VITAMIN-D-RECEPTOR POLYMORPHISMS, CIRCULATING VITAMIN-D METABOLITES, AND RISK OF PROSTATE-CANCER IN UNITED-STATES PHYSICIANS

Prostatic cells express vitamin D receptor (VDR), which mediates the f unctions of 1,25-dihydroxyvitamin D. Two recent case-control studies s uggested strong inverse associations between two VDR polymorphisms, Ta qI and poly(A), and risk of prostate cancer, These two and a third pol ymorphism, BsmI, are closely linked. In a case-control study nested in the Physicians' Health Study, a randomized double-blind trial of aspi rin and p-carotene among 22,071 United States male physicians, we exam ined the associations between BsmI and TaqI and prostate cancer risk a nd whether the associations varied according to age and vitamin D meta bolite levels among 372 incident cases and 591 controls. Among control s, the BE genotype was significantly associated with higher 1,25-dihyd roxyvitamin D (median = 36.2 pg/ml for the BE versus 33.9 pg/ml for th e bb genotype; P = 0.02), suggesting an association of the VDR polymor phisms with VDR function. Overall, we observed no significant associat ions of these VDR polymorphisms with prostate cancer risk: relative ri sk (RR) = 0.86 [95% confidence interval (CI) = 0.57-1.29] for the BE g enotype and RR = 0.92 (95% CI = 0.69-1.22) for the Bb genotype, compar ed with the bb genotype (results were similar for the TaqI polymorphis m). Stratification by age (less than or equal to 61 and >61 years) and tumor aggressiveness showed no significant associations. However, in an analysis restricted to men with plasma 25-hydroxyvitamin D below th e median, we observed a 57% reduction (RR = 0.43, 95% CI = 0.19-0.98) in risk for those with the BE versus the bb genotype; the risk reducti on was particularly marked among older men (RR = 0.18, 95% CI = 0.05-0 .68), We did not observe this inverse association among men with 25-hy droxyvitamin D levels above the median, nor did we observe it among yo unger men.