BACKGROUND. A strong cumulative effect of five genetic variants and family history on prostate cancer risk was recently reported in a Swedish population (CAPS). We carried out this study to confirm the finding in two U.S. study populations and perform a combined analysis to obtain a more stable estimate of the odds ratio (OR) for prostate cancer. METHODS. We evaluated three SNPs at 8q24 and one SNP each at 17q12 and 17q24.3 in two study populations in the U.S. The first was a hospital-based case-control study population at Johns Hopkins Hospital (JHH), including 1,563 prostate cancer patients and 576 control subjects. The second was the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, including 1,172 prostate cancer patients and 1,157 control subjects. RESULTS. We confirmed a cumulative effect of five risk variants on prostate cancer risk. Based on a total of 5,628 cases and 3,514 controls from JHH, CGEMS, and CAPS, men who carry any combination of 1,2,3, and 4 or more of these five risk variants have an estimated OR (95% CI) of 1.41 (1.20-1.67), 1.88 (1.59-2.22), 2.36 (1.95-2.85), and 3.80 (2.77-5.22) for prostate cancer, respectively, compared to men who do not have any of these five risk variants. When family history was included, the cumulative effect was stronger. DISCUSSION. These results provide an important confirmation for the cumulative effect of five genetic risk variants on prostate cancer risk. The more stable OR estimates of the cumulative effect of these six risk factors are a major step toward individual risk characterization for this disease.
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