1. ¹Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
2. ²Scripps Genomic Medicine, La Jolla, CA, USA
3. ³Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
4. ⁴Max F Perutz Laboratories, University of Vienna, Vienna, Austria
5. ⁵1st Department of Medicine, Semmelweis University, Budapest, Hungary
6. ⁶Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Vienna, Austria

Correspondence: Professor Dr C Gasche, AKH-KIM 3, Division of Gastroenterology and Hepatology, Medical University Vienna, Wahringer Gurtel 18-20, Vienna A-1090, Austria. E-mail: christoph.gasche@meduniwien.ac.at

Received 11 July 2008; Revised 14 August 2008; Accepted 27 August 2008; Published online 18 September 2008.

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=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.