Vitamin D Receptor Gene Polymorphism and the Risk of Colorectal Cancer: A Nested Case-Control Study

<div><p>Epidemiological and experimental evidence suggest that vitamin D is protective against the risk of colorectal cancer. Polymorphisms in the gene encoding vitamin D receptor (VDR), which mediates most of the known cellular effects of vitamin D, have been suggested to alter this association. Here, using a tag SNP approach, we comprehensively evaluated the role of common genetic variants in <i>VDR</i> and their interaction with plasma vitamin D levels in relation to colorectal cancer risk in Japanese populations. A total of 356 colorectal cancer cases and 709 matched control subjects were selected from the participants of the Japan Public Health Center-based Prospective Cohort Study. Among these subjects, 29 <i>VDR</i> single nucleotide polymorphisms (SNPs) were selected and genotyped, and plasma vitamin D concentrations were measured. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of colorectal cancer, with adjustment for potential confounding factors. Among the results, eight <i>VDR</i> SNPs, namely rs2254210, rs1540339, rs2107301, rs11168267, rs11574113, rs731236, rs3847987 and rs11574143, the latter 5 of which were located in the 3′ region, were nominally associated with the risk of colorectal cancer (<i>P</i> = 0.01–0.048). Furthermore, of the above 5 3′ region SNPs, the inverse associations for 3 SNPs (rs11574113, rs3847987 and rs11574143) appeared to be evident only in those with high plasma vitamin D concentration. However, neither of these direct and suggestive interaction analysis associations was significant after multiple testing adjustment. Overall, the findings of this study provide only limited support for an association between common genetic variations in <i>VDR</i> and colorectal cancer risk in the Japanese population.</p></div

<i>VDR</i> and <i>GC</i> gene polymorphisms and colorectal cancer risk.

<p><i>VDR</i> and <i>GC</i> gene polymorphisms and colorectal cancer risk.</p

Baseline characteristics of cases and controls.

<p>Baseline characteristics of cases and controls.</p

Baseline characteristics of participants according to height category in men and women.

<p>Baseline characteristics of participants according to height category in men and women.</p

Hazard ratios for all-cause and cause-specific mortality according to height category by birth decade in men.

<p>Hazard ratios for all-cause and cause-specific mortality according to height category by birth decade in men.</p

Hazard ratios for all-cause and cause-specific mortality according to height category in women.

<p>Hazard ratios for all-cause and cause-specific mortality according to height category in women.</p

Association of <i>VDR</i> and <i>GC</i> gene polymorphisms with colorectal cancer risk according to plasma vitamin D concentration.

<p>Association of <i>VDR</i> and <i>GC</i> gene polymorphisms with colorectal cancer risk according to plasma vitamin D concentration.</p

Baseline characteristics in women (n = 45,229).

<p>Baseline characteristics in women (n = 45,229).</p

Deprivation index and cancer risk in women (n = 45,229).

<p>*Adjusted for age (age at diagnosis for cancer survival), area, population density (quartile), occupation (professionals and office worker, sales clerks or others, farmers, manual labors and others), smoking, alcohol drinking, body mass index, and leisure-time sport activity.</p><p>Deprivation index and cancer risk in women (n = 45,229).</p

Systematic biases in DNA methylation profile caused by difference of DNA collection protocols.

<p><b>A</b>. Differences of cell proportion between conditions (Ctrl1 vs. Ctrl2, TMM, BBJ, Hisayama, and JPHC) within the same individual are estimated by the cell-type composition from DNA methylation profiles. CD8T, CD8+ T cells; CD4T, CD4+ T cells; NK, natural killer cells; Bcell, B cells; Mono, monocytes; Gran, granulocytes. *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001 (Wilcoxon sighed rank test compared with Ctrl1). <b>B-F</b>. QQ plots for the comparison of 16 individuals between conditions (Ctrl1 vs. Ctrl2, TMM, BBJ, Hisayama, and JPHC) before (brown points) and after adjustment for the change in the estimated proportion of granulocytes (blue points). The genomic inflation factor lambda (median <i>P</i>-value of obs/exp) is shown.</p