title: 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=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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Grundtner
authors.forename: S
authors.initials: S
authors.lastname: Gruber
authors.forename: S S
authors.initials: SS
authors.lastname: Murray
authors.forename: S
authors.initials: S
authors.lastname: Vermeire
authors.forename: P
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: T
authors.initials: T
authors.lastname: Decker
authors.forename: P L
authors.initials: PL
authors.lastname: Lakatos
authors.forename: C
authors.initials: C
authors.lastname: Gasche
mesh_terms: D000483:Alleles; D000818:Animals; D001391:Azo Compounds / Q000378:metabolism; D002460:Cell Line; D002999:Clone Cells; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D004396:Coloring Agents / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D049408:Luminescent Agents / Q000378:metabolism; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D053701:Receptors, Interleukin-10 / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014162:Transfection
chemical_list: D001391:Azo Compounds; D004396:Coloring Agents; D049408:Luminescent Agents; D053701:Receptors, Interleukin-10; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; C032756:ponceau S