the genetic content of the two diploid nuclei in each individual must exist. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Genetics

    International Nuclear Information System (INIS)

    Hubitschek, H.E.

    1975-01-01

    Progress is reported on the following research projects: genetic effects of high LET radiations; genetic regulation, alteration, and repair; chromosome replication and the division cycle of Escherichia coli; effects of radioisotope decay in the DNA of microorganisms; initiation and termination of DNA replication in Bacillus subtilis; mutagenesis in mouse myeloma cells; lethal and mutagenic effects of near-uv radiation; effect of 8-methoxypsoralen on photodynamic lethality and mutagenicity in Escherichia coli; DNA repair of the lethal effects of far-uv; and near uv irradiation of bacterial cells

  18. Genetics

    DEFF Research Database (Denmark)

    Christensen, Kaare; McGue, Matt

    2016-01-01

    The sequenced genomes of individuals aged ≥80 years, who were highly educated, self-referred volunteers and with no self-reported chronic diseases were compared to young controls. In these data, healthy ageing is a distinct phenotype from exceptional longevity and genetic factors that protect...

  19. A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

    NARCIS (Netherlands)

    David Carmona, F.; Mackie, Sarah L.; Martin, Jose-Ezequiel; Taylor, John C.; Vaglio, Augusto; Eyre, Stephen; Bossini-Castillo, Lara; Castaneda, Santos; Cid, Maria C.; Hernandez-Rodriguez, Jose; Prieto-Gonzalez, Sergio; Solans, Roser; Ramentol-Sintas, Marc; Francisca Gonzalez-Escribano, M.; Ortiz-Fernandez, Lourdes; Morado, Inmaculada C.; Narvaez, Javier; Miranda-Filloy, Jose A.; Beretta, Lorenzo; Lunardi, Claudio; Cimmino, Marco A.; Gianfreda, Davide; Santilli, Daniele; Ramirez, Giuseppe A.; Soriano, Alessandra; Muratore, Francesco; Pazzola, Giulia; Addimanda, Olga; Wijmenga, Cisca; Witte, Torsten; Schirmer, Jan H.; Moosig, Frank; Schoenau, Verena; Franke, Andre; Palm, Oyvind; Molberg, Oyvind; Diamantopoulos, Andreas P.; Carette, Simon; Cuthbertson, David; Forbess, Lindsy J.; Hoffman, Gary S.; Khalidi, Nader A.; Koening, Curry L.; Langford, Carol A.; McAlear, Carol A.; Moreland, Larry; Monach, Paul A.; Pagnoux, Christian; Seo, Philip; Spiera, Robert; Sreih, Antoine G.; Warrington, Kenneth J.; Ytterberg, Steven R.; Gregersen, Peter K.; Pease, Colin T.; Gough, Andrew; Green, Michael; Hordon, Lesley; Jarrett, Stephen; Watts, Richard; Levy, Sarah; Patel, Yusuf; Kamath, Sanjeet; Dasgupta, Bhaskar; Worthington, Jane; Koeleman, Bobby P. C.; de Bakker, Paul I. W.; Barrett, Jennifer H.; Salvarani, Carlo; Merkel, Peter A.; Gonzalez-Gay, Miguel A.; Morgan, Ann W.; Martin, Javier

    2015-01-01

    We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip

  20. Predisposição genética, hereditariedade e reabsorções radiculares em Ortodontia: cuidados com interpretações precipitadas: uma análise crítica do trabalho de Al-Qawasmi et al Genetics predisposition, heredity and radicular resorption, in Orthodontics: cares with precipitated interpretations and a critical analysis of Al-Qawasmi´s work

    Directory of Open Access Journals (Sweden)

    Alberto Consolaro

    2004-05-01

    Full Text Available O trabalho de Al-Qawasmi et al.¹, publicado em março de 2003 pelo American Journal of Orthodontics and Dentofacial Orthopedics, procurou estabelecer uma predisposição genética para justificar as reabsorções dentárias em Ortodontia, mas apresentou algumas limitações metodológicas e equívocos na interpretação de seus resultados. A análise criteriosa deste artigo ressalta que, na maioria, estas limitações foram mencionadas e reconhecidas pelos autores na discussão do trabalho, mas o seu resumo e título foram muito taxativos e conclusivos. A linguagem de estudos genéticos nem sempre é familiar a todos os clínicos e isto também requer uma análise esclarecedora à luz de uma visão mais aplicada ao cotidiano ortodôntico. Referenciar ou citar este trabalho de Al-Qawasmi et al.¹, para afirmar de forma taxativa que se demonstrou a natureza hereditária das reabsorções dentárias em Ortodontia, pode denotar falta de conhecimento sobre o assunto ou uma leitura ou compreensão apenas do seu título. Ou ainda, a citação deste trabalho como prova definitiva de associação entre hereditariedade e reabsorções dentárias em Ortodontia pode traduzir também o desejo de excluir da prática clínica a responsabilidade de planejar de forma individualizada e detalhada cada tratamento com base no conhecimento das possibilidades e limitações técnicas oferecidas pela ciência ortodôntica, bem como nas suas bases biológicas, por exemplo, valorizando a morfologia radicular e da crista óssea alveolar e o papel dos cementoblastos na proteção da superfície radicular.The study published in the American Journal of Orthodontics and Dentofacial Orthopedics last March by Al-Qawasmi et al. tried to implicate dental resorption during orthodontic treatment to genetic predisposition. The methodology used, however, presents limitations and interpretative mistakes of the results. When analyzing the article sensibly, one is able to find that

  1. Genomic selection strategies in breeding programs: Strong positive interaction between application of genotypic information and intensive use of young bulls on genetic gain

    DEFF Research Database (Denmark)

    Buch, Line Hjortø; Sørensen, Morten Kargo; Berg, Peer

    2012-01-01

    ) a positive interaction exists between the use of genotypic information and a short generation interval on ΔGAG and (iii) the inclusion of an indicator trait in the selection index will only result in a negligible increase in ΔGAG if genotypic information about the breeding goal trait is known. We examined......We tested the following hypotheses: (i) breeding schemes with genomic selection are superior to breeding schemes without genomic selection regarding annual genetic gain of the aggregate genotype (ΔGAG), annual genetic gain of the functional traits and rate of inbreeding per generation (ΔF), (ii...... four breeding schemes with or without genomic selection and with or without intensive use of young bulls using pseudo-genomic stochastic simulations. The breeding goal consisted of a milk production trait and a functional trait. The two breeding schemes with genomic selection resulted in higher ΔGAG...

  2. The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

    Directory of Open Access Journals (Sweden)

    Pi-Lin Sung

    Full Text Available An important role of genetic factors in the development of breast cancer (BC or ovarian cancer (OC in Taiwanese (ethnic Chinese patients has been suggested. However, other than germline BRCA1 or BRCA2 mutations, which are related to hereditary breast-ovarian cancer (HBOC, cancer-predisposition genes have not been well studied in this population. The aim of the present study was to more accurately summarize the prevalence of genetic mutations in HBOC patients using various gene panels ranging in size from BRCA1/2 alone to multi-gene panels. Among 272 HBOC patients analyzed, the prevalence of BRCA1, BRCA2 and non-BRCA1/2 pathogenic mutations was 7.7% (21/272, 6.8% (16/236 and 8.2% (13/159, respectively. The total mutation rate was 18.4% (50/272. Although no founder mutations were identified in this study, two recurrent mutations, BRCA1 (c.3607C>T and BRCA2 (c.5164_5165 delAG, were found. The main pathogenic/likely pathogenic mutations in non-BRCA1/2 genes included ATM, BRIP1, FANCI, MSH2, MUYTH, RAD50, RAD51C and TP53. The prevalence rate of gene mutations in HBOC patients did not differ with respect to whether BC or OC was the first diagnosis or they presented a family history of the disease or their age at diagnosis. HBOC patients with both BC and OC exhibited a higher prevalence rate of mutations (50.0% than patients with OC (25.0% or BC (8.6% alone. In conclusion, evaluation of hereditary cancer risk in Taiwan HBOC patients, particularly individuals with double cancer, is strongly encouraged. Panel testing can yield additional genomic information, and widespread and well-designed panel testing will help in assessing more accurate mutational prevalence of risk genes.

  3. Genetic background strongly modifies the severity of symptoms of Hirschsprung disease, but not hearing loss in rats carrying Ednrb(sl mutations.

    Directory of Open Access Journals (Sweden)

    Ruihua Dang

    Full Text Available Hirschsprung disease (HSCR is thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. However, it remains unknown whether the single complete deletion of important HSCR-associated genes is sufficient to result in HSCR disease. In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrb(sl mutations. Moreover, we found that this mutation results in serious congenital sensorineural deafness, and these strains may be used as ideal models of Waardenburg Syndrome Type 4 (WS4. Furthermore, we evaluated how the same changed genetic background modifies three features of WS4 syndrome, aganglionosis, hearing loss, and pigment disorder in these congenic strains. We found that the same genetic background markedly changed the aganglionosis, but resulted in only slight changes to hearing loss and pigment disorder. This provided the important evidence, in support of previous studies, that different lineages of neural crest-derived cells migrating along with various pathways are regulated by different signal molecules. This study will help us to better understand complicated diseases such as HSCR and WS4 syndrome.

  4. Genetic structure of wild pea (Pisum sativum subsp. elatius) populations in the northern part of the Fertile Crescent reflects moderate cross-pollination and strong effect of geographic but not environmental distance.

    Science.gov (United States)

    Smýkal, Petr; Trněný, Oldřich; Brus, Jan; Hanáček, Pavel; Rathore, Abhishek; Roma, Rani Das; Pechanec, Vilém; Duchoslav, Martin; Bhattacharyya, Debjyoti; Bariotakis, Michalis; Pirintsos, Stergios; Berger, Jens; Toker, Cengiz

    2018-01-01

    Knowledge of current genetic diversity and mating systems of crop wild relatives (CWR) in the Fertile Crescent is important in crop genetic improvement, because western agriculture began in the area after the cold-dry period known as Younger Dryas about 12,000 years ago and these species are also wild genepools of the world's most important food crops. Wild pea (Pisum sativum subsp. elatius) is an important source of genetic diversity for further pea crop improvement harbouring traits useful in climate change context. The genetic structure was assessed on 187 individuals of Pisum sativum subsp. elatius from fourteen populations collected in the northern part of the Fertile Crescent using 18,397 genome wide single nucleotide polymorphism DARTseq markers. AMOVA showed that 63% of the allelic variation was distributed between populations and 19% between individuals within populations. Four populations were found to contain admixed individuals. The observed heterozygosity ranged between 0.99 to 6.26% with estimated self-pollination rate between 47 to 90%. Genetic distances of wild pea populations were correlated with geographic but not environmental (climatic) distances and support a mixed mating system with predominant self-pollination. Niche modelling with future climatic projections showed a local decline in habitats suitable for wild pea, making a strong case for further collection and ex situ conservation.

  5. MAJOR MOLECULAR GENETIC DRIVERS IN SPORADIC PRIMARY HYPERPARATHYROIDISM.

    Science.gov (United States)

    Arnold, Andrew

    2016-01-01

    Primary hyperparathyroidism is primarily due to a solitary parathyroid adenoma but multi-gland disease, parathyroid carcinoma, and ectopic parathyroid hormone production can occur. Although primary hyperparathyroidism mostly presents sporadically, strong familial predispositions also exist. Much is known about heritable genetic mutations responsible for these syndromes, including multiple endocrine neoplasia types 1 and 2A, hyperparathyroidism-jaw tumor syndrome, and familial hypocalciuric hypercalcemia. Acquired mutations in common sporadic hyperparathyroidism have also been discovered. Here we focus on the most common and well-established genetic drivers: 1) involvement of the oncogene cyclin D1 in human neoplasia was first established in parathyroid adenomas, followed by recognition of its importance in other tumor types including breast cancer and B-lymphoid malignancy; and 2) somatic mutation of the MEN1 gene, first identified as the source of pathogenic germline mutations in patients with familial endocrinopathies, is found in a substantial fraction of non-familial parathyroid adenomas.

