Genetic predictors of circulating 25-hydroxyvitamin D and prognosis after colorectal cancer

Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer–specific survival. Methods: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer–specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. Results: The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D–binding protein) was associated with poorer colorectal cancer–specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR ¼ 1.54; confidence interval (CI), 0.86–2.78] and colorectal cancer–specific mortality (HR ¼ 1.76; 95% CI, 0.86–3.58). A significant increased risk of overall mortality was observed in women (HR ¼ 3.26; 95% CI, 1.45–7.33; P_{heterogeneity} ¼ 0.01) and normal-weight individuals (HR ¼ 4.14; 95% CI, 1.50–11.43, P_{heterogeneity} ¼ 0.02). Conclusions: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer–specific survival, although power might have been an issue. Impact: Further studies are warranted to investigate the association in specific subgroups.