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  • 1
    Keywords: RECEPTOR ; CANCER ; tumor ; COHORT ; DISEASE ; EPIDEMIOLOGY ; RISK ; GENE ; METABOLISM ; TUMORS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; BREAST ; breast cancer ; BREAST-CANCER ; PROSTATE-CANCER ; INDIVIDUALS ; POSTMENOPAUSAL WOMEN ; SUBSET ; RE ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; ESTROGEN ; single-nucleotide ; haplotype-tagging ; MULTIETHNIC COHORT ; BASE-LINE CHARACTERISTICS ; 17-BETA-HYDROXYSTEROID-DEHYDROGENASE TYPE-1 ; HORMONE-RECEPTOR
    Abstract: The 17 beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X-2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study
    Type of Publication: Journal article published
    PubMed ID: 16489054
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  • 2
    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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  • 3
    Keywords: CANCER ; COHORT ; RISK ; GENE ; ASSOCIATION ; FREQUENCY ; LINKAGE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; PATTERNS ; HEALTH ; WOMEN ; SNP ; PROSPECTIVE COHORT ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; HUMAN GENOME ; REGION ; LINKAGE DISEQUILIBRIUM ; nutrition ; POSTMENOPAUSAL WOMEN ; ONCOLOGY ; ASSOCIATIONS ; RE ; INCREASE ; SNPs ; ESTROGEN ; LEVEL ; ENZYME ; analysis ; HAPLOTYPE ; HAPLOTYPES ; LOCUS ; single-nucleotide ; single-nucleotide polymorphism ; HORMONES ; prospective ; cancer research ; CANCER-RISK ; MULTIETHNIC COHORT ; BASE-LINE CHARACTERISTICS ; PREDICT ; NONCARRIERS ; AROMATASE
    Abstract: The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (〉= 5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP-19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 X 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CM19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer
    Type of Publication: Journal article published
    PubMed ID: 17325027
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  • 4
    Keywords: COHORT ; RISK ; GENES ; PROSTATE-CANCER ; LIFE-STYLE ; NURSES HEALTH ; COMMON DISEASES ; GENOME-WIDE ASSOCIATION ; RARE VARIANTS ; LINE CHARACTERISTICS
    Abstract: Population-based epidemiologic studies often gather information from study participants on disease history among their family members. Although investigators widely recognize that family history will be associated with genotypes of the participants at disease susceptibility loci, they commonly ignore such information in primary genetic association analyses. In this report, we propose a simple approach to association testing by incorporating family history information as a "phenotype." We account for the expected attenuation in strength of association of the genotype of study participants with family history under Mendelian transmission. The proposed analysis can be performed using standard statistical software adopting either a meta- or pooled-analysis framework. Re-analysis of a total of 115 known susceptibility single-nucleotide polymorphisms, discovered through genome-wide association studies for several disease traits, indicates that incorporation of family history information can increase efficiency by as much as 40%. Efficiency gain depends on the type of design used for conducting the primary study, extent of family history, and accuracy and completeness of reporting.
    Type of Publication: Journal article published
    PubMed ID: 24408355
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