Genetic Associations in the Vitamin D Receptor and Colorectal Cancer in African Americans and Caucasians

Sonia S Kupfer,Nathan A Ellis,Andrew Skol,Robert S Sandler,Temitope O Keku,Angel Carracedo,Antoni Castells,Anton E Ludvik,Rick A Kittles,Clara Ruiz-Ponte,Sergi Castellvi-Bel,Jeffrey R Anderson,Stanley Hooker

doi:10.1371/journal.pone.0026123

Abstract

Low vitamin D levels are associated with an increased incidence of colorectal cancer (CRC) and higher mortality from the disease. In the US, African Americans (AAs) have the highest CRC incidence and mortality and the lowest levels of vitamin D. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been previously associated with CRC, but few studies have included AAs. We studied 795 AA CRC cases and 985 AA controls from Chicago and North Carolina as well as 1324 Caucasian cases and 990 Caucasian controls from Chicago and Spain. We genotyped 54 tagSNPs in VDR (46586959 to 46521297 Mb) and tested for association adjusting for West African ancestry, age, gender, and multiple testing. Untyped markers were imputed using MACH1.0. We analyzed associations by gender and anatomic location in the whole study group as well as by vitamin D intake in the North Carolina AA group. In the joint analysis, none of the SNPs tested was significantly associated with CRC. For four previously tested restriction fragment length polymorphisms, only one (referred to as ApaI), tagged by the SNP rs79628898, had a nominally significant p-value in AAs; none of these polymorphisms were associated with CRC in Caucasians. In the North Carolina AAs, for whom we had vitamin D intake data, we found a significant association between an intronic SNP rs11574041 and vitamin D intake, which is evidence for a VDR gene-environment interaction in AAs. In summary, using a systematic tagSNP approach, we have not found evidence for significant associations between VDR and CRC in AAs or Caucasians.

Highlights

Vitamin D has numerous physiological effects, including effects on regulation of calcium homeostasis, immunity, insulin secretion, and blood pressure
Analysis of the individual AA study groups were consistent with the combined AA study group, in as much as each single nucleotide polymorphisms (SNPs) that was nominally significant in the combined study group was nominally significantly associated with colorectal cancer (CRC) in one of the two AA study groups (Supplementary Table S2)
We noted that both rs12308082 and the SNP with the second smallest p-value, rs11574065, (p = 0.04) had relatively low allele frequencies in controls (0.09 and 0.02, respectively); these SNPs were monomorphic in Caucasians

Summary

Introduction

Vitamin D has numerous physiological effects, including effects on regulation of calcium homeostasis, immunity, insulin secretion, and blood pressure. Vitamin D3 (cholecalciferol) is formed from the precursor steroid 7-dehydrocholesterol (7-DHC), which is concentrated in the plasma membrane of the basal keratinocytes in the skin [1]. Upon stimulation of sunlight (UVB, 280–320 nm), 7DHC is converted to vitamin D3. Serum 25(OH)D3 level, which is the most widely accepted indicator of vitamin D status, is the sum of dietary/supplementary intake and endogenous synthesis. Up to 95% of vitamin D is attributable to synthesis in the skin with sunlight exposure, because there are relatively few dietary sources that contain vitamin D [2]. Factors that negatively impact vitamin D status include lack of sun exposure, lack of vitamin D intake, dark skin, aging, and obesity among others

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