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

Grundtner, P. and Gruber, S. and Murray, S. S. and Vermeire, S. and Rutgeerts, P. and Decker, T. and Lakatos, Péter László and Gasche, C. (2009) The IL-10R1 S138G loss-of-function allele and ulcerative colitis. Genes and Immunity, 10 (1). pp. 84-92. ISSN 1466-4879

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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 (n¼185, allele frequency 11.6 versus 17.5%; P¼0.017) but not in an independent Belgian cohort (n¼666, allele frequency 15.9 versus 15.5%; P¼0.8). 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.

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