Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.

BACKGROUNDEvidence from experimental animal and cell line studies supports a beneficial role for vitamin D in prostate cancer (PCa). Although the results from human studies have been mainly null for overall PCa risk, there may be a benefit for survival. This study assessed the associations of circulating 25-hydroxyvitamin D (25(OH)D) and common variations in key vitamin D-related genes with fatal PCa. METHODSIn a large cohort consortium, 518 fatal cases and 2986 controls with 25(OH)D data were identified. Genotyping information for 91 single-nucleotide polymorphisms (SNPs) in 7 vitamin D-related genes (vitamin D receptor, group-specific component, cytochrome P450 27A1 [CYP27A1], CYP27B1, CYP24A1, CYP2R1, and retinoid X receptor ) was available for 496 fatal cases and 3577 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of 25(OH)D and SNPs with fatal PCa. The study also tested for 25(OH)D-SNP interactions among 264 fatal cases and 1169 controls. RESULTSNo statistically significant relationship was observed between 25(OH)D and fatal PCa (OR for extreme quartiles, 0.86; 95% CI, 0.65-1.14; P for trend=.22) or the main effects of the SNPs and fatal PCa. There was evidence suggesting that associations of several SNPs, including 5 related to circulating 25(OH)D, with fatal PCa were modified by 25(OH)D. Individually, these associations did not remain significant after multiple testing; however, the P value for the set-based test for CYP2R1 was .002. CONCLUSIONSStatistically significant associations were not observed for either 25(OH)D or vitamin D-related SNPs with fatal PCa. The effect modification of 25(OH)D associations by biologically plausible genetic variation may deserve further exploration. Cancer 2015;121:1949-1956. (c) 2015 American Cancer Society. Because of the high prevalence of prostate cancer (PCa) and the wide international variation in vitamin D status, identifying causal links between the two could have a large public health impact. Few studies have addressed the risk of fatal PCa. In this study, a convincing association is not observed between circulating 25-hydroxyvitamin D (25(OH)D) or single-nucleotide polymorphisms (SNPs) in key vitamin D-related genes and fatal PCa. However, interactions between biologically relevant SNPs and circulating 25(OH)D with respect to fatal PCa may deserve further investigation.