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=185, allele frequency 11.6 versus 17.5%; P=0.017) but not in an independent Belgian cohort (n=666, allele frequency 15.9 versus 15.5%; P=0.8). In conclusion, the IL-10R1 S138G variant is a loss-of-function allele for IL-10-induced STAT1 and STAT3 activation but does not protect from UC susceptibility.
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We are grateful to Dr Rainer de Martin (Medical University of Vienna) for inspiring advice and Birgit Rapp, Verena Kratzer and Manuela Nemeth for excellent technical assistance and to the Foundation Jean Dausset (CEPH) for providing the DNA samples. The study has been supported by the Austrian Science Fund (P15314 and P17943 to CG) and the OeNB Anniversary Fund (ONB10543 to CG).
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Grundtner, P., Gruber, S., Murray, S. et al. The IL-10R1 S138G loss-of-function allele and ulcerative colitis. Genes Immun 10, 84–92 (2009). https://doi.org/10.1038/gene.2008.72
- inflammatory bowel disease
- ulcerative colitis
- interleukin-10 receptor
- single-nucleotide polymorphism
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