Why might the finding of a new genetic association with inflammatory bowel disease be of potential value in disease control?

See corresponding article on page 1508.

Inflammatory bowel disease (IBD) has long been recognized as an exaggerated inflammatory response to common antigenic stimuli in the gut. Ulcerative colitis (UC) (1) and Crohn disease (CD) (2) are the 2 major forms currently identified, although genome-wide association studies (GWAS) conducted by the International Inflammatory Bowel Disease Consortium have suggested that CD might better be classified as 2 distinct diseases (3, 4). There is no question that IBD is a chronic debilitating syndrome, associated with considerable morbidity and resulting in high public health costs (5). Although early treatment options were largely reliant on surgery (1), the use of antibiotics became popular for a time (6). However, the more sophisticated treatment options now available, when done successfully, have the potential to modify the natural course of IBD (7). Dietary interventions have also been recognized as beneficial, but again, there is no single dietary approach that can be safely recommended (8). IBD provides an excellent example of the importance of understanding gene-diet interactions (9). Both personalized medicine and personalized nutrition require a solid understanding of the genetic basis of an individual’s disease.

In 2012, Jostins et al. (3) undertook a meta-analysis of CD and UC GWAS previously reported, followed by extensive validation of significant findings, with a combined total of >75,000 cases and controls. They identified 71 new associations, bringing the total number to 163 IBD loci that met GWAS significance thresholds at that time. Among these loci were solute carrier (SLC) 2A4RG, SLC9A3, SLC10A4, SLC11A1, SLC22A4, and SLC22A5. At that time, they also commented that it was highly likely that many more loci are important, and that with evolving technologies, these will continue to be reported.

Eck and colleagues have been very successful in identifying IBD loci, such as SLC22A23, SLC23A1, and now SLC2A14 [glucose transporter member 14 (GLUT14)] (10–12). The SLC2A14 gene encodes for GLUT14, an orphan member of the facilitated membrane glucose transporter family, which was originally believed to be exclusively expressed in human testes. However, genetic variations in SLC2A14 have been associated with various chronic diseases that are not generally associated with testicular expression. This group previously reported on its genomic location, tissue expression, splice variants, and protein subcellular location (13). They confirmed that the exon utilization was tissue specific, with major expression in the testis. However, when the 2 major protein isoforms were expressed in mammalian cells, they located to the plasmalemma membrane, suggesting to the authors that GLUT14 could function as a membrane transporter. This hypothesis provided the background to the present study (12).

The starting hypothesis was that GLUT14 mediates glucose and dehydroascorbic acid uptake. In this issue of the Journal, Amir Shaghaghi et al. (12) studied the uptake of radio-labeled substrates into Xenopus laevis oocytes expressing the 2 previously identified GLUT14 isoforms. They also considered whether there could be genetic associations of SLC2A14 with IBD, through the genotyping of single nucleotide polymorphisms, by using the Manitoba Inflammatory Bowel Disease Cohort Study. The authors were able to show that both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes and that 3 alleles in the SLC2A14 gene independently associated with the risk of IBD. This work opens the door to subsequent studies that will help determine which pharmaceutical or dietary interventions might enable a precise intervention for patients of specific SLC2A14 variants with IBD.