Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk

Abstract

We systematically investigated the association of 48 SNPS in four vitamin D metabolizing genes [CYP27A1, GC, CYP27B1 and CYP24A1] with serum 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels and the association of these SNPS and an additional 164 SNPS in eight downstream mediators of vitamin D signaling [VDR, RXRA, RXRB, PPAR, NCOA1, NCOA2, NCOA3 and SMAD3] with prostate cancer risk in the 749 incident prostate cancer cases and 781 controls of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. 25(OH)D (all cases and controls) and 1,25(OH)(2)D (a subset of 150 controls) levels were measured by radioimmunoassay and SNP data were genotyped as part of a genome-wide scan. Among investigated SNPS, only four tag SNPS in GC, the major serum 25(OH)D carrier, were associated with 25(OH)D levels; no SNPS were associated with 1,25(OH)(2)D levels. None of the 212 SNPS examined were associated with cancer risk overall. Among men in the lowest tertile of serum 25(OH)D (<48.9 nmol/l), however, prostate cancer risk was related to tag SNPS in or near the 3' untranslated region (UTR) of VDR, with the strongest association for rs11574143 [odds ratio (95% confidence interval) for risk allele carriers versus wild-type: 2.49 (1.51-4.11), P = 0.0007]; the genotype associations were null among men in tertile 2 and tertile 3. Results from the most comprehensive evaluation of serum vitamin D and its related genes to date suggest that tag SNPS in the 3' UTR of VDR may be associated with risk of prostate cancer in men with low vitamin D status.

Fig. 1.

Vitamin D metabolism and function.

Fig. 2.

Consort flow diagram of the study.

Fig. 3.

P values for the association between tag SNPS in GC and 25(OH) vitamin D concentrations in the control group of the PLCO Trial (chromosome 4; shown 3′ → 5′ direction).

Fig. 4.

P values for the association between tag SNPS in VDR and prostate cancer risk according to tertiles of 25(OH) vitamin D. Each red dot represents –log (P value) among men in the lowest tertile of 25(OH) vitamin D and each triangle and each square represents among men in the second and third tertile of 25(OH) vitamin D, respectively (chromosome 12; shown 3′ → 5′ direction). Note: ApaI and TaqI are located between rs757343 and rs11574143 (see supplementary Figure 1, available at Carcinogenesis Online).