  6. Unifying diseases through common genetic mechanisms: the example of the genetic theory of infectious diseases

    OpenAIRE

    Darrason, Marie

    2013-01-01

    International audience; In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, M...

  7. Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry.

    Directory of Open Access Journals (Sweden)

    Cameron M Scott

    Full Text Available DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development. We applied the Infinium HumanMethylation450 Beadchip (HM450K array to blood and tumor-derived DNA from 43 women diagnosed with breast cancer before the age of 40 years and measured the methylation profiles across promoter regions of BRCA1, BRCA2, ATM, PALB2, CDH1, TP53, FANCM, CHEK2, MLH1, MSH2, MSH6 and PMS2. Prior genetic testing had demonstrated that these women did not carry a germline mutation in BRCA1, ATM, CHEK2, PALB2, TP53, BRCA2, CDH1 or FANCM. In addition to the BRCA1 promoter region, this work identified regions with variable methylation at multiple breast cancer susceptibility genes including PALB2 and MLH1. Methylation at the region of MLH1 in these breast cancers was not associated with microsatellite instability. This work informs future studies of the role of methylation in breast cancer susceptibility gene silencing.

  8. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer.

    Science.gov (United States)

    Rummel, Seth K; Lovejoy, Leann; Shriver, Craig D; Ellsworth, Rachel E

    2017-08-01

    Although breast cancer in young women accounts for cancer predisposition genes is needed to improve the understanding of breast cancer etiology in young women. All female patients enrolled in the Clinical Breast Cancer Project between 2001 and 2015 and diagnosed with invasive breast cancer before age 40 were included in this study. Family history was classified using the NCCN Familial Risk Assessment guidelines. Targeted sequencing of 94 cancer predisposition genes was performed using peripheral blood DNA. Variants were detected using VariantStudio and classified using ClinVar. Seven percent (141/1980) of patients were young women and 44 had a significant family history. Sequencing was completed for 118 women with genomic DNA. Pathogenic mutations were present in 27 patients: BRCA1 (n = 10), BRCA2 (n = 12), TP53 (n = 1), and CHEK2 (n = 4). Mutations classified as pathogenic were also detected in APC (n = 1) and MUTYH (n = 2). Variants of uncertain significance (VUS) were detected in an additional 17 patients in ten genes. Pathogenic mutations in high- and moderate-risk breast cancer genes were detected in 23% of young women with an additional 3% having pathogenic mutations in colon cancer predisposition genes. VUS were observed in 14% of women in genes such as ATM, BRCA2, CDH1, CHEK2, and PALB2. Identification of those non-genetic factors is critical to reduce the burden of breast cancer in this population.

  9. Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry.

    Science.gov (United States)

    Scott, Cameron M; Joo, JiHoon Eric; O'Callaghan, Neil; Buchanan, Daniel D; Clendenning, Mark; Giles, Graham G; Hopper, John L; Wong, Ee Ming; Southey, Melissa C

    2016-01-01

    DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development. We applied the Infinium HumanMethylation450 Beadchip (HM450K) array to blood and tumor-derived DNA from 43 women diagnosed with breast cancer before the age of 40 years and measured the methylation profiles across promoter regions of BRCA1, BRCA2, ATM, PALB2, CDH1, TP53, FANCM, CHEK2, MLH1, MSH2, MSH6 and PMS2. Prior genetic testing had demonstrated that these women did not carry a germline mutation in BRCA1, ATM, CHEK2, PALB2, TP53, BRCA2, CDH1 or FANCM. In addition to the BRCA1 promoter region, this work identified regions with variable methylation at multiple breast cancer susceptibility genes including PALB2 and MLH1. Methylation at the region of MLH1 in these breast cancers was not associated with microsatellite instability. This work informs future studies of the role of methylation in breast cancer susceptibility gene silencing.

  10. Genetics Home Reference: parathyroid cancer

    Science.gov (United States)

    ... of parathyroid cancer are not caused by inherited genetic factors. These cancers are associated with somatic mutations that are acquired during a person's lifetime, and they do not cluster in families. A predisposition to parathyroid cancer caused by a germline mutation ...

  11. Molecular genetics of hemophilia A: Clinical perspectives

    African Journals Online (AJOL)

    Azza A.G. Tantawy

    incompletely explained by genetic predisposition [71]. The observation of hemophilic monozygotic twins discor- dant for inhibitors points out the interplay of non-genetic fac- tors. Theoretically, challenges of the immune system brought about by infections, vaccinations, and tissue damage in associ- ation with FVIII exposure ...

  12. Genetic association studies in lumbar disc degeneration

    DEFF Research Database (Denmark)

    Eskola, Pasi J; Lemmelä, Susanna; Kjaer, Per

    2012-01-01

    Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI) in humans....

  13. Ashkenazi Jewish genetic disorders.

    Science.gov (United States)

    Charrow, Joel

    2004-01-01

    The frequency of several genes responsible for 'single-gene' disorders and disease predispositions is higher among Ashkenazi Jews than among Sephardi Jews and non-Jews. The disparity is most likely the result of founder effect and genetic drift, rather than heterozygote advantage. The more common Mendelian Ashkenazi Jewish genetic disorders are summarized, and examples of variable expressivity and penetrance, inconsistent genotype-phenotype correlation, and potential modifiers are presented. The importance of genetic counseling in both the pre- and post-test phases of population screening is emphasized.

  14. Interactions between genetic variants associated with adiposity traits and soft drinks in relation to longitudinal changes in body weight and waist circumference

    DEFF Research Database (Denmark)

    Olsen, Nanna J; Ängquist, Lars; Larsen, Sofus C

    2016-01-01

    Background: Intake of sugar-sweetened beverages is associated with obesity, and this association may be modified by a genetic predisposition to obesity. Objective: We examined the interactions between a molecular genetic predisposition to various aspects of obesity and the consumption of soft...... drinks, which are a major part of sugar-sweetened beverages, in relation to changes in adiposity measures. Design: A total of 4765 individuals were included in the study. On the basis of 50 obesity- Associated single nucleotide polymorphisms that are associated with body mass index (BMI), waist...... circumference (WC), or the waist- To-hip ratio adjusted for BMI (WHRBMI), the following 4 genetic predisposition scores (GRSs) were constructed: A complete genetic predisposition score including all 50 single nucleotide polymorphisms (GRSComplete), a genetic predisposition score including BMI- Associated single...

  15. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

    Science.gov (United States)

    Ye, Byong Duk; McGovern, Dermot P.B.

    2016-01-01

    Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD. PMID:27156530

  16. Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

    DEFF Research Database (Denmark)

    Ciofu, Oana; Mandsberg, Lotte F.; Bjarnsholt, Thomas

    2010-01-01

    During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated...

  17. Comparative analyses of genetic risk prediction methods reveal ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 94; Issue 1. Comparative analyses of genetic risk prediction methods reveal extreme diversity of genetic predisposition to nonalcoholic fatty liver disease (NAFLD) among ethnic populations of India. Ankita Chatterjee Analabha Basu Abhijit Chowdhury Kausik Das Neeta ...

  18. Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer.

    Science.gov (United States)

    Eisen, A; Rebbeck, T R; Wood, W C; Weber, B L

    2000-05-01

    To review the published literature on the efficacy and adverse effects of prophylactic mastectomy (PM) and prophylactic oophorectomy (PO) in women with a hereditary predisposition to breast and ovarian cancer and to provide management recommendations for these women. Using the terms "prophylactic," "preventive," "bilateral," "mastectomy," "oophorectomy," and "ovariectomy," a MEDLINE search of the English-language literature for articles related to PM and PO was performed. The bibliographies of these articles were reviewed to identify additional relevant references. There have been no prospective trials of PM or PO for the reduction of breast cancer or ovarian cancer incidence or mortality. Most of the available retrospective studies are composed of women who had surgery for a variety of indications and in whom genetic risk was not well characterized. However, some reports in women at increased risk of breast or ovarian cancer have shown that PM and PO can reduce cancer incidence. Interest in and use of PM and PO are high among physicians and high-risk women. PM and PO seem to be associated with considerable reduction in the risk of breast and ovarian cancer, albeit incomplete. The surgical morbidity of PM and PO is low, but the complications of premature menopause may be significant, and few studies address quality-of-life issues in women who have opted for PM and PO. Management recommendations for high-risk individuals are presented on the basis of the available evidence.

  19. Cliff-edge model predicts intergenerational predisposition to dystocia and Caesarean delivery.

    Science.gov (United States)

    Mitteroecker, Philipp; Windhager, Sonja; Pavlicev, Mihaela

    2017-10-31

    Recently, we presented the cliff-edge model to explain the evolutionary persistence of relatively high incidences of fetopelvic disproportion (FPD) in human childbirth. According to this model, the regular application of Caesarean sections since the mid-20th century has triggered an evolutionary increase of fetal size relative to the dimensions of the maternal birth canal, which, in turn, has inflated incidences of FPD. While this prediction is difficult to test in epidemiological data on Caesarean sections, the model also implies that women born by Caesarean because of FPD are more likely to develop FPD in their own childbirth compared with women born vaginally. Multigenerational epidemiological studies indeed evidence such an intergenerational predisposition to surgical delivery. When confined to anatomical indications, these studies report risks for Caesarean up to twice as high for women born by Caesarean compared with women born vaginally. These findings provide independent support for our model, which we show here predicts that the risk of FPD for mothers born by Caesarean because of FPD is 2.8 times the risk for mothers born vaginally. The congruence between these data and our prediction lends support to the cliff-edge model of obstetric selection and its underlying assumptions, despite the genetic and anatomical idealizations involved. Copyright © 2017 the Author(s). Published by PNAS.

  20. The Effect of Phototherapy on Cancer Predisposition Genes of Diabetic and Normal Human Skin Fibroblasts

    Directory of Open Access Journals (Sweden)

    Pongsathorn Chotikasemsri

    2017-01-01

    Full Text Available The purpose of this study was to investigate whether LED light at different wavelengths affects the expression profile of 143 cancer predisposition genes in both diabetic and normal human fibroblasts. In this study, both diabetic and normal fibroblast cell lines were cultured and irradiated with red (635 nm, green (520 nm, and blue (465 nm LED light for 10 minutes at 0.67 J/cm2 each. After that, mRNA from all cell lines was extracted for microarray analysis. We found that green light activates EPHB2, KIT, ANTXR2, ESCO2, MSR1, EXT1, TSC1, KIT, NF1, BUB1B, FANCD2, EPCAM, FANCD2, NF, DIS3L2, and RET in normal fibroblast cells, while blue and red light can upregulate RUNX1, PDGFRA, EHBP1, GPC3, AXIN2, KDR, GLMN, MSMB, EPHB2, MSR1, KIT, FANCD2, BMPR1A, BUB1B, PDE11A, and RET. Therefore, genetic screening before phototherapy treatment may be required.

  1. The Effect of Phototherapy on Cancer Predisposition Genes of Diabetic and Normal Human Skin Fibroblasts.

    Science.gov (United States)

    Chotikasemsri, Pongsathorn; Tangtrakulwanich, Boonsin; Sangkhathat, Surasak

    2017-01-01

    The purpose of this study was to investigate whether LED light at different wavelengths affects the expression profile of 143 cancer predisposition genes in both diabetic and normal human fibroblasts. In this study, both diabetic and normal fibroblast cell lines were cultured and irradiated with red (635 nm), green (520 nm), and blue (465 nm) LED light for 10 minutes at 0.67 J/cm 2 each. After that, mRNA from all cell lines was extracted for microarray analysis. We found that green light activates EPHB2, KIT, ANTXR2, ESCO2, MSR1, EXT1, TSC1, KIT, NF1, BUB1B, FANCD2, EPCAM, FANCD2, NF, DIS3L2, and RET in normal fibroblast cells, while blue and red light can upregulate RUNX1, PDGFRA, EHBP1, GPC3, AXIN2, KDR, GLMN, MSMB, EPHB2, MSR1, KIT, FANCD2, BMPR1A, BUB1B, PDE11A, and RET. Therefore, genetic screening before phototherapy treatment may be required.

