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  • GENOME-WIDE ASSOCIATION  (12)
  • GENES  (7)
  • VARIANTS  (6)
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  • 1
    Keywords: DISEASE ; DISEASES ; GENE ; GENES ; PROTEIN ; PROTEINS ; RNA ; DNA ; recombination ; tumour ; BIOLOGY ; SEQUENCE ; chromosome ; NUMBER ; MUTATION ; inactivation ; REGION ; MUTATIONS ; EVOLUTION ; DEGRADATION ; CHROMOSOMES ; GENE FAMILY ; AID ; HUMAN GENOME SEQUENCE ; INACTIVATION CENTER ; LINKED MENTAL-RETARDATION ; MAMMALIAN Y-CHROMOSOME ; REPEAT HYPOTHESIS
    Abstract: The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence
    Type of Publication: Journal article published
    PubMed ID: 15772651
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  • 2
    Keywords: LOCI ; GENOME-WIDE ASSOCIATION ; MISSING HERITABILITY
    Abstract: Objectives: We aimed at extending the Natural and Orthogonal Interaction (NOIA) framework, developed for modeling gene-gene interactions in the analysis of quantitative traits, to allow for reduced genetic models, dichotomous traits, and gene-environment interactions. We evaluate the performance of the NOIA statistical models using simulated data and lung cancer data. Methods: The NOIA statistical models are developed for additive, dominant, and recessive genetic models as well as for a binary environmental exposure. Using the Kronecker product rule, a NOIA statistical model is built to model gene-environment interactions. By treating the genotypic values as the logarithm of odds, the NOIA statistical models are extended to the analysis of case-control data. Results: Our simulations showed that power for testing associations while allowing for interaction using the NOIA statistical model is much higher than using functional models for most of the scenarios we simulated. When applied to lung cancer data, much smaller p values were obtained using the NOIA statistical model for either the main effects or the SNP-smoking interactions for some of the SNPs tested. Conclusion: The NOIA statistical models are usually more powerful than the functional models in detecting main effects and interaction effects for both quantitative traits and binary traits.
    Type of Publication: Journal article published
    PubMed ID: 22889990
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  • 3
    Keywords: RISK ; MEN ; GLIOMA ; JAPANESE ; GENOME-WIDE ASSOCIATION ; COMMON VARIANTS ; MYOSIN VI ; 22Q13
    Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of 〉10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P 〈 5 x 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
    Type of Publication: Journal article published
    PubMed ID: 25217961
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; tumor ; THERAPY ; RISK ; BREAST ; OVARIAN-CANCER ; FACTOR-I ; BINDING PROTEIN-3 ; GENOME-WIDE ASSOCIATION
    Abstract: Background The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. Methods Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided. Results The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P-trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r(2) = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r(2) = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P-trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P-trend 〈 .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P-trend.corr =.04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality. Conclusions The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
    Type of Publication: Journal article published
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  • 5
    Keywords: COLON-CANCER ; microsatellite instability ; POPULATION-BASED SAMPLE ; ULCERATIVE-COLITIS ; CROHNS-DISEASE ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; ISLAND METHYLATOR PHENOTYPE ; MOLECULAR-FEATURES ; MAIT CELLS
    Abstract: We identified the minor allele (T) in SNP rs11676348 to have pleiotropic effect on risk of UC and CRC, particularly in tumors with an inflammatory component. Our findings offer the promise of risk stratification of UC patients for developing CRC.Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P (heterogeneity) = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P (heterogeneity) = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P (heterogeneity) = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.
