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

Abstract

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. CONCLUSION In this population of men, none of the VDR polymorphisms studied was associated with susceptibility to PC. Prostate 67: 911–923, 2007.