The IL-10R1 S138G loss-of-function allele and ulcerative colitis

Abstract

Genetic predisposition is a risk factor for the development of inflammatory bowel diseases (IBDs). Disruption of the interleukin (IL)-10 pathway in mice causes intestinal inflammation similar to human IBD. Two common non-synonymous IL-10R1 variants, S138G and G330R, were cloned and expressed in HeLa and Ba/F3. A reduction in IL-10-induced STAT1 and STAT3 activation was seen for IL-10R1-S138G (but not IL-10R1-G330R) by phosphospecific western blotting in both cell types. When analyzing 52 world populations for the presence of IL-10R1 variants, a strong dissimilarity was found between major geographical regions. In addition, when 182 IBD-parent trios were genotyped for both variants, a reduced transmission of haplotype -7 (carrying the S138G variant allele) to offspring with ulcerative colitis (UC) was observed. This UC-protective effect of S138G was confirmed in a Hungarian cohort (n ¼ 185, allele frequency 11.6 versus 17.5%; P ¼ 0.017) but not in an independent Belgian cohort (n ¼ 666, allele frequency 15.9 versus 15.5%; P ¼ 0.8). In conclusion, the IL-10R1 S138G variant is a loss-offunction allele for IL-10-induced STAT1 and STAT3 activation but does not protect from UC susceptibility.

Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease

“…20,21 These data suggested that the variant (p.G330R) did not affect the signaling events upstream to STAT3 activation including IL-10 binding and IL-10R1 activation, but other mechanisms contributed to the dysfunction of this variant. Herein, we found that the novel compound heterozygous mutations (p.T84I and p.R101W) abrogated IL-10R1 activation and led to impaired IL-10R function.…”

“…23 The correlation of a SNP of IL-10R1 with IBD was demonstrated in some ethnic populations but not in others. 21,24 Therefore, besides the discovery in European and Lebanese, 13,14 it is useful to examine the rare variants of IL-10R in neonatal-onset IBD in other populations. In this study we further identified such rare variant in the Han Chinese.…”

Biology of interleukin-10

“…Nevertheless, correlations between certain haplotypes of the IL-10 and IL-10R1 genes and the occurrence and/or course of various diseases were described (230)(231)(232)(233)(234)(235). In fact, in Lupus erythematosus, not only was the correlation statistically significant between the haplotype and the occurrence of disease, but also between the type of antibody and the severity of the clinical condition (230,232,236).…”

IL10R2 Overexpression Promotes IL22/STAT3 Signaling in Colorectal Carcinogenesis

“…Recently, IL10R mutations causing functional impairment of IL10 signaling were implicated in early-onset enterocolitis (5). Also, the S138G variant of IL10R1 was linked to ulcerative colitis (6). This IL10R2 variant likely represents an adaptive change in the human genome as it reduces the ability of cmvIL10 to utilize the host's IL10 signaling pathway (7).…”