  2. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens.

    Science.gov (United States)

    Giménez-Barcons, Mireia; Casteràs, Anna; Armengol, Maria del Pilar; Porta, Eduard; Correa, Paula A; Marín, Ana; Pujol-Borrell, Ricardo; Colobran, Roger

    2014-10-15

    Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals. Copyright © 2014 by The American Association of Immunologists, Inc.

  3. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer.

    Science.gov (United States)

    Ruark, Elise; Snape, Katie; Humburg, Peter; Loveday, Chey; Bajrami, Ilirjana; Brough, Rachel; Rodrigues, Daniel Nava; Renwick, Anthony; Seal, Sheila; Ramsay, Emma; Duarte, Silvana Del Vecchio; Rivas, Manuel A; Warren-Perry, Margaret; Zachariou, Anna; Campion-Flora, Adriana; Hanks, Sandra; Murray, Anne; Ansari Pour, Naser; Douglas, Jenny; Gregory, Lorna; Rimmer, Andrew; Walker, Neil M; Yang, Tsun-Po; Adlard, Julian W; Barwell, Julian; Berg, Jonathan; Brady, Angela F; Brewer, Carole; Brice, Glen; Chapman, Cyril; Cook, Jackie; Davidson, Rosemarie; Donaldson, Alan; Douglas, Fiona; Eccles, Diana; Evans, D Gareth; Greenhalgh, Lynn; Henderson, Alex; Izatt, Louise; Kumar, Ajith; Lalloo, Fiona; Miedzybrodzka, Zosia; Morrison, Patrick J; Paterson, Joan; Porteous, Mary; Rogers, Mark T; Shanley, Susan; Walker, Lisa; Gore, Martin; Houlston, Richard; Brown, Matthew A; Caufield, Mark J; Deloukas, Panagiotis; McCarthy, Mark I; Todd, John A; Turnbull, Clare; Reis-Filho, Jorge S; Ashworth, Alan; Antoniou, Antonis C; Lord, Christopher J; Donnelly, Peter; Rahman, Nazneen

    2013-01-17

    Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

  4. The Influence of Familial Predisposition to Cardiovascular Complications upon Childhood Obesity Treatment

    DEFF Research Database (Denmark)

    Nielsen, Louise A; Bøjsøe, Christine; Kloppenborg, Julie T

    2015-01-01

    INTRODUCTION: The aim was to investigate whether a familial predisposition to obesity related cardiovascular complications was associated with the degree of obesity at baseline and/or changes in the degree of obesity during a multidisciplinary childhood obesity treatment program. METHODS: The study......) calculated, and self-reported information on familial predisposition to obesity, hypertension, type 2 diabetes mellitus (T2DM), thromboembolic events, and dyslipidaemia were obtained. A familial predisposition included events in biological parents, siblings, grandparents, uncles, and aunts. The treatment...... outcomes were categorically analysed according to the prevalence of familial predispositions. RESULTS: The median BMI SDS at enrollment was 3.2 in boys and 2.8 in girls. One-thousand-and-forty-one children had obesity in their family, 773 had hypertension, 551 had T2DM, 568 had thromboembolic events...

  5. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people.

    NARCIS (Netherlands)

    Henquet, C.J.; Krabbendam, L.; Spauwen, P.H.M.; Kaplan, C.; Lieb, R.; Wittchen, H.U.; Os, J. van

    2005-01-01

    OBJECTIVE: To investigate the relation between cannabis use and psychotic symptoms in individuals with above average predisposition for psychosis who first used cannabis during adolescence. DESIGN: Analysis of prospective data from a population based sample. Assessment of substance use,

  6. Verification of the model of predisposition in triathlon – structural model of confirmative factor analysis

    Directory of Open Access Journals (Sweden)

    Lenka Kovářová

    2012-09-01

    Full Text Available BACKGROUND: The triathlon is a combination of three different types of sport – swimming, cycling, and running. Each of these requires different top level predispositions and complex approach to talent selection is a rather difficult process. Attempts to identify assumptions in the triathlon have so far been specific and focused only on some groups of predispositions (physiology, motor tests, and psychology. The latest studies missed the structural approach and were based on determinants of sport performance, theory of sports training and expert assessment. OBJECTIVE: The aim of our study was to verify the model of predisposition in the short triathlon for talent assessment of young male athletes age 17–20 years. METHODS: The research sample consisted of 55 top level triathletes – men, who were included in the Government supported sports talent programme in the Czech Republic at the age of 17–20 years. We used a confirmative factor analysis (FA and Path diagram to verify the model, which allow us to explain mutual relationships among observed variables. For statistical data processing we used a structure equating modeling (SEM by software Lisrel L88. RESULTS: The study confirms best structural model for talent selection in triathlon at the age of 17–20 years old men, which composed seventeen indicators (tests and explained 91% of all cross-correlations (Goodness of Fit Index /GFI/ 0.91, Root Mean Square Residual /RMSR/ 0.13. Tests for predispositions in triathlons were grouped into five items, three motor predispositions (swimming, cycling and running skills, aerobic and psychological predispositions. Aerobic predispositions showed the highest importance to the assumptions to the general factor (1.00; 0. Running predispositions were measured as a very significant factor (–0.85; 0.28 which confirms importance of this critical stage of the race. Lower factor weight showed clusters of swimming (–0.61; 0.63 and cycling (0.53; 0

  7. Genetics of upper and lower airway diseases in the horse.

    OpenAIRE

    Gerber V; Tessier C; Marti E

    2014-01-01

    Genetic predispositions for guttural pouch tympany recurrent laryngeal neuropathy and recurrent airway obstruction (RAO) are well documented. There is also evidence that exercise induced pulmonary haemorrhage and infectious diseases of the respiratory tract in horses have a genetic component. The clinical expression of equine respiratory diseases with a genetic basis results from complex interactions between the environment and the genetic make up of each individual horse. The genetic effects...

  8. Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

    DEFF Research Database (Denmark)

    Baillie, J Kenneth; Bretherick, Andrew; Haley, Christopher S

    2018-01-01

    Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns...... the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes...... in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely...

  9. Melanoma genetics

    DEFF Research Database (Denmark)

    Read, Jazlyn; Wadt, Karin A W; Hayward, Nicholas K

    2015-01-01

    Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of herita......Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence...... in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely...... polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some 'melanoma' predisposition genes have been linked to other cancers, with cancer clustering observed...

  10. From predisposition to psychosis: progression of symptoms in schizophrenia

    DEFF Research Database (Denmark)

    Parnas, Josef

    1999-01-01

    Schizophrenia is increasingly viewed as a neurodevelopmental process caused by an interaction between genetic factors and environmental stressors. Prospective studies and retrospective research using objective data indicate that behavioural deviations can be dated to early infancy and cut across...

  11. Unifying diseases from a genetic point of view: the example of the genetic theory of infectious diseases.

    Science.gov (United States)

    Darrason, Marie

    2013-08-01

    In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, and major gene and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call "a regional genetic theory." I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease.

  12. BRCA1 and BRCA2: Cancer Risk and Genetic Testing

    Science.gov (United States)

    ... MR imaging in women with a familial or genetic predisposition. Breast Cancer Research and Treatment 2010; 119(2):399–407. [PubMed Abstract] Evans DG, Gaarenstroom KN, Stirling D, et al. Screening for familial ovarian cancer: Poor ... Genetics 2009; 46(9):593–597. [PubMed Abstract] Domchek ...

  13. Untangling genetic networks of panic, phobia, fear and anxiety

    Science.gov (United States)

    Villafuerte, Sandra; Burmeister, Margit

    2003-01-01

    As is the case for normal individual variation in anxiety levels, the conditions panic disorder, agoraphobia and other phobias have a significant genetic basis. Recent reports have started to untangle the genetic relationships between predispositions to anxiety and anxiety disorders. PMID:12914652

  14. Genetics Home Reference: Sjögren syndrome

    Science.gov (United States)

    ... syndrome in particular. The inheritance pattern of this predisposition is unknown. Related Information What does it mean if a disorder seems to run in my family? What are the different ways in which a genetic condition can be inherited? More about Inheriting Genetic ...

  15. Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia

    NARCIS (Netherlands)

    Schubert, Stephanie A.; Ruano, Dina; Elsayed, Fadwa A.; Boot, Arnoud; Crobach, Stijn; Sarasqueta, Arantza Farina; Wolffenbuttel, Bruce; van der Klauw, Melanie M.; Oosting, Jan; Tops, Carli M.; van Eijk, Ronald; Vasen, Hans F. A.; Vossen, Rolf H. A. M.; Nielsen, Maartje; Castellvi-Bel, Sergi; Ruiz-Ponte, Clara; Tomlinson, Ian; Dunlop, Malcolm G.; Vodicka, Pavel; Wijnen, Juul T.; Hes, Frederik J.; Morreau, Hans; de Miranda, Noel F. C. C.; Sijmons, Rolf H.; van Wezel, Tom

    2017-01-01

    Background: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. Methods: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various

  16. [Hormonotherapy for breast cancer prevention: What about women with genetic predisposition to breast cancer?].

    Science.gov (United States)

    Sénéchal, Claire; Reyal, Fabien; Callet, Nasrine; This, Pascale; Noguès, Catherine; Stoppa-Lyonnet, Dominique; Fourme, Emmanuelle

    2016-03-01

    In France, women carrying BRCA1/2 mutation, at an identified high risk of breast cancer are recommended to undergo breast MRI screening. That screening does not however prevent the risk of developing a breast cancer. The only alternative to breast cancer screening available in France is surgical prevention by prophylactic mastectomy. An interesting option for women who wish to reduce their breast cancer risk, but are unready for prophylactic mastectomy is a preventive hormonal treatment by aromatase inhibitors, or selective estrogens receptor modulators (SERMs). Reliable clinical trials show the efficiency of tamoxifen, raloxifen, exemestane, and anastrozole especially, in reducing breast cancer incidence by 33%, 34%, 65% and 53% respectively. This article tries to sum up the main published trials of breast cancer prevention with hormonal treatment, and presents the latest American and English clinical guidelines concerning hormonal prevention for women at high risk of breast cancer, and starts thinking about the possibilities of hormonoprevention, especially among women carrying a BRCA1/2 mutation in France. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  17. Effects and Costs of Breast Cancer screening in women with a familial or genetic predisposition

    OpenAIRE

    Rijnsburger, Rian

    2005-01-01

    textabstract"Women with a BRCA1 or BRCA2 mutation, who have a considerable increased risk of developing breast cancer, now face the choice of intensive screening, prophylactic surgery or chemoprevention. The efficacy of the various medical options and the durability of its effects are of major concern to female BRCA1/2 mutation carriers, and will influence their choices. Although prophylactic mastectomy reduces the rate of breast cancer risk of 90 % or more, the intervention is irreversible, ...

  18. Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

    DEFF Research Database (Denmark)

    Sawyer, Elinor; Roylance, Rebecca; Petridis, Christos

    2014-01-01

    Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast......(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P... for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs...

  19. Research Directions in Genetic Predispositions to Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis.

    Science.gov (United States)

    Manolio, Teri A; Hutter, Carolyn M; Avigan, Mark; Cibotti, Ricardo; Davis, Robert L; Denny, Joshua C; Grenade, Lois La; Wheatley, Lisa M; Carrington, Mary N; Chantratita, Wasun; Chung, Wen-Hung; Dalton, Andrea D; Hung, Shuen-Iu; Lee, Ming Ta Michael; Leeder, J Steven; Lertora, Juan J L; Mahasirimongkol, Surakameth; McLeod, Howard L; Mockenhaupt, Maja; Pacanowski, Michael; Phillips, Elizabeth J; Pinheiro, Simone; Pirmohamed, Munir; Sung, Cynthia; Suwankesawong, Wimon; Trepanier, Lauren; Tumminia, Santa J; Veenstra, David; Yuliwulandari, Rika; Shear, Neil H

    2018-03-01

    Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  20. Genetic predisposition to ductal carcinoma in situ of the breast

    DEFF Research Database (Denmark)

    Petridis, Christos; Brook, Mark N; Shah, Vandna

    2016-01-01

    BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, o...

