Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk

BACKGROUND. The vitamin D receptor (VDR) is required for actions of vitamin D. The binding of 1,25-dihydroxyvitamin D to the VDR on prostatic epithelial cells prompts the regulation of cancer-related genes. METHODS. We conducted a nested case-control study in the Health Professionals Follow-up Study to investigate the role of the VDR Cdx2, Fok1, and Bsm1 gene polymorphisms and associated haplotypes and their interaction with plasma vitamin D metabolites in relation to prostate cancer (PC) risk. RESULTS. No association was found between these SNPs or their associated haplotypes and all PC subtypes except that haplotype 2 (A-f-b) with Cdx2 A, Fok1 f, and Bsm1 b alleles and haplotype 3 (A-F-B) with Cdx2 A, Fok1 F and Bsm1 B alleles compared to the most common haplotype (A-F-b), were associated with reduced risk of aggressive PC (high stage or Gleason sum >= 7; P = 0.02), both with two alleles suspected of being low risk. Carriers of the variant Cdx2 A allele who were deficient in plasma 25-hydroxyvitamin D (<= 15 ng/ml) compared to non-carriers with normal 25-hydroxyvitamin D, had a lower risk of total and poorly differentiated PCs (Gleason sum >= 7) (P for interaction = 0.02 and 0.04, respectively). Plasma 1,25-dihydroxyvitamin D deficiency (<= 26 pg/ml) was associated with a threefold risk of poorly differentiated PC (P for interaction = 0.01) when comparing carriers of the Cdx2 A allele to non-carriers with normal 1,25-dihydroxyvitamin D.