The Contribution of OCTN1/2 Variants Within the IBD5 Locus to Disease Susceptibility and Severity in Crohn’s Disease

Abstract

Background & Aims:Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C¡T), and OCTN2 variant (SLC22A5 ؊207G¡C) was performed using the TaqMan system. Results: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D=, >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P ‫؍‬ .0046) and homozygosity (21% vs 14.8%; P ‫؍‬ .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P ‫؍‬ .0008) and OCTN2 (56.1% vs 48.4%; P ‫؍‬ .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P ‫؍‬ .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P ‫؍‬ .011 and P ‫؍‬ .011, respectively) and disease progression (P ‫؍‬ .038 and P ‫؍‬ .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P ‫؍‬ .016 and P ‫؍‬ .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. Conclusions: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required.

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

“…Also, in individuals who were negative for the IBD5 risk haplotype, we did not find a significantly increased frequency of the L503F-G-207C TC haplotype in CD cases versus controls. Our findings are consistent with several very recent studies of the contribution of these variants to CD susceptibility, [13][14][15] that do not support a causal role for these variants and are not consistent with the findings of Peltekova et al 12,25 Taken together, the weight of current evidence suggests that despite the effect of the L503F and G-207C variants on the function of the cation transporters OCTN1 and OCTN2, 12 they are unlikely to have a direct causal role in the pathogenesis of CD.…”

“…[13][14][15][16] The original purpose of our study was to fine-map the region of association with CD and to try to identify functional sequence variants that were directly related to pathogenesis. Our analysis of LD across the region is consistent with the model proposed by Daly et al 11 of discrete blocks characterized by stretches of high LD interspersed with short intervals of LD breakdown and high levels of recombination.…”

“…However, it remains unclear whether these two genes are the causative genes at the IBD5 locus, as some studies have shown that the variants are not independent of the general risk haplotype at this locus. [13][14][15][16] In addition, mutations within SLC22A5 that have been associated with systemic carnitine deficiency do not show any evidence of gastrointestinal disturbance. 17 It is therefore possible that causal genes or mutations for CD at this locus are yet to be identified.…”

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

“…These studies included diverse populations and originated from Canada [6,13,14], the UK [15][16][17][18], Germany [19], New Zealand [20], Spain [21], Italy [22,23], Belgium [24], Greece [25], Sweden [26] and Japan [27,28]. One Japanese and another Hungarian study with a small number of subjects found no association between OCTN 1&2 transporter polymorphisms and CD [28,29]; thus there could be ethnic differences in IBD5 locus mutations and propensity for Crohn's disease [7].…”

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

“…I nflammatory bowel diseases (IBD), 4 Crohn's disease (CD) and ulcerative colitis, are disorders of unknown etiology characterized by chronic relapsing-remitting inflammation of the gastrointestinal tract. Pathophysiological and genetic evidence points to an important role of intestinal barrier function in the initiation and perpetuation of the disease (1-7).…”