  1. Subclinical psychotic experiences in healthy young adults: associations with stress and genetic predisposition.

    Science.gov (United States)

    Bruenig, Dagmar; White, Melanie J; Young, Ross McD; Voisey, Joanne

    2014-10-01

    Stress has been identified as a common trigger for psychosis. Dopamine pathways are suggested to be affected by chronic and severe stress and to play an important role in psychosis. This pilot study investigates the potential relationship of stress and psychosis in subclinical psychotic experiences. It was hypothesized that single-nucleotide polymorphisms (SNPs) previously found to be associated with psychiatric disorders would be associated with both stress and subclinical psychotic experiences. University students (N=182) were genotyped for 17 SNPs across 11 genes. Higher stress reporting was associated with rs4680 COMT, rs13211507 HLA region, and rs13107325 SLC39A8. Reports of higher subclinical psychotic experiences were associated with DRD2 SNPs rs17601612 and rs658986 and an AKT1 SNP rs2494732. Replication studies are recommended to further pursue this line of research for identification of markers of psychosis for early diagnosis and intervention.

  2. Women's acceptance of MRI in breast cancer surveillance because of a familial or genetic predisposition

    NARCIS (Netherlands)

    Essink-Bot, M. L.; Rijnsburger, A. J.; van Dooren, S.; de Koning, H. J.; Seynaeve, C.

    2006-01-01

    Magnetic resonance imaging (MRI) of the breasts is a promising screening modality for early detection in women at increased breast cancer risk. We investigated the subjective experiences with MRI and the preferences for MRI, mammography or clinical breast examination in 178 high-risk women adhering

  3. Environmental Exposure and Genetic Predisposition as Risk Factors for Asthma in China.

    Science.gov (United States)

    Chen, Yan; Wong, Gary W K; Li, Jing

    2016-03-01

    Asthma is the most common chronic pulmonary disease worldwide and places a considerable economic burden on society. China is the world's largest developing country and has the largest population. China has undergone dramatic changes in the past few decades. The traditional lifestyle and living environment have changed in ways that directly affect the prevalence of asthma. The prevalence of asthma is lower in Chinese children and adults than in developed countries, but the prevalence has been on the rise during the past 30 years. The prevalence significantly varies among different parts of China. Polymorphisms of multiple genes, outdoor air pollution caused by PM2.5, PM10, SO₂, NO₂, environmental tobacco smoke, and coal, indoor pollution, and inhaled allergens, such as house dust mites, pollen, and cockroach particles, are risk factors for asthma.

  4. Effects and Costs of Breast Cancer screening in women with a familial or genetic predisposition

    NARCIS (Netherlands)

    A.J. Rijnsburger (Rian)

    2005-01-01

    textabstract"Women with a BRCA1 or BRCA2 mutation, who have a considerable increased risk of developing breast cancer, now face the choice of intensive screening, prophylactic surgery or chemoprevention. The efficacy of the various medical options and the durability of its effects are of major

  5. Prevalence of Hyperinsulinemia Associated with Body Mass Index, Genetic Predisposition, and Lifestyle in College Freshmen Students

    Science.gov (United States)

    Hopper, Mari K.; Brown, Gordon W.; Funke, Katharine A.; Pike Brown, Leslie R.

    2012-01-01

    Objective: College lifestyle places an individual at greater risk for the development of insulin resistance (IR) and disease. The aim of this study was to establish a baseline measurement of insulin, and other variables influencing IR in college freshmen. Participants: Twenty-two men and women, 18 to 19 years of age, during first month of college.…

  6. Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia.

    Czech Academy of Sciences Publication Activity Database

    Schubert, S.A.; Ruano, D.; Elsayed, F.A.; Boot, A.; Crobach, S.; Sarasqueta, A.F.; Wolffenbuttel, B.; van der Klauw, M.M.; Oosting, J.; Tops, C.M.; van Eijk, R.; Vasen, H.F.; Vossen, R.H.; Nielsen, M.; Castellví-Bel, S.; Ruiz-Ponte, C.; Tomlinson, I.; Dunlop, M.G.; Vodička, Pavel; Wijnen, J.T.; Hes, F.J.; Morreau, H.; de Miranda, N.F.; Sijmons, R.H.; van Wezel, T.

    2017-01-01

    Roč. 117, č. 8 (2017), s. 1215-1223 ISSN 0007-0920 R&D Projects: GA MŠk(CZ) LD14050 Institutional support: RVO:68378041 Keywords : hereditary colorectal cancer * colorectal polyps * homozygosity mapping Subject RIV: EB - Gene tics ; Molecular Biology OBOR OECD: Biochemistry and molecular biology Impact factor: 6.176, year: 2016

  7. Genetic Predisposition and Sensory Experience in Language Development: Evidence from Cochlear-Implanted Children

    Science.gov (United States)

    Coene, Martine; Schauwers, Karen; Gillis, Steven; Rooryck, Johan; Govaerts, Paul J.

    2011-01-01

    Recent neurobiological studies have advanced the hypothesis that language development is not continuously plastic but is governed by biological constraints that may be modified by experience within a particular time window. This hypothesis is tested based on spontaneous speech data from deaf cochlear-implanted (CI) children with access to…

  8. A possible association between the genetic predisposition for dizygotic twinning and schizophrenia

    DEFF Research Database (Denmark)

    Kläning, Ulla; Pedersen, Carsten Bøcker; Mortensen, Preben Bo

    2002-01-01

    BACKGROUND: A previous study demonstrated a 40% higher rate of schizophrenia in dizygotic twins than in the general population. The aim of the present study is to evaluate whether genes influencing the rate of dizygotic twinning and genes of importance for developing schizophrenia can be associat...

  9. Cannabis use and genetic predisposition for schizophrenia : a case-control study

    NARCIS (Netherlands)

    Veling, W; Mackenbach, J P; van Os, J; Hoek, H W

    BACKGROUND: Cannabis use may be a risk factor for schizophrenia. Part of this association may be explained by genotype-environment interaction, and part of it by genotype-environment correlation. The latter issue has not been explored. We investigated whether cannabis use is associated with

  10. Response to Comments on ?High Altitude Pulmonary Edema in an Experienced Mountaineer. Possible Genetic Predisposition?

    OpenAIRE

    Whitlow, Kenneth S.

    2015-01-01

    We appreciate the letter to the editor and are pleased to respond regarding our recent case study regarding high altitude pulmonary edema in an experienced mountaineer. The letter raises some valid questions regarding our treatment decisions.

  11. Characterization of genetic predisposition and autoantibody profile in atypical hemolytic uremic syndrome.

    Science.gov (United States)

    Gurjar, Bahadur Singh; Sriharsha, T Manikanta; Bhasym, Angika; Prabhu, Savit; Puraswani, Mamta; Khandelwal, Priyanka; Saini, Himanshi; Saini, Savita; Verma, Anita Kamra; Chatterjee, Priyadarshini; Gucchait, Prasenjit; Bal, Vineeta; George, Anna; Rath, Satyajit; Sahu, Arvind; Sharma, Amita; Hari, Pankaj; Sinha, Aditi; Bagga, Arvind

    2018-02-27

    We previously reported that Indian pediatric patients of atypical hemolytic-uremic syndrome (aHUS) showed high frequencies of anti-complement factor H (FH) autoantibodies that are correlated with homozygous deletion of the genes for FH-related proteins 1 and 3 (FHR1 and FHR3) (FHR1/3-/-). We now report that Indian pediatric aHUS patients without anti-FH autoantibodies also showed modestly higher frequencies of the FHR1/3-/- genotype. Further, when we characterized epitope specificities and binding avidities of anti-FH autoantibodies in aHUS patients, most anti-FH autoantibodies were directed towards the FH cell-surface anchoring polyanionic binding site-containing C-terminal short conservative regions (SCRs) 17-20 with higher binding avidities than for native FH. FH SCR17-20-binding anti-FH autoantibodies also bound the other cell-surface anchoring polyanionic binding site-containing region FH SCR5-8, at lower binding avidities. Anti-FH autoantibody avidities correlated with antibody titres. These anti-FH autoantibody characteristics did not differ between aHUS patients with or without the FHR1/3-/- genotype. Our data suggest a complex matrix of interactions between FHR1-FHR3 deletion, immunomodulation and anti-FH autoantibodies in the etiopathogenesis of aHUS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. Cancer predispostition, radiosensitivity and the risk of radiation-induced cancers. II. A mendelian single-locus model of cancer predisposition and radiosensitivity for predicting cancer risks in populations

    International Nuclear Information System (INIS)

    Chakraborty, R.; Sankaranarayanan, K.

    1995-01-01

    Individuals genetically predisposed to cancer may be more sensitive to cancers induced by ionizing radiation than those who are not so predisposed. Should this be true, under conditions of radiation exposure, a population consisting of cancer-predisposed and non-predisposed individuals will be expected to respond with a higher total frequency of induced cancers than one in which all the individuals are assumed to have the same sensitivity to radiation-induced cancers. To study this problem quantitatively, we have developed a Mendelian autosomal one-locus, two-allele model; this model assumes that one of the alleles is mutant and the genotypes carrying the mutant allele(s) are cancer-predisposed and are also more sensitive to radiation-induced cancer. Formal analytical predictions as well as numerical illustrations of this model show that: (1) when such heterogeneity with respect to cancer predisposition and radiosensitivity is present in the population, irradiation results in a greater increase in the frequency of induced cancers than when it is absent; (2) this increase is detectable only when the proportion of cancers due to genetic predisposition is large and when the degree of predisposition is considerable; and (3) even when the effect is small, most of the radiation-induced cancers will occur in predisposed individuals. These conclusions are valid for models of cancer when predisposition and radiosensitivity may be either dominant or recessive. The published data on breast cancers in Japanese A-bomb survivors show that at 1 Sv, the radiation-related excess relative risk in women irradiated before age 20 is 13 compared to about 2 for those irradiated at later ages. We examined the application of our model to the above data using two assumptions, namely, that the proportion of cancers due to genetic susceptibility at the BRCA1 locus and the frequency of the mutant allele estimated for Western populations are valid for Japanese women. 14 refs., 3 figs., 5 tabs

  13. Personality Predispositions to Depression in Children of Affectively-Ill Parents: The Buffering Role of Self-Esteem

    Science.gov (United States)

    Abela, John R. Z.; Fishman, Michael B.; Cohen, Joseph R.; Young, Jami F.

    2012-01-01

    A major theory of personality predispositions to depression posits that individuals who possess high levels of self-criticism and/or dependency are vulnerable to developing depression following negative life events. The goal of the current study was to test this theory of personality predispositions and the self-esteem buffering hypothesis in a…

  14. Genetic modification and genetic determinism

    Directory of Open Access Journals (Sweden)

    Vorhaus Daniel B

    2006-06-01

    Full Text Available Abstract In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions.

  15. Bridging Home and Host Country: Educational Predispositions of Chinese and Indian Recent Immigrant Families

    Science.gov (United States)

    Gordon, June A.; Liu, Xiangyan

    2015-01-01

    This research focuses on the predispositions that recent Chinese and Indian immigrant families bring with them to the United States and how these are reinforced by the communities in which they locate. The findings draw from 144 interviews in California. Three themes dominate: positioning through schooling, transnational family, and extended…

  16. Predisposition Factors of Career and Technical Education Transfer Students: A Hermeneutic Phenomenology Study

    Science.gov (United States)

    Hioki, Warren; Lester, Derek; Martinez, Mario

    2015-01-01

    Six college students, who were career and technical education (CTE) transfer students in the state of Nevada, were interviewed Spring Semester of 2009. The study used a hermeneutic phenomenology framework as the method to identify those predisposition variables that heavily influenced the students in their decision to transfer to a senior…

  17. The Role of Social Factors in Iranian University Students' Predispositions towards Autonomous Language Learning

    Science.gov (United States)

    Naeeini, Sara Kashefian; Riazi, Abdolmehdi; Salehi, Hadi

    2012-01-01

    In order to meet the demands of the changing world, students should become endowed with the ability to learn perpetually and regard learning as a life-long enterprise. This study investigated those learners belief which showed learners' predispositions toward autonomy and some social factors such as gender, academic achievement, marital status and…

  18. The influence of water table depth and the free atmospheric state on convective rainfall predisposition

    Science.gov (United States)

    Sara Bonetti; Gabriele Manoli; Jean-Christopher Domec; Mario Putti; Marco Marani; Gabriel G. Katul

    2015-01-01

    A mechanistic model for the soil-plant system is coupled to a conventional slab representation of the atmospheric boundary layer (ABL) to explore the role of groundwater table (WT) variations and free atmospheric (FA) states on convective rainfall predisposition (CRP) at a Loblolly pine plantation site situated in the lower coastal plain of North Carolina....