    Type of Publication: Journal article published
    PubMed ID: 26071399
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  • 6
    Keywords: CANCER ; tumor ; carcinoma ; PROSTATE ; COMMON ; DIAGNOSIS ; COHORT ; MORTALITY ; RISK ; GENE ; GENES ; SAMPLE ; SAMPLES ; TUMORS ; validation ; MARKER ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; NO ; STAGE ; COMPARATIVE GENOMIC HYBRIDIZATION ; HEALTH ; DIFFERENCE ; AGE ; WOMEN ; MEN ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; REGION ; POPULATIONS ; CARRIERS ; case-control studies ; PREDICTORS ; LIFE-STYLE ; NESTED CASE-CONTROL ; SINGLE ; ONCOLOGY ; case control study ; case-control study ; RE ; VARIANT ; ALLELE ; GROWTH-FACTOR-I ; case control studies ; INTERVAL ; CARRIER ; GENOTYPE ; single-nucleotide ; USA ; NO ASSOCIATION ; cancer research ; CANCER-RISK ; MULTIETHNIC COHORT ; BASE-LINE CHARACTERISTICS ; nested case-control study ; case control ; case-control ; AFRICAN-AMERICAN
    Abstract: Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rsl447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 x 10(-13)). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 X 10(-13)). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an ORAC = 1.34 (99% confidence intervals, 1.19-1.50) and carriers with two copies of the minor allele had an ORAA = 1.86 (99% confidence intervals, 1.30-2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result
    Type of Publication: Journal article published
    PubMed ID: 17409400
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  • 7
    Keywords: CANCER ; PATHWAY ; PROSTATE ; COHORT ; RISK ; GENE ; GENES ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; CANDIDATE GENE ; POLYMORPHISMS ; hormone ; genetics ; SNP ; MEN ; prostate cancer ; PROSTATE-CANCER ; CARRIERS ; molecular biology ; VARIANT ; SNPs ; CANDIDATE GENES ; LEVEL ; USA ; HORMONES ; TESTOSTERONE ; CIRCULATING LEVELS ; LOCI ; HORMONE-BINDING GLOBULIN ; SERUM ANDROGENS ; CONSORTIUM ; ESTROGEN-RECEPTOR-ALPHA ; sex hormone-binding globulin ; 3 ; Genetic ; genetic variation ; SEX-STEROID-HORMONES
    Abstract: Twin studies suggest a heritable component to circulating sex steroid hormones and sex hormone-binding globulin (SHBG). In the NCI-Breast and Prostate Cancer Cohort Consortium, 874 SNPs in 37 candidate genes in the sex steroid hormone pathway were examined in relation to circulating levels of SHBG (N = 4720), testosterone (N = 4678), 3 alpha-androstanediol-glucuronide (N = 4767) and 17 beta-estradiol (N = 2014) in Caucasian men. rs1799941 in SHBG is highly significantly associated with circulating levels of SHBG (P = 4.52 x 10(-21)), consistent with previous studies, and testosterone (P = 7.54 x 10(-15)), with mean difference of 26.9 and 14.3%, respectively, comparing wild-type to homozygous variant carriers. Further noteworthy novel findings were observed between SNPs in ESR1 with testosterone levels (rs722208, mean difference = 8.8%, P = 7.37 x 10(-6)) and SRD5A2 with 3 alpha-androstanediol-glucuronide (rs2208532, mean difference = 11.8%, P = 1.82 x 10(-6)). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones
    Type of Publication: Journal article published
    PubMed ID: 19574343
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  • 8
    Keywords: COHORT ; HETEROCYCLIC AMINES ; POLYMORPHISMS ; smoking ; COLON-CANCER ; CONSUMPTION ; EXCISION-REPAIR ; GENETIC SUSCEPTIBILITY ; GENOME-WIDE ASSOCIATION ; POULTRY INTAKE
    Abstract: Background: Red meat intake has been associated with risk of colorectal cancer, potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and colorectal cancer has been inconsistently reported. Methods: We used pooled individual-level data from the Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium. Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. Results: From 11 studies, 8,290 colorectal cancer cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of colorectal cancer compared with the lowest quartile [ OR, 1.41; 95% confidence interval (CI), 1.29-1.55]. However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with colorectal cancer in those with a rapid/intermediate NAT2 genotype (OR, 1.38; 95% CI, 1.20-1.59) as with a slow genotype (OR, 1.43; 95% CI, 1.28-1.61; P interaction = 0.9). Conclusion: We found that high red meat intake was associated with increased risk of colorectal cancer only from retrospective case-control studies and not modified by NAT2 enzyme activity. Impact: Our results suggest no interaction between NAT2 genotype and red meat intake in mediating risk of colorectal cancer.
