Vitamin D receptor polymorphisms in patients with cutaneous melanoma

Abstract

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.

Figure 1

Position of the SNPs studied GEM in relation to the VDR structure. SNPs with significant associations in multivariate analyses after adjusting for age, sex, age-sex interaction, center are shown in bold font. The vertical bars represent promoters 1F – 1C green) and exons (blue). The numbers 1 to 36 refer to the SNP’s relative position from 5’ to 3’ (Table 2). The polymorphism TaqI is located near the stop codon on exon 9, however is strongly linked to the 3’ regulatory region. The grey box represents the 3’ UTR.

Figure 2

Uniform Q-Q Plot for the VDR SNPs risk trend p-values. Quantiles of the obtained p-values were plotted against the theoretical uniform quantiles.

Figure 3

Meta-analysis of VDR SNPs reported in other investigations of melanoma in relation to risk. (A) SNP rs4516035 (variant allele G), (B) SNP rs1544410 (variant allele A or ‘B’); and (C) SNP rs731236 (variant allele C or ‘t’). Unadjusted ORs and 95% CI are shown.