  19. Informing family members about a hereditary predisposition to cancer: attitudes and practices among clinical geneticists

    NARCIS (Netherlands)

    Stol, Y.; Menko, F.H.; Westerman, M.J.; Janssens, M.J.P.A.

    2010-01-01

    If a hereditary predisposition to colorectal cancer or breast cancer is diagnosed, most guidelines state that clinical geneticists should request index patients to inform their at-risk relatives about the existence of this condition in their family, thus enabling them to consider presymptomatic

  20. Knowledge, attitudes and preferences regarding genetic testing for smoking cessation. A cross-sectional survey among Dutch smokers.

    Science.gov (United States)

    Quaak, Marieke; Smerecnik, Chris; van Schooten, Frederik J; de Vries, Hein; van Schayck, Constant P

    2012-01-01

    Objectives Recent research strongly suggests that genetic variation influences smokers' ability to stop. Therefore, the use of (pharmaco) genetic testing may increase cessation rates. This study aims to assess the intention of smokers concerning undergoing genetic testing for smoking cessation and their knowledge, attitudes and preferences about this subject. Design Online cross-sectional survey. Setting Database internet research company of which every inhabitant of the Netherlands of ≥12 years with an email address and capable of understanding Dutch can become a member. Participants 587 of 711 Dutch smokers aged ≥18 years, daily smokers for ≥5 years and smoke on average ≥10 cigarettes/day (response rate=83%). Primary and secondary outcome measures Smokers' knowledge, attitudes and preferences and their intention to undergo genetic testing for smoking cessation. Results Knowledge on the influence of genetic factors in smoking addiction and cessation was found to be low. Smokers underestimated their chances of having a genetic predisposition and the influence of this on smoking cessation. Participants perceived few disadvantages, some advantages and showed moderate self-efficacy towards undergoing a genetic test and dealing with the results. Smokers were mildly interested in receiving information and participating in genetic testing, especially when offered by their general practitioner (GP). Conclusions For successful implementation of genetic testing for smoking in general practice, several issues should be addressed, such as the knowledge on smoking cessation, genetics and genetic testing (including advantages and disadvantages) and the influence of genetics on smoking addiction and cessation. Furthermore, smokers allocate their GPs a crucial role in the provision of information and the delivery of a genetic test for smoking; however, it is unclear whether GPs will be able and willing to take on this role.

  1. Evidence for a genetical contribution to non-smoking-related lung cancer.

    Science.gov (United States)

    Carr, Shamus R; Akerley, Wallace; Hashibe, Mia; Cannon-Albright, Lisa A

    2015-11-01

    The majority of lung cancers are smoking-related, with environmental and genetical factors contributing. The interplay between environmental and genetical contributions in non-smoking-related lung cancers is less clear. We analysed a population-based computerised genealogy resource linked to a state-wide cancer registry of lung cancer cases (n=5544) for evidence of a genetical contribution to lung cancer predisposition in smoking (n=1747) and non-smoking cases (n=784). Statistical methods were used to test for significant excess relatedness of cases and estimate relative risk (RR) in close and distant relatives of lung cancer cases. Significant excess relatedness was observed for all lung cancer cases (psmoking-related (psmoking-related (prelationships were considered. Only the non-smoking-related subset of cases showed significant excess relatedness when close relationships were ignored (p=0.020). First-degree, second-degree, and fourth-degree relatives of non-smoking-related lung cancer cases had significantly elevated RR. An even higher elevated RR was observed for first-degree, second-degree, third-degree and fourth-degree relatives of smoking-related lung cancer cases. Non-smoking-related lung cancer cases show significant excess relatedness for close and distant relationships, providing strong evidence for a genetical contribution as well as an environmental contribution. Significant excess relatedness for only close family relationships in all lung cancer cases and in only smoking-related lung cancer cases implies environmental contribution. Additionally, the highest RR for lung cancer was observed in the relatives of smoking-related lung cancer, suggesting predisposition gene carriers who smoke are at highest risk for lung cancer. Screening and gene identification should focus on high-risk pedigrees. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  2. Genetics and Genetic Testing in Pancreatic Cancer.

    Science.gov (United States)

    Whitcomb, David C; Shelton, Celeste A; Brand, Randall E

    2015-10-01

    Genetic testing of germline DNA is used in patients suspected of being at risk of pancreatic ductal adenocarcinoma (PDAC) to better define the individual's risk and to determine the mechanism of risk. A high genetic risk increases the pretest probability that a biomarker of early cancer is a true positive and warrants further investigation. The highest PDAC risk is generally associated with a hereditary predisposition. However, the majority of PDAC results from complex, progressive gene-environment interactions that currently fall outside the traditional risk models. Over many years, the combination of inflammation, exposure to DNA-damaging toxins, and failed DNA repair promote the accumulation of somatic mutations in pancreatic cells; PDAC risk is further increased by already present oncogenic germline mutations. Predictive models and new technologies are needed to classify patients into more accurate and mechanistic PDAC risk categories that can be linked to improved surveillance and preventative strategies. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Genetics of diabetic nephropathy

    DEFF Research Database (Denmark)

    Parving, H H; Tarnow, L; Rossing, P

    1996-01-01

    of diabetic nephropathy is multifactorial, with contributions from metabolic abnormalities, hemodynamic alterations, and various growth factors and genetic factors. Epidemiologic and family studies have demonstrated that only a subset of the patients develop this complication that family clustering...... of nephropathy is present, and that ethnicity plays an important role in the risk of developing this kidney disease. Short stature and low birth weight are both associated with increased risk of developing diabetic nephropathy, supporting the hypothesis that genetic predisposition or factors operating in utero...... nephropathy have yielded conflicting results. Recently, studies of genetic markers involved in the regulation of blood pressure and levels of cardiovascular risk factors have been conducted. Several studies have demonstrated that the deletion polymorphism in the angiotensin-I-converting enzyme acts as a risk...

  4. Predisposition and genome instability: studies with mouse embryos

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, C. [Essen Universitatsklinikum, (Germany). Institut fur Medizinische Strahlenbiologie

    1997-03-01

    The preimplantation mouse embryo is a useful system for radiobiological studies. Chromosomal aberrations were determined after exposure to X-rays and neutrons during the zygote (1-cell stage). New aberrations developed and were expressed during the 2. and 3. mitosis after irradiation. These later aberration developed from DNA damage which was originally not a DSB. Further chromosomal aberrations were studied in fibroblasts of fetuses 19 days post conception. A significant increase of chromosome aberrations was found in the fetuses which were irradiated in the 1-cell stage and which had developed a malformation. These data can only be explained by the induction of a genome instability through the radiation exposure which had been performed many cell generations earlier. Until recently is was generally accepted that an exposure which had been performed many cell generations earlier. Until recently it was generally accepted that an exposure to ionizing radiation during the preimplantation period of mammalian development will not induce malformations. However, recently it could be shown that certain sensitive mouse strains exist in which malformations are induced by exposure to X-rays and neutrons during the preimplantation period. It was further demonstrated that this effect can be suppressed if the sensitive mouse strain is crossbred with mice from a resistant mouse train. These data show that this radiation effect is due to a genetic phenomenon with a recessive trait. Studies on protein patterns in normal fetuses and in fetuses with the malformation showed that characteristic changes occur. There are proteins which are no longer expressed in the malformed fetuses nd new proteins may appear. Certain changes in glycoproteins and phosphoproteins were found not only in liver of malformed fetuses but also in skin and kidney of these organisms. The analysis of the genome of these malformed fetuses have given evidence that changes in two or three genes are responsible for

  5. Identification ofKANSARLas the first cancer predisposition fusion gene specific to the population of European ancestry origin.

    Science.gov (United States)

    Zhou, Jeff Xiwu; Yang, Xiaoyan; Ning, Shunbin; Wang, Ling; Wang, Kesheng; Zhang, Yanbin; Yuan, Fenghua; Li, Fengli; Zhuo, David D; Tang, Liren; Zhuo, Degen

    2017-08-01

    Gene fusion is one of the hallmarks of cancer. Recent advances in RNA-seq of cancer transcriptomes have facilitated the discovery of fusion transcripts. In this study, we report identification of a surprisingly large number of fusion transcripts, including six KANSARL ( KANSL1 - ARL17A ) transcripts that resulted from the fusion between the KANSL1 and ARL17A genes using a RNA splicingcode model. Five of these six KANSARL fusion transcripts are novel. By systematic analysis of RNA-seq data of glioblastoma, prostate cancer, lung cancer, breast cancer, and lymphoma from different regions of the World, we have found that KANSARL fusion transcripts were rarely detected in the tumors of individuals from Asia or Africa. In contrast, they exist in 30 - 52% of the tumors from North Americans cancer patients. Analysis of CEPH/Utah Pedigree 1463 has revealed that KANSARL is a familially-inherited fusion gene. Further analysis of RNA-seq datasets of the 1000 Genome Project has indicated that KANSARL fusion gene is specific to 28.9% of the population of European ancestry origin. In summary, we demonstrated that KANSARL is the first cancer predisposition fusion gene associated with genetic backgrounds of European ancestry origin.

  6. Assimetria cerebral e lateralização da linguagem: déficits nucleares na esquizofrenia como indicadores da predisposição genética Asimetría cerebral y lateralización del lenguaje: déficits nucleares en la esquizofrenia como indicadores de predisposición genética Cerebral asymmetry and the lateralization of language: core deficits in schizophrenia as pointers to the genetic predisposition

    Directory of Open Access Journals (Sweden)

    Timothy J. Crow

    2004-08-01

    asymmetry stands out as the variable that can make sense of observations across fields of investigation, and provides a key to the genetic basis of psychosis. Discordant monozygotic twin studies have indicated strongly that the relevant variation is epigenetic; this is consistent with the possibility that the variation is related to recent structural changes (the Xq21.3/Yp duplicative transposition on the sex chromosomes.

  7. Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders

    Science.gov (United States)

    Miller, Frederick W.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy; Isenberg, David A.; Chinoy, Hector; Ollier, William E. R.; O’Hanlon, Terrance P.; Peng, Bo; Lee, Annette; Lamb, Janine A.; Chen, Wei; Amos, Christopher I.; Gregersen, Peter K.

    2014-01-01

    Objective To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. PMID:23983088

  8. Role of genetics in the diagnosis and prognosis of Crohn's disease

    Science.gov (United States)

    Tsianos, Epameinondas V; Katsanos, Konstantinos H; Tsianos, Vasileios E

    2012-01-01

    Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn’s disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn’s disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn’s disease and many attempts have been made to classify genetic profiles in Crohn’s disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn’s disease. Enriching our understanding on Crohn’s disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians. PMID:22253516

  9. Testing strong interaction theories

    International Nuclear Information System (INIS)

    Ellis, J.

    1979-01-01

    The author discusses possible tests of the current theories of the strong interaction, in particular, quantum chromodynamics. High energy e + e - interactions should provide an excellent means of studying the strong force. (W.D.L.)