    Type of Publication: Journal article published
    PubMed ID: 25342387
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  • 9
    Keywords: RECEPTOR ; carcinoma ; VARIANTS ; PANCREATIC-CANCER ; METAANALYSIS ; 8Q24 ; SCAN ; RISK LOCUS ; GENOTYPE IMPUTATION ; NEGATIVE REGULATOR LRIG1
    Abstract: Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P〈5.0E - 08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.
    Type of Publication: Journal article published
    PubMed ID: 26151821
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  • 10
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; CELL ; CELL-PROLIFERATION ; MODEL ; MODELS ; PROSTATE ; COMMON ; COHORT ; HISTORY ; RISK ; GENE ; GENES ; FAMILY ; INDEX ; SEQUENCE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; VARIANTS ; BREAST ; NO ; STAGE ; HEALTH ; AGE ; family history ; SNP ; MEN ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; HUMAN GENOME ; BETA ; POPULATIONS ; case-control studies ; BODY ; ESTROGEN-RECEPTOR ; REGRESSION-MODELS ; MASS INDEX ; MASSES ; BODIES ; SINGLE ; ONCOLOGY ; case control study ; case-control study ; REGRESSION ; FAMILIES ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; GRADE ; regulation ; cell proliferation ; GROWTH-FACTOR-I ; ESTROGEN ; biomarker ; case control studies ; INTERVAL ; analysis ; methods ; HAPLOTYPE ; HAPLOTYPES ; LOCUS ; single-nucleotide ; estrogen receptor ; FAMILY-HISTORY ; USA ; INCREASED RISK ; cancer research ; CANCER-RISK ; MULTIETHNIC COHORT ; SET ; nested case-control study ; case control ; LOGISTIC-REGRESSION ; BODY-MASS ; BODY-MASS-INDEX ; ER-BETA ; EXONS ; GENETIC-VARIATION ; TAG SNPS
    Abstract: Background: Estrogen receptor beta (ESR2) may play a role in modulating prostate carcirtogenesis through the regulation of genes related to cell proliferation and apoptosis. Methods: We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group. We characterized genetic variation in ESR2 by resequencing exons in 190 breast and prostate cancer cases and genotyping a dense set of single nucleotide polymorphisms (SNP) spanning the locus in a multiethnic panel of 349 cancer-free subjects. We selected four haplotype-tagging SNPs (htSNP) to capture common ESR2 variation in Whites; these htSNPs were then genotyped in all cohorts. Conditional logistic regression models were used to assess the association between sequence variants of ESR2 and the risk of prostate cancer. We also investigated the effect modification by age, body mass index, and family history, as well as the association between sequence variants of ESR2 and advanced-stage (〉= T3b, N-1, or M-1) and high-grade (Gleason sum 〉= 8) prostate cancer, respectively. Results: The four tag SNPs in ESR2 were not significantly associated with prostate cancer risk, individually. The global test for the influence of any haplotype on the risk of prostate cancer was not significant (P = 0.31). However, we observed that men carrying two copies of one of the variant haplotypes (TACC) had a 1.46-fold increased risk of prostate cancer (99% confidence interval, 1.06-2.01) compared with men carrying zero copies of this variant haplotype. No SNPs or haplotypes were associated with advanced stage or high grade of prostate cancer. Conclusion: In our analysis focused on genetic variation common in Whites, we observed little evidence for any substantial association of inherited variation in ESR2 with risk of prostate cancer. A nominally significant (P 〈 0.01) association between the TACC haplotype and prostate cancer risk under the recessive model could be a chance finding and, in any event, would seem to contribute only slightly to the overall burden of prostate cancer
    Type of Publication: Journal article published
    PubMed ID: 17932344
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