The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

Abstract

Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD.Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD.Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene.Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1.95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively).Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.

Keywords: SLC2A14; antioxidants; genetic association; inflammatory bowel disease; vitamin C.

FIGURE 1

GLUT14 isoforms mediate DHA and deoxyglucose uptake. Xenopus laevis oocytes expressing S-GLUT14 and L-GLUT14 isoforms and exhibit uptake of radiolabeled deoxyglucose (A) and dehydroascorbic acid (B). Incubations were performed with 300 μM [¹⁴C]DHA or 300 μM deoxy-d-glucose,2-[1,2-3H(N)] on 20 oocytes in each group in 3 independent experiments. Data are expressed as means ± SDs. Lowercase letters indicate statistically significant differences determined through 1-factor ANOVA, P < 0.05. GLUT14, facilitated glucose transporter 14; L-GLUT14, long GLUT14 isoform; S-GLUT, short GLUT14 isoform.

FIGURE 2

Genetic linkage across the SLC2A14 locus in individuals with Crohn disease (A) and ulcerative colitis (B). The degree of linkage (diamonds) is given as a percentage, and the darker color indicates a higher degree of linkage. SNPs with relevant associations to any form of inflammatory bowel disease are indicated by rectangles. The single nucleotide polymorphisms associated with inflammatory bowel disease are not in genetic linkage. SLC2, solute carrier family 2; SNP, single nucleotide polymorphism.