  10. Genetic Aspects of Nephrotic Syndrome

    DEFF Research Database (Denmark)

    Joshi, Shivani

    steroid dependence or become frequent relapsers. Repeated courses of corticosteroid treatment often cause significant associated morbidity. Familial occurrence of SSNS is rare and suggests a potential genetic origin. However, very little data on molecular genetics of familial SSNS is available...... with SSNS are rare, but do indicate a genetic predisposition. In study III we investigated a potential genetic linkage in 9 European SSNS families with at least two affected siblings. Using SNP6 whole genome linkage analysis we could establish linkage of the disease phenotype to chromosome 15 with a maximum...... immunosuppressive treatment in future patients with the same genotype. Our findings also demonstrate that inheritance of different alleles at independent genetic loci in NS may contribute to the disease phenotype. SSNS is clinically distinct from SRNS and its pathogenesis is still unclear. Our study showed linkage...

  11. Predisposition for Empathy, Intercultural Sensitivity, and Intentions for Using Motivational Interviewing in First Year Pharmacy Students.

    Science.gov (United States)

    Ekong, Gladys; Kavookjian, Jan; Hutchison, Amber

    2017-10-01

    Objective. To assess first-year pharmacy (P1) students' predispositions (eg, perceptions for empathy, intercultural sensitivity, and motivational interviewing (MI) as a patient-centered communication skillset) and identify potential curricula content/communication skills training needs. Methods. A cross-sectional survey was used to collect students' self-reported perceptions for empathy, intercultural sensitivity, counseling contexts, and projected future MI use. Relationships between variables were explored and logistic regression was used to evaluate intention for using MI in future patient encounters. Results. There were 134 students who participated. Higher predisposition for empathy and for intercultural sensitivity were significantly correlated. Significant predictors for applying MI in future patient encounters were sex, confidence with counseling skills, and current use of MI. Conclusion. Results suggest the need to incorporate innovative training strategies in communication skills curricula. Potential areas include empathy, intercultural sensitivity and significant predictor variables for future MI use. Further investigation in other schools is needed.

  12. Predisposition to essential hypertension and development of diabetic nephropathy in IDDM patients

    DEFF Research Database (Denmark)

    Fagerudd, J A; Tarnow, L; Jacobsen, P

    1998-01-01

    Conflicting results have been reported on the relationship between familial predisposition to hypertension and development of diabetic nephropathy in IDDM. In our case-control study, we assessed the prevalence of hypertension among parents of 73 IDDM patients with diabetic nephropathy (DN...... for hypertension than were patients with DN+ and without parental treatment for hypertension (100 vs. 61%; P = 0.034; difference 39% [21-57%]). In conclusion, familial predisposition to essential hypertension increases the risk of diabetic nephropathy and may also contribute to the development of systemic......+; persistent albuminuria > 200 microg/min or > 300 mg/24 h) and 73 IDDM patients without diabetic nephropathy (DN-; urinary albumin excretion or = 135/85 mm...

  13. Examining the ethical predisposition of the next generation of business leaders in China and the Republic of South Africa

    Directory of Open Access Journals (Sweden)

    Sam Fullerton

    2011-09-01

    Full Text Available This study was undertaken in an effort to determine the attitudes of business students in South Africa and China toward a battery of questionable actions undertaken by anonymous business entities.  In general, practices such as the outsourcing of labour and celebrity endorsements met with little opposition on the part of the students.  Conversely, actions such as the shipment of unsafe products to overseas markets and a doctor smuggling a potentially beneficial (but illegal drug across international borders in an effort to help a patient were strongly condemned.  A comparison of the means of the 14 scenarios resulted in statistically significant differences for the two countries on eight of the questionable actions.  In seven of the eight, the South Africans exhibited stronger opposition (or a lower level of support for the behaviour of the organization.  Furthermore, the grand means for the two countries also favored the RSA as the country with the higher ethical predisposition.

  14. A blueprint for vocal learning: auditory predispositions from brains to genomes

    Science.gov (United States)

    Wheatcroft, David; Qvarnström, Anna

    2015-01-01

    Memorizing and producing complex strings of sound are requirements for spoken human language. We share these behaviours with likely more than 4000 species of songbirds, making birds our primary model for studying the cognitive basis of vocal learning and, more generally, an important model for how memories are encoded in the brain. In songbirds, as in humans, the sounds that a juvenile learns later in life depend on auditory memories formed early in development. Experiments on a wide variety of songbird species suggest that the formation and lability of these auditory memories, in turn, depend on auditory predispositions that stimulate learning when a juvenile hears relevant, species-typical sounds. We review evidence that variation in key features of these auditory predispositions are determined by variation in genes underlying the development of the auditory system. We argue that increased investigation of the neuronal basis of auditory predispositions expressed early in life in combination with modern comparative genomic approaches may provide insights into the evolution of vocal learning. PMID:26246333

  15. Evaluation criteria of the individual motor predisposition of female sport gymnastics

    Directory of Open Access Journals (Sweden)

    Boraczynski T.

    2010-10-01

    Full Text Available In the paper were presented the results of research, aimed to improve criteria for assessing the motor predisposition of girls in sports gymnastics at the initial stage of training. The studies included 24 gymnasts divided into two age groups: A 6,0-7,5 years of age and B (8,3-13,0. The level of physical fitness was assessed with the use of the EUROFIT battery tests. easurements of the maximum moment of muscle strength in the bending forearm in the elbow joint in terms of isometric contraction were also performed. Assessment f the level of individual strengthspeed and coordination abilities and physical fitness structure including the pace of biological development were the basis for the development of objective criteria for assessing the sports predispositions of young gymnasts at the initial stage of training. Our results provide the basis for improving the control system and optimization of assessment criteria in women gymnastics, including age, training experience and sports level. The results presented in this paper demonstrated the usefulness of the research methodology used to assess the physical fitness and predispositions of gymnasts at the initial stage of training, what enables individualization of training process.

  16. Hereditariedade e suscetibilidade à reabsorção radicular em Ortodontia não se fundamentam: erros metodológicos e interpretativos repetidamente publicados podem gerar falsas verdades. Análise crítica do trabalho de Al-Qawasmi et al.² sobre a predisposição genética à reabsorção radicular de natureza ortodôntica Heredity and susceptibility to radicular resorption in Odontology do not base: methodological and interpretative repeatedly published mistakes can generate false truths. Critical analysis of Al-Qawasmi work about genetics predisposition to radicular reabsorption of orthodontic kind

    Directory of Open Access Journals (Sweden)

    Alberto Consolaro

    2004-05-01

    Full Text Available O trabalho de Al-Qawasmi et al.², publicado em agosto de 2003 no periódico Journal of Dental Research, procurou estabelecer um gene candidato para a hereditariedade e predisposição genética nas reabsorções dentárias em Ortodontia, mas apresentou e repetiu algumas limitações metodológicas e equívocos na interpretação de seu trabalho anterior de março de 2003¹. Nas conclusões afirmam explicitamente que os achados são preliminares e sugestivos, necessitando de confirmação por meio de estudos adicionais. Os resultados são correlacionados fundamentando-se em dados de outros autores sobre síndromes ósseas associadas a reabsorções por substituição, cervicais externas e não com as reabsorções radiculares externas apicais induzidas ortodonticamente. O gene da reabsorção radicular externa apical relacionada a tratamentos ortodônticos não foi determinado e muito menos a sua natureza hereditária. Nem tampouco, a suscetibilidade à reabsorção radicular em Ortodontia foi detectada ou provada. O trabalho analisado e os demais relacionados com o mesmo tema não conseguiram comprovar suas hipóteses porque ignoram que o primeiro passo para a reabsorção radicular externa é a destruição da camada cementoblástica e isto apenas ocorre a partir da ação de fatores locais. Analisando criticamente estes trabalhos podemos afirmar que procurar o gene da reabsorção radicular e da suscetibilidade a partir de pesquisas em mediadores e células clásticas demonstra a falta de um conhecimento completo e amplo da etiopatogenia deste importante fenômeno biológico, imprescindível para o estabelecimento da premissa dos trabalhos.The study of Al-Qawasmi et al.² published in August 2003 on Journal of Dental Research, aimed to establish a candidate gene for heritability and genetic predisposition to external root resorption in orthodontic patients. This paper, however, presents and repeated some methodological faults and equivocated

  17. Pathogenesis of Preeclampsia: The Genetic Component

    Directory of Open Access Journals (Sweden)

    Francisco J. Valenzuela

    2012-01-01

    Full Text Available Preeclampsia (PE is one of the main causes of maternal and fetal morbidity and mortality in the world, causing nearly 40% of births delivered before 35 weeks of gestation. PE begins with inadequate trophoblast invasion early in pregnancy, which produces an increase in oxidative stress contributing to the development of systemic endothelial dysfunction in the later phases of the disease, leading to the characteristic clinical manifestation of PE. Numerous methods have been used to predict the onset of PE with different degrees of efficiency. These methods have used fetal/placental and maternal markers in different stages of pregnancy. From an epidemiological point of view, many studies have shown that PE is a disease with a strong familiar predisposition, which also varies according to geographical, socioeconomic, and racial features, and this information can be used in the prediction process. Large amounts of research have shown a genetic association with a multifactorial polygenic inheritance in the development of this disease. Many biological candidate genes and polymorphisms have been examined in their relation with PE. We will discuss the most important of them, grouped by the different pathogenic mechanisms involved in PE.

  18. Cholesterol-Induced Hepatic Inflammation Does Not Underlie the Predisposition to Insulin Resistance in Dyslipidemic Female LDL Receptor Knockout Mice

    NARCIS (Netherlands)

    Gruben, Nanda; Funke, Anouk; Kloosterhuis, Niels J.; Schreurs, Marijke; Sheedfar, Fareeba; Havinga, Rick; Houten, Sander M.; Shiri-Sverdlov, Ronit; van de Sluis, Bart; Kuivenhoven, Jan Albert; Koonen, Debby P. Y.; Hofker, Marten H.

    2015-01-01

    Chronic inflammation is considered a causal risk factor predisposing to insulin resistance. However, evidence is accumulating that inflammation confined to the liver may not be causal to metabolic dysfunction. To investigate this, we assessed if hepatic inflammation explains the predisposition

  19. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

    2016-01-01

    Background--Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and

  20. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

    2016-01-01

    BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND

  1. Molecular genetic study of hemophilia B in an Algerian population

    African Journals Online (AJOL)

    DELL

    2016-12-21

    Dec 21, 2016 ... genetic predisposition of developing inhibitors. The objective of this study were, to identify the mutations that produce different forms of HB disease among Algerian patients, to characterise mutations of the. FIX gene and to develop our knowledge about the molecular basis of this disease. MATERIALS AND ...

  2. Preventing organ damage by genetic testing for hereditary ...

    African Journals Online (AJOL)

    Haemochromatosis can be prevented by regular blood donation or phlebotomy and therefore detection of a genetic predisposition at an early age, before irreversible damage to cardiac, hepatic and endocrine tissue occurs, represents an important clinical goal. South African Family Practice Vol. 47(2) 2005: 44-45 ...

  3. Ovine Reference Materials and Assays for Prion Genetic Testing

    Science.gov (United States)

    Background: Genetic predisposition to scrapie in sheep is associated with variation in the peptide sequence of the ovine prion protein encoded by Prnp. Codon variants implicated in scrapie susceptibility or disease progression include those at amino acid positions 112, 136, 141, 154, and 171. Nin...

  4. Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review

    NARCIS (Netherlands)

    Oussalah, A.; Mayorga, C.; Blanca, M.; Barbaud, A.; Nakonechna, A.; Cernadas, J.; Gotua, M.; Brockow, K.; Caubet, J.-C.; Bircher, A.; Atanaskovic, M.; Demoly, P.; K Tanno, L.; Terreehorst, I.; Laguna, J. J.; Romano, A.; Guéant, J.-L.

    2016-01-01

    Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations,

  5. Phenotype-Environment Interactions in Genetic Syndromes Associated with Severe or Profound Intellectual Disability

    Science.gov (United States)

    Tunnicliffe, Penny; Oliver, Chris

    2011-01-01

    The research literature notes both biological and operant theories of behavior disorder in individuals with intellectual disabilities. These two theories of genetic predisposition and operant reinforcement remain quite distinct; neither theory on its own is sufficient to explain challenging behavior in genetic syndromes and an integrated approach…

  6. Genetic and environmental interactions

    International Nuclear Information System (INIS)

    Strong, L.C.

