Comprehensive Association Analysis of the Vitamin D Pathway Genes, VDR, CYP27B1, and CYP24A1, in Prostate Cancer

Abstract

Genetic variation in vitamin D -related genes has not been investigated comprehensively and findings are equivocal. We studied the association between polymorphisms across the entire vitamin D receptor (VDR) gene and genes encoding for vitamin D activating enzyme 1-A-hydroxylase (CYP27B1) and deactivating enzyme 24-hyroxylase (CYP24A1) and prostate cancer risk among middle-aged men using a population-based case-control study design. DNA samples and survey data were obtained from incident cases (n = 630), 40 to 64 years old, identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry from 1993 to 1996 and from random controls (n = 565) of similar age without a history of prostate cancer. We selected and genotyped tag single-nucleotide polymorphisms to predict common variants across VDR (n = 22), CYP27B1 (n = 2), and CYP24A1 (n = 14). Haplotypes of VDR and CYP24A1 were not associated with prostate cancer risk. In the genotype analysis, homozygotes at two VDR loci (rs2107301 and rs2238135) were associated with a 2-to 2.5-fold higher risk of prostate cancer compared with the homozygote common allele [odds ratio, 2.47 (95% confidence interval, 1.52-4.00; P = 0.002) and 1.95 (95% confidence interval, 1.17-3.26; P = 0.007), respectively; P value corrected for multiple comparisons for VDR = 0.002]. We found no evidence that the two associated VDR single-nucleotide polymorphisms were modified by age at diagnosis, prostate cancer aggressiveness, first-degree family history of prostate cancer, or vitamin D intake. Genotypes of CYP27B1 and CYP24A1 were not associated with prostate cancer risk. Our findings suggest that polymorphisms in the VDR gene may be associated with prostate cancer risk and, therefore, that the vitamin D pathway might have an etiologic role in the development of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(10):1990 -9)

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

“…rs2107301 is, however, located in intron 4 and in weak LD with the risk-related SNPS in our study (Figure 3), whereas rs2238135 is located upstream in a different LD block. Our findings of no association between tag SNPS in CYP27B1 or CYP24A1 with prostate cancer risk are consistent with the Holick et al study (22). (20).…”

“…Metaanalyses for five restriction fragment length polymorphisms (RFLPs; BsmI, ApaI, TaqI, poly(A) and FokI) in VDR show null or inconsistent results (20); however, recent resequencing data show that these few SNPS cover the common genetic variation within this large gene only to a very limited extent (21). A recent population based case-control study, evaluating 22 VDR tag SNPS, reported associations between two tag SNPS in VDR and prostate cancer risk, but did not observe associations with tag SNPS in CYP27B1 or CYP24A1 (22). Three studies examined the interaction of the limited number of VDR RFLPs and serum vitamin D levels in relation to prostate cancer, but results were also inconsistent (10,11,23).…”

Genetic Variants in the Vitamin D Receptor Are Associated with Advanced Prostate Cancer at Diagnosis: Findings from the Prostate Testing for Cancer and Treatment Study and a Systematic Review

“…Only 19.4% of patients with Gleason score ≥7 have cancer stage ≥T 2c , whereas 72.2% of patients at stage ≥T 2c have Gleason score ≥7. A similar situation also occurs in other studies in our systematic review, suggesting that Gleason score may be a more sensitive measure of aggressive prostate cancer than TNM stage (14,32,48). However, it is important to recognize that complete pathologic staging was not available in the majority of our cases and that histologic evaluation of Gleason scores is well known to be subject to variability, with both these factors potentially confounding the lack of correlation shown in our study.…”

Placenta-specific Methylation of the Vitamin D 24-Hydroxylase Gene

“…Each of these pathways relies on external inputs for the production of precursor molecules, and enzymes involved in each pathway (including VDR and CYP27B1) have known functional polymorphic variants implicated in moderating disease risk (76 -83), including adverse pregnancy outcomes (84 -89). There are numerous polymorphisms throughout the CYP24A1 exonic, intronic, and regulatory gene regions (56), but as yet there is little information regarding the functionality or clinical relevance of such variants. The convergence/intersection of 1-carbon metabolism with other metabolic and signaling pathways is potentially very important in modulating disease risk and warrants further investigation.…”