Association of rs2282679 A>C Polymorphism in Vitamin D Binding Protein Gene with Colorectal Cancer Risk and Survival: Effect Modification by Dietary Vitamin D in Newfoundland Population

Peizhong Peter Wang¹, Yun Zhu¹, Guangju Zhai², Sevtap Savas², Roger Green²

Departments of 1. Community Health & Humanities, 2. Genetics, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada

Introduction: A single nucleotide polymorphism (SNP) rs2282679 A>C in vitamin D binding protein gene has been associated with lower serum levels of vitamin D. We investigated whether this genetic polymorphism influences colorectal cancer (CRC) risk or mortality and whether the effects vary by vitamin D intake and tumor molecular phenotype.

Methods: A population-based case-control study was performed in 637 CRC incident cases (including 489 follow-up cases) and 489 matched controls in Newfoundland. The cohort was previously genotyped with the Illumina Omni-Quad 1 Million chip in cases and the Affymetrix Axiom® myDesign™ Array in controls. The genotype data on rs2282679 was retrieved from the genotype database for the purpose of the current study. The relationship between the rs2282679 polymorphism and CRC risk was examined using multivariate logistic regressions. For those cases with follow-up data, Kaplan Meier and multivariate Cox models were applied to assess the SNP in relation to CRC overall (OS) and disease-free survival (DFS).

Results: Our data showed no significant association of rs2282679 polymorphism with overall CRC risk. However, we observed some evidence for effect modification of this variant and CRC incidence by total vitamin D intake (P interaction=0.019). Survival analysis showed that the polymorphic C allele of SNP rs2282679 was correlated with poor DFS of CRC (per-allele HR, 1.36; 95% CI, 1.05-1.77). The effect of this SNP on DFS was limited to BRAF wild-type tumors (HR, 1.58; 95% CI, 1.12-2.23). For OS, carriage of the minor C allele conferred an enhanced significant risk for all-cause mortality among patients in higher categories of dietary vitamin D (HR, 2.11; 95% CI, 2.29-3.74; P interaction=0.040), calcium (HR, 1.93; 95% CI, 1.08-3.46; P interaction=0.043), milk (HR, 2.36; 95% CI, 1.26-4.44; P interaction=0.004), and total dairy product intakes (HR, 2.03; 95% CI, 1.11-3.72; P interaction=0.024).

Conclusions: SNP rs2282679 was not associated with susceptibility to overall CRC, but possibly related to decreased DFS after cancer diagnosis. The effect of this SNP on survival among CRC patients varied by vitamin D, calcium, and tumor BRAF mutation status.