    1977-01-01

    Cancer may result from a multistage process occurring over a long period of time. Presumably, initial and progressive stages of carcinogenesis may be modified by both genetic and environmental factors. Theoretically, genetic factors may alter susceptibility to the carcinogenic effects of an environmental agent at the initial exposure due to variation in metabolism of the carcinogen or variation in specific target cell response to the active carcinogen, or during the latent phase due to numerous factors that might increase the probability of tumor expression, including growth-promoting factors or immunodeficiency states. Observed genetic and environmental interactions in carcinogenesis include an association between genetically determined inducibility of aryl hydrocarbon hydroxylase and smoking-related cancers, familial susceptibility to certain environmental carcinogens, an association between hereditary disorders of mutagenesis and carcinogenesis, and enhancement of tissue-specific, dominantly inherited tumor predisposition by radiation. Multiple primary tumors occur frequently in genetically predisposed individuals. Specific markers for susceptibility must be sought in order that high-risk individuals be identified and appropriate measures taken for early cancer detection or prevention. Study of the nature of the genetically determined susceptibility and interactions with environmental agents may be revealing in the understanding of carcinogenesis in general

  7. Population genetic structure of the common warthog (Phacochoerus africanus) in Uganda: evidence for a strong philopatry among warthogs and social structure breakdown in a disturbed population

    DEFF Research Database (Denmark)

    Muwanka, V.B.; Nyakaana, S.; Siegismund, Hans Redlef

    2007-01-01

    populations from five localities in Uganda are genetically structured using both mitochondrial control region sequence and microsatellite allele length variation. Four of the localities (Queen Elizabeth, Murchison Falls, Lake Mburo and Kidepo Valley) are national parks with relatively good wildlife protection......Fine-scale genetic structure of large mammals is rarely analysed. Yet it is potentially important in estimating gene flow between the now fragmented wildlife habitats and in predicting re-colonization following local extinction events. In this study, we examined the extent to which warthog...... geographical distances between populations, significant genetic differentiation was observed in all pair-wise population comparisons at the two marker sets (mtDNA FST = 0.21-0.79, P 

  8. Interactions between genetic variants associated with adiposity traits and soft drinks in relation to longitudinal changes in body weight and waist circumference.

    Science.gov (United States)

    Olsen, Nanna J; Ängquist, Lars; Larsen, Sofus C; Linneberg, Allan; Skaaby, Tea; Husemoen, Lise Lotte N; Toft, Ulla; Tjønneland, Anne; Halkjær, Jytte; Hansen, Torben; Pedersen, Oluf; Overvad, Kim; Ahluwalia, Tarunveer S; Sørensen, Thorkild Ia; Heitmann, Berit L

    2016-09-01

    Intake of sugar-sweetened beverages is associated with obesity, and this association may be modified by a genetic predisposition to obesity. We examined the interactions between a molecular genetic predisposition to various aspects of obesity and the consumption of soft drinks, which are a major part of sugar-sweetened beverages, in relation to changes in adiposity measures. A total of 4765 individuals were included in the study. On the basis of 50 obesity-associated single nucleotide polymorphisms that are associated with body mass index (BMI), waist circumference (WC), or the waist-to-hip ratio adjusted for BMI (WHRBMI), the following 4 genetic predisposition scores (GRSs) were constructed: a complete genetic predisposition score including all 50 single nucleotide polymorphisms (GRSComplete), a genetic predisposition score including BMI-associated single nucleotide polymorphisms (GRSBMI), a genetic predisposition score including waist circumference-associated single nucleotide polymorphisms (GRSWC), and a genetic predisposition score including the waist-to-hip ratio adjusted for BMI-associated single nucleotide polymorphisms (GRSWHR). Associations between soft drink intake and the annual change (Δ) in body weight (BW), WC, or waist circumference adjusted for BMI (WCBMI) and possible interactions with the GRSs were examined with the use of linear regression analyses and meta-analyses. For each soft drink serving per day, soft drink consumption was significantly associated with a higher ΔBW of 0.07 kg/y (95% CI: 0.01, 0.13 kg/y; P = 0.020) but not with the ΔWC or ΔWCBMI In analyses of the ΔBW, we showed an interaction only with the GRSWC (per risk allele for each soft drink serving per day: -0.06 kg/y; 95% CI: -0.10, -0.02 kg/y; P = 0.006). In analyses of the ΔWC, we showed interactions only with the GRSBMI and GRSComplete [per risk allele for each soft drink serving per day: 0.05 cm/y (95% CI: 0.02, 0.09 cm/y; P = 0.001) and 0.05 cm/y (95% CI: 0.02, 0.07 cm

  9. Strongly Correlated Topological Insulators

    Science.gov (United States)

    2016-02-03

    Strongly Correlated Topological Insulators In the past year, the grant was used for work in the field of topological phases, with emphasis on finding...surface of topological insulators. In the past 3 years, we have started a new direction, that of fractional topological insulators. These are materials...in which a topologically nontrivial quasi-flat band is fractionally filled and then subject to strong interactions. The views, opinions and/or

  10. Strong Cosmic Censorship

    Science.gov (United States)

    Isenberg, James

    2017-01-01

    The Hawking-Penrose theorems tell us that solutions of Einstein's equations are generally singular, in the sense of the incompleteness of causal geodesics (the paths of physical observers). These singularities might be marked by the blowup of curvature and therefore crushing tidal forces, or by the breakdown of physical determinism. Penrose has conjectured (in his `Strong Cosmic Censorship Conjecture`) that it is generically unbounded curvature that causes singularities, rather than causal breakdown. The verification that ``AVTD behavior'' (marked by the domination of time derivatives over space derivatives) is generically present in a family of solutions has proven to be a useful tool for studying model versions of Strong Cosmic Censorship in that family. I discuss some of the history of Strong Cosmic Censorship, and then discuss what is known about AVTD behavior and Strong Cosmic Censorship in families of solutions defined by varying degrees of isometry, and discuss recent results which we believe will extend this knowledge and provide new support for Strong Cosmic Censorship. I also comment on some of the recent work on ``Weak Null Singularities'', and how this relates to Strong Cosmic Censorship.

  11. Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci

    Directory of Open Access Journals (Sweden)

    Houlston Richard S

    2011-02-01

    Full Text Available Abstract Background Common single-nucleotide polymorphisms (SNPs in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. Methods Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions. Results No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC. Conclusions The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered.

  12. Individual predisposition, household clustering and risk factors for human infection with Ascaris lumbricoides: new epidemiological insights.

    Science.gov (United States)

    Walker, Martin; Hall, Andrew; Basáñez, María-Gloria

    2011-04-26

    Much of our current understanding of the epidemiology of Ascaris lumbricoides infections in humans has been acquired by analyzing worm count data. These data are collected by treating infected individuals with anthelmintics so that worms are expelled intact from the gastrointestinal tract. Analysis of such data established that individuals are predisposed to infection with few or many worms and members of the same household tend to harbor similar numbers of worms. These effects, known respectively as individual predisposition and household clustering, are considered characteristic of the epidemiology of ascariasis. The mechanisms behind these phenomena, however, remain unclear. In particular, the impact of heterogeneous individual exposures to infectious stages has not been thoroughly explored. Bayesian methods were used to fit a three-level hierarchical statistical model to A. lumbricoides worm counts derived from a three-round chemo-expulsion study carried out in Dhaka, Bangladesh. The effects of individual predisposition, household clustering and household covariates of the numbers of worms per host (worm burden) were considered simultaneously. Individual predisposition was found to be of limited epidemiological significance once household clustering had been accounted for. The degree of intra-household variability among worm burdens was found to be reduced by approximately 58% when household covariates were included in the model. Covariates relating to decreased affluence and quality of housing construction were associated with a statistically significant increase in worm burden. Heterogeneities in the exposure of individuals to infectious eggs have an important role in the epidemiology of A. lumbricoides infection. The household covariates identified as being associated with worm burden provide valuable insights into the source of these heterogeneities although above all emphasize and reiterate that infection with A. lumbricoides is inextricably associated

  13. Race and ethnicity as a victimogenic predisposition of exceeding and abuse of police authority

    Directory of Open Access Journals (Sweden)

    Kesić Zoran

    2012-01-01

    Full Text Available The unique position in society and the specific functions make the police one of the key holders of protection of the fundamental rights and freedoms of citizens. At the same time, their position and function provide police officers significant opportunities to violate the same freedoms and rights, by resorting to various forms of violation and abuse of power. This dual nature of the police authority gives us reason to question the police from a completely different angle - as a source of a specific form of victimization. The risk degree of victimization by police authority is determined by the different predispositions, and above all by the victim’s behavior. However, some individual characteristics (gender, age, sexual orientation, ethnic and social origin are also a kind of victimogenic predisposition, as they contribute to the process of victimization independently or in combination with the behavior of the victim. In this work we draw attention to the fact that race (ethnicity often makes an independent criterion which the police use when deciding how to act in the concrete case. This circumstance contributes to a distinctive form of police procedure, known as racial profiling. The fact that the race of a person is taken as a criterion for treatment suggests the conclusion that here is actually about a form of discriminatory behavior. Considered in this context, race may be treated as victimogenic predisposition of police authority, and racial profiling as a process of victimization. [Projekat Ministarstva nauke Republike Srbije, br. 179045: Razvoj institucionalnih kapaciteta, standarda i procedura za suprotstavljanje organizovanom kriminalu i terorizmu u uslovima međunarodnih integracija

  14. The Effect of Phototherapy on Cancer Predisposition Genes of Diabetic and Normal Human Skin Fibroblasts

    OpenAIRE

    Chotikasemsri, Pongsathorn; Tangtrakulwanich, Boonsin; Sangkhathat, Surasak

    2017-01-01

    The purpose of this study was to investigate whether LED light at different wavelengths affects the expression profile of 143 cancer predisposition genes in both diabetic and normal human fibroblasts. In this study, both diabetic and normal fibroblast cell lines were cultured and irradiated with red (635 nm), green (520 nm), and blue (465 nm) LED light for 10 minutes at 0.67 J/cm2 each. After that, mRNA from all cell lines was extracted for microarray analysis. We found that green light activ...

  15. Germline mutation in the RAD51B gene confers predisposition to breast cancer

    International Nuclear Information System (INIS)

    Golmard, Lisa; Nicolas, André; Castéra, Laurent; Sastre-Garau, Xavier; Stern, Marc-Henri; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; Davy, Grégoire; Al Ageeli, Essam; Poirot, Brigitte; Tirapo, Carole; Michaux, Dorothée; Barbaroux, Catherine; D'Enghien, Catherine Dubois

    2013-01-01

    Most currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition. The study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis. Three splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5-1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases. This study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals

  16. Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes

    DEFF Research Database (Denmark)

    Schmiegelow, K.

    2016-01-01

    Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3-5% of all...... childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL...... patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring...

  17. Exploring cancer genetics and care of the family: an evolving challenge for palliative care.

    Science.gov (United States)

    Lillie, Alison Kate

    2006-02-01

    There is a growing scientific understanding and increasing public awareness of the influence of genetics on the development of cancer. This article, which is based on a review of the literature, focuses on how the awareness of genetic predisposition to cancer is affecting patients and their families. It highlights the way that risk assessment for predisposition to cancer can conflict with traditional models of informed consent and can cause concern for families. It suggests that there is need for informed discussion within palliative care about how best to support families with concerns about a family history of cancer.

  18. Strong Arcwise Connectedness

    OpenAIRE

    Espinoza, Benjamin; Gartside, Paul; Kovan-Bakan, Merve; Mamatelashvili, Ana

    2012-01-01

    A space is `n-strong arc connected' (n-sac) if for any n points in the space there is an arc in the space visiting them in order. A space is omega-strong arc connected (omega-sac) if it is n-sac for all n. We study these properties in finite graphs, regular continua, and rational continua. There are no 4-sac graphs, but there are 3-sac graphs and graphs which are 2-sac but not 3-sac. For every n there is an n-sac regular continuum, but no regular continuum is omega-sac. There is an omega-sac ...

