Background: The association of vitamin D status with prostate cancer is controversial, with no association observed for overall incidence, but a potential link with lethal disease.

Methods: We assessed prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] and variation in vitamin D related genes and the risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1328 incident cases diagnosed following blood draw (1993–95) and 1331 controls. Men with prostate cancer were followed through March 2011 for lethal outcomes (n=111). We selected 97 linkage disequilibrium tagSNPs to represent common genetic variation across seven vitamin D related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, VDR). We used a logistic kernel machine test to assess the multimarker pathway global association for ‘SNP-sets’ defined by the seven genes with prostate cancer.

Results: Higher levels of 25(OH)D were associated with about half the risk of lethal prostate cancer (OR comparing extreme quartiles: 0.45; 95% CI:0.25–0.81). This finding did not vary by time from blood draw to diagnosis. We found no significant association of 25(OH)D with overall prostate cancer risk(OR comparing extreme quartiles: 1.05; 95% CI: 0.85–1.30). The total vitamin D pathway SNP-set (seven genes) as well as SNP-sets defined by the individual genes (VDR, RXRA, or CYP27A1) were nominally associated with lethal prostate cancer risk (p<0.05), but not overall prostate cancer (p=0.41). Conclusions: In this large prospective study, plasma 25(OH)D and common variation across vitamin D pathway genes were associated with lethal prostate cancer risk. Studies of vitamin D and prostate cancer should focus on lethal disease.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A60.