Polymorphisms in the sodium-dependent ascorbate transporter gene SLC23A1 are associated with susceptibility to Crohn disease

Abstract

Background: Crohn disease (CD) and ulcerative colitis (UC) are 2 common inflammatory bowel diseases (IBDs) associated with intestinal inflammation and tissue damage. Oxidative stress is suggested to play a major role in the initiation and progression of IBD. Vitamin C (ascorbate, ascorbic acid) supplementation has reduced oxidative stress in persons with IBD. The role of ascorbate transporters in IBD remains to be determined. SLC23A1 is a major ascorbate transporter in the intestinal tract, and some of its genetic variants have been associated with severely decreased ascorbate transport and lower systemic concentrations.

Objective: This study aimed to determine whether common genetic variants in the vitamin C transporter SLC23A1 are associated with the risk of IBD.

Design: Genomic DNA samples from patients with CD (n = 162) and UC (n = 149) from the Manitoba IBD Cohort Study and ethnically matched controls (n = 142) were genotyped for 3 SLC23A1 polymorphisms (rs6596473, rs33972313, and rs10063949) by using TaqMan assays.

Results: Variation at rs10063949 (G allele for heterozygote and homozygote) was associated with increased susceptibility to CD (OR: 2.54; 95% CI: 1.38, 4.66; OR: 4.72; 95% CI: 2.53, 8.81; P < 0.0001; respectively). A strong linkage disequilibrium (LD) was observed across the SLC23A1 region (variation rs6596473 with rs10063949) for CD and UC (D' = 0.94 and 0.96, respectively). The risk alleles confirmed a haplotype (CGG) that is carried more in CD patients (65.3%, P < 0.0001) than in controls (43.5%).

Conclusions: A genetic variant (rs10063949-G) in the SLC23A1 ascorbate transporter locus was identified and is associated with an increased risk of CD in a white Canadian IBD cohort. The presented evidence that SLC23A1 variations can modulate the risk of CD has implications for understanding ascorbate transport in CD patients and provides a novel opportunity toward individualized nutritional therapy for patients carrying the disease-associated genotype.