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Evaluating genetic risk for prostate cancer among Japanese and Latinos.

ABSTRACT: BACKGROUND:There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos. METHODS:Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 × 10(-4)) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894). RESULTS:No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ? 8.0 × 10(-6)) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10(-5) and stage II: OR = 1.58; P = 3.05 × 10(-7)). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10(-25) and OR = 1.07; P = 1.02 × 10(-16) for Japanese and Latinos, respectively). CONCLUSION AND IMPACT:Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos.

SUBMITTER: Cheng I

PROVIDER: S-EPMC3494732 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Evaluating genetic risk for prostate cancer among Japanese and Latinos.

Cheng Iona I Chen Gary K GK Nakagawa Hidewaki H He Jing J Wan Peggy P Laurie Cathy C CC Shen Jess J Sheng Xin X Pooler Loreall C LC Crenshaw Andrew T AT Mirel Daniel B DB Takahashi Atsushi A Kubo Michiaki M Nakamura Yusuke Y Al Olama Ali Amin AA Benlloch Sara S Donovan Jenny L JL Guy Michelle M Hamdy Freddie C FC Kote-Jarai Zsofia Z Neal David E DE Wilkens Lynne R LR Monroe Kristine R KR Stram Daniel O DO Muir Kenneth K Eeles Rosalind A RA Easton Douglas F DF Kolonel Laurence N LN Henderson Brian E BE Le Marchand Loïc L Haiman Christopher A CA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20120824 11

<h4>Background</h4>There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos.<h4>Methods</h4>Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls ...[more]

PMID: 22923026

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Project description:BACKGROUND:Men of African-ancestry have elevated prostate cancer (PCa) incidence and mortality compared to men of other racial groups. There is support for a genetic contribution to this disparity, with evidence of genetic heterogeneity in the underlying risk alleles between populations. Studies of PCa among African men may inform the contribution of genetic risk factors to the elevated disease burden in this population. METHODS:We conducted an association study of >100 previously reported PCa risk alleles among 571 incidence cases and 485 controls among Uganda men. Unconditional logistic regression was used to test genetic associations and a polygenic risk score (PRS) was derived to assess the cumulative effect of the known risk alleles in association with PCa risk. In an exploratory analysis, we also tested associations of 17?125?421 genotyped and imputed markers genome-wide in association with PCa risk. RESULTS:Of the 111 known risk loci with a frequency >1%, 75 (68%) had effects that were directionally consistent with the initial discovery population,14 (13%) of which were nominally significantly associated with PCa risk at P?<?0.05. Compared to men with average risk (25th -75th percentile in PRS distribution), Ugandan men in the top 10% of the PRS, constructed of alleles outside of 8q24, had a 2.9-fold (95%CI: 1.75, 4.97) risk of developing PCa; risk for the top 10% increased to 4.86 (95%CI: 2.70, 8.76) with the inclusion of risk alleles at 8q24. In genome-wide association testing, the strongest associations were noted with known risk alleles located in the 8q24 region, including rs72725854 (OR?=?3.37, P?=?2.14?×?10-11 ) that is limited to populations of African ancestry (6% frequency). CONCLUSIONS:The ?100 known PCa risk variants were shown to effectively stratify PCa risk in Ugandan men, with 10% of men having a >4-fold increase in risk. The 8q24 risk region was also found to be a major contributor to PCa risk in Ugandan men, with the African ancestry-specific risk variant rs72725854 estimated to account for 12% of PCa in this population.

Dataset Information

Evaluating genetic risk for prostate cancer among Japanese and Latinos.

Publications

Evaluating genetic risk for prostate cancer among Japanese and Latinos.

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