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  • GENOME-WIDE ASSOCIATION  (12)
  • VARIANTS  (6)
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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    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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  • 8
    Keywords: CANCER ; GROWTH ; PROSTATE ; COMMON ; COHORT ; RISK ; GENE ; CARCINOGENESIS ; BIOMARKERS ; LINKAGE ; polymorphism ; POLYMORPHISMS ; VARIANTS ; BREAST ; hormone ; HEALTH ; AGE ; MEN ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; LINKAGE DISEQUILIBRIUM ; GERMLINE ; POSTMENOPAUSAL WOMEN ; SINGLE ; VARIANT ; DETERMINANTS ; prospective studies ; GROWTH-FACTOR-I ; LEVEL ; biomarker ; EPIDEMIOLOGIC EVIDENCE ; HAPLOTYPE ; HAPLOTYPES ; LOCUS ; USA ; HORMONES ; HORMONE LEVELS ; TESTOSTERONE ; prospective ; prospective study ; STEROID-HORMONES ; JAPANESE ; UNIT ; cancer research ; CANCER-RISK ; ESTROGEN-LEVELS ; MULTIETHNIC COHORT ; ANDROGEN ; COMMON VARIANT ; SEX-HORMONES ; JAPANESE POPULATION ; androgens ; NONCARRIERS ; FREE TESTOSTERONE ; SERUM ANDROGENS ; CONSORTIUM ; 3 ; Genetic ; genetic variation ; COMMON VARIANTS ; GENE VARIANT ; ALLELIC VARIANTS ; ANDROGEN BIOSYNTHESIS ; UNRELATED INDIVIDUALS
    Abstract: Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nuclecitide polymorphisms (htSNP) that efficiently predict common variants in U.S. and Europe-an whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs; in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734-44)
    Type of Publication: Journal article published
    PubMed ID: 19789370
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  • 9
    Keywords: GENES ; METAANALYSIS ; GROWTH-FACTOR-I ; BINDING PROTEIN-3 ; 8Q24 ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; SEQUENCE VARIANTS ; MULTIPLE ; PSA LEVELS
    Abstract: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10(-28)). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade,8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined
    Type of Publication: Journal article published
    PubMed ID: 21390317
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  • 10
    Keywords: POPULATION ; RISK ; GENES ; ASSOCIATION ; single nucleotide polymorphism ; AGE ; MEN ; PREDICTORS ; GROWTH-FACTOR-I ; BINDING PROTEIN-3 ; cancer research ; GENOME-WIDE ASSOCIATION
    Abstract: BACKGROUND: A recent genome-wide association study (GWAS) of prostate cancer in a Japanese population identified five novel regions not previously discovered in other ethnicities. In this study, we attempt to replicate these five loci in a series of nested prostate cancer case-control studies of European ancestry. METHODS: We genotyped five single-nucleotide polymorphism (SNP): rs13385191 (chromosome 2p24), rs12653946 (5p15), rs1983891 (6p21), rs339331 (6p22), and rs9600079 (13q22), in 7,956 prostate cancer cases and 8,148 controls from a series of nested case-control studies within the National cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We tested each SNP for association with prostate cancer risk and assessed whether associations differed with respect to disease severity and age of onset. RESULTS: Four SNPs (rs13385191, rs12653946, rs1983891, and rs339331) were significantly associated with prostate cancer risk (P values ranging from 0.01 to 1.1 x 10(-5)). Allele frequencies and ORs were overall lower in our population of European descent than in the discovery Asian population. SNP rs13385191 (C2orf43) was only associated with low-stage disease (P = 0.009, case-only test). No other SNP showed association with disease severity or age of onset. We did not replicate the 13q22 SNP, rs9600079 (P = 0.62). CONCLUSIONS: Four SNPs associated with prostate cancer risk in an Asian population are also associated with prostate cancer risk in men of European descent. IMPACT: This study illustrates the importance of evaluation of prostate cancer risk markers across ethnic groups.
    Type of Publication: Journal article published
    PubMed ID: 22056501
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