  19. Abortion: Strong's counterexamples fail

    DEFF Research Database (Denmark)

    Di Nucci, Ezio

    2009-01-01

    This paper shows that the counterexamples proposed by Strong in 2008 in the Journal of Medical Ethics to Marquis's argument against abortion fail. Strong's basic idea is that there are cases--for example, terminally ill patients--where killing an adult human being is prima facie seriously morally......'s scenarios have some valuable future or admitted that killing them is not seriously morally wrong. Finally, if "valuable future" is interpreted as referring to objective standards, one ends up with implausible and unpalatable moral claims....

  20. A strong comeback

    International Nuclear Information System (INIS)

    Marier, D.

    1992-01-01

    This article presents the results of a financial rankings survey which show a strong economic activity in the independent energy industry. The topics of the article include advisor turnover, overseas banks, and the increase in public offerings. The article identifies the top project finance investors for new projects and restructurings and rankings for lenders

  1. Examining the Use of Distance-Mediated Case Conferencing for Case-Based Training in Clinical Cancer Genetics

    Science.gov (United States)

    Blazer, Kathleen R.

    2010-01-01

    Individuals with a cancer-predisposing genetic trait have a lifetime risk to develop cancer approaching 100 percent, and cancer often strikes early in age, before standard recommended cancer screening begins. Identifying hereditary cancer predisposition through genetic cancer risk assessment (GCRA) allows for intensified measures to prevent…

  2. [Predisposition of citizens to use Internet-based channels to communicate with doctors in Spain].

    Science.gov (United States)

    Herrera-Usagre, Manuel; Reyes-Alcázar, Víctor; Valverde, José A

    2014-01-01

    Analyze factors affecting the predisposition of Spanish citizens to use Internet-based communication channels (E-mail, blogs, social networks, and online recommendations). Secondary data were analyzed by applying a boosted regression tree (BRT) to the results obtained from the survey "Use and Applications of Information and Communications Technology in Health," administered to a representative sample of the Spanish population between 16 and 85 years of age who use the Internet. Model forecasts achieved different degrees of precision for each of the communication channels: for E-mail, AUC (area under the curve) = 0.79; for the physician's blog or personal website, AUC = 0.736; for social networks, AUC = 0.73; for recommendations of websites related to health problems, AUC = 0.768. Being young was the most important parameter in citizen predisposition to communicate through social networks (relative influence; RI = 21.05%), while population density was the most important parameter in likelihood that the physician would have a blog or personal health-related website (RI = 19.48%). Having a positive perception of the technology when facilitating health-related transactions was the most important characteristic in wanting to receive recommendations on health-related Internet resources (RI = 18.66%), while having a higher level of education was the best predictor of wanting to establish E-mail communication (RI = 18.98%). Many of Spanish people are open to using physician-patient interaction channels on the Internet.

  3. The Role of Social Factors in Iranian University Students' Predispositions towards Autonomous Language Learning

    Directory of Open Access Journals (Sweden)

    Sara Kashefian Naeeini

    2012-07-01

    Full Text Available In order to meet the demands of the changing world, students should become endowed with the ability to learn perpetually and regard learning as a life-long enterprise. This study investigated those learners belief which showed learners’ predispositions toward autonomy  and some social factors such as gender, academic achievement, marital status and age were taken into consideration. All BA and MA students majoring in English Literature at the department of Foreign Languages of Shiraz University of Iran were involved. The data were collected through a questionnaire the items of which were obtained from two questionnaires by Cotterall (1995 and Cotterall (1999 which were incorporated into a five-point Likert-type rating scale. Factor analysis of responses of students revealed the existence of five underlying factors for learner autonomy which were learner independence, dependence on the teacher, learner confidence, attitudes towards language learning and self-assessment. Based on t-test for independent samples and Analysis of Variance it came to light that age and gender did not have impact on students’ readiness for autonomy while martial statues influenced students’  self-assessment. Moreover, good academic achievement positively influenced their predispositions towards autonomous language learning.

  4. NAT2 polymorphism in Omani gastric cancer patients-risk predisposition and clinicopathological associations

    Science.gov (United States)

    Al-Moundhri, Mansour S; Al-Kindi, Mohamed; Al-Nabhani, Maryam; Al-Bahrani, Bassim; Burney, Ikram A; Al-Madhani, Ali; Ganguly, Shyam S; Tanira, Misbah

    2007-01-01

    AIM: To study whether N-acetyltransferase 2 (NAT2) genotypes and phenotypes are associated with increased risk factor for gastric cancer in Omani patients and to study the clinico-pathological correlations and the prognostic significance of NAT2. METHODS: Genomic DNA was extracted from peripheral blood of 100 gastric cancer patients and 100 control subjects. NAT2 genotyping was performed using DNA sequencing. The prognostic significance of NAT2 and other clinicopathological features was assessed by univariate and multivariate analyses. RESULTS: We observed no significant association between NAT2 genotypes and phenotypes and gastric cancer risk. The NAT2 phenotype polymorphisms and gastric cancer risk predisposition were not modified by concomitant H pylori infection and smoking. There was no significant association between NAT2 and clinicopathological features, and NAT2 had no independent prognostic significance. CONCLUSION: In the current study, NAT2 genotypes and phenotypes are not associated with gastric cancer risk predisposition. Moreover NAT2 phenotypes had no clinicopathological associations or prognostic significance. PMID:17569138

  5. Impaired mucociliary clearance in allergic rhinitis patients is related to a predisposition to rhinosinusitis.

    Science.gov (United States)

    Vlastos, Ioannis; Athanasopoulos, Ioannis; Mastronikolis, Nicholas S; Panogeorgou, Theodora; Margaritis, Vassilios; Naxakis, Stefanos; Goumas, Panos D

    2009-04-01

    Although mucociliary clearance has been shown to be impaired in patients with allergic rhinitis and chronic rhinosinusitis, its exact role in relation to a predisposition to rhinosinusitis is unknown. To investigate this possible association, we conducted a prospective study of 125 patients with allergic rhinitis. Of this group, 23 patients were classified as being sinusitis-prone based on their history of antibiotic consumption for the treatment of rhinosinusitis; the remaining 102 patients were deemed to be not sinusitis-prone. The saccharine test was used to evaluate mucociliary clearance in all patients. Several variables-age, sex, smoking habits, rhinitis severity, and medication history-were examined. We found that the sinusitis-prone patients had a significantly greater mucociliary clearance time than did those who were not prone (median: 15 and 12 min, respectively; p = 0.02). No other statistically significant differences were seen between the 2 groups with respect to any other variables that might have affected mucociliary clearance. We conclude that impaired mucociliary clearance in allergic rhinitis patients is associated with a predisposition to rhinosinusitis.

  6. Strong Electroweak Symmetry Breaking

    CERN Document Server

    Grinstein, Benjamin

    2011-01-01

    Models of spontaneous breaking of electroweak symmetry by a strong interaction do not have fine tuning/hierarchy problem. They are conceptually elegant and use the only mechanism of spontaneous breaking of a gauge symmetry that is known to occur in nature. The simplest model, minimal technicolor with extended technicolor interactions, is appealing because one can calculate by scaling up from QCD. But it is ruled out on many counts: inappropriately low quark and lepton masses (or excessive FCNC), bad electroweak data fits, light scalar and vector states, etc. However, nature may not choose the minimal model and then we are stuck: except possibly through lattice simulations, we are unable to compute and test the models. In the LHC era it therefore makes sense to abandon specific models (of strong EW breaking) and concentrate on generic features that may indicate discovery. The Technicolor Straw Man is not a model but a parametrized search strategy inspired by a remarkable generic feature of walking technicolor,...

  7. Plasmons in strong superconductors

    International Nuclear Information System (INIS)

    Baldo, M.; Ducoin, C.

    2011-01-01

    We present a study of the possible plasmon excitations that can occur in systems where strong superconductivity is present. In these systems the plasmon energy is comparable to or smaller than the pairing gap. As a prototype of these systems we consider the proton component of Neutron Star matter just below the crust when electron screening is not taken into account. For the realistic case we consider in detail the different aspects of the elementary excitations when the proton, electron components are considered within the Random-Phase Approximation generalized to the superfluid case, while the influence of the neutron component is considered only at qualitative level. Electron screening plays a major role in modifying the proton spectrum and spectral function. At the same time the electron plasmon is strongly modified and damped by the indirect coupling with the superfluid proton component, even at moderately low values of the gap. The excitation spectrum shows the interplay of the different components and their relevance for each excitation modes. The results are relevant for neutrino physics and thermodynamical processes in neutron stars. If electron screening is neglected, the spectral properties of the proton component show some resemblance with the physical situation in high-T c superconductors, and we briefly discuss similarities and differences in this connection. In a general prospect, the results of the study emphasize the role of Coulomb interaction in strong superconductors.

  8. Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

    Science.gov (United States)

    Lahm, Harald; Schön, Patric; Doppler, Stefanie; Dreßen, Martina; Cleuziou, Julie; Deutsch, Marcus-André; Ewert, Peter; Lange, Rüdiger; Krane, Markus

    2015-01-01

    In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS. PMID:26069455

  9. Practicability of comprehensive care in clinical genetics in the brazilian unified health system: expanding the debate

    OpenAIRE

    Lopes-Júnior, Luís Carlos; Flória-Santos, Milena; Ferraz, Victor Evangelista de Faria; Villa, Tereza Cristina Scatena; Palha, Pedro Fredemir; Bomfim, Emiliana de Omena; Abrahão, Camila Aparecida; Silva, Sara da

    2014-01-01

    This article aims to highlight the discussions on the National Policy for Comprehensive Care in Clinical Genetics and reflect on its pending regulation when genomic discoveries change the model of health care. Nine of the ten causes of morbidity and mortality worldwide presents genetic/genomic predisposition. Based on strategic planning, this Policy proposes the organization of a network of referral services and specialized centers in genetics, with capacity to meet the needs of the populatio...

  10. Exploring the Role of Genetic Modifiers in DNA Repair and Breast Cancer

    Science.gov (United States)

    2013-09-01

    09-1-0029 TITLE: Exploring the role of genetic modifiers in DNA repair and breast cancer PRINCIPAL INVESTIGATOR: Brian D...1 September 2009 - 31 August 2013Annual SummarySeptember 2013 Exploring the Role of Genetic Modifiers in DNA Repair and Breast Cancer Brian D...cause sensitivity to DNA damage in the yeast Saccharomyces cerevisiae in an attempt to identify genetic factors which cause predisposition to breast

  11. Investigating Ductal Carcinoma in Situ Using Noninvasive Imaging of Genetically Engineered Mouse Models

    Science.gov (United States)

    2013-08-01

    PJ, Gupta PB, Klebba I, Jones AD, et al. (2011) Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem...Albertson DG, Simin K. Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution. PLoS Genet . 2012;8(11). 16. Behbod F, Kittrell FS...Cre lines for genetic recombination, specifically WAP-Cre and K14Cre, which are widely utilized in mouse models of breast cancer (Liu et al. PNAS

  12. Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

    Science.gov (United States)

    2015-06-01

    normal development and tumor predisposition , in mice lacking exon 23a of Nf1. Nat Genet 27, 399-405 (2001). 8 Silva, A. J. et al. A mouse model for...AD______________ Award Number: W81XWH-13-1-0117 TITLE: Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1...DATES COVERED 1 June 2014 – 31 May 2015 4. TITLE AND SUBTITLE Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in

  13. Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis

    Science.gov (United States)

    2015-10-01

    with a dystrophic genetic predisposition , more. Earlier diagnosis of dystrophic scoliosis could inform clinical decision-making regarding early surgical...AWARD NUMBER: W81XWH-10-1-0469 TITLE: Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis...31Jul2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER " Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis." 5b