Author:

Keywords:

inflammatory bowel disease, ulcerative colitis, interleukin-10 receptor, single-nucleotide polymorphism, stat, inflammatory-bowel-disease, recombinant human interleukin-10, genome-wide association, active crohns-disease, chronic enterocolitis, t-cells, receptors, gene, mice, susceptibility, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, Immunology, STAT, INFLAMMATORY-BOWEL-DISEASE, RECOMBINANT HUMAN INTERLEUKIN-10, GENOME-WIDE ASSOCIATION, ACTIVE CROHNS-DISEASE, CHRONIC ENTEROCOLITIS, T-CELLS, RECEPTORS, GENE, MICE, SUSCEPTIBILITY, Alleles, Animals, Azo Compounds, Cell Line, Clone Cells, Cohort Studies, Colitis, Ulcerative, Coloring Agents, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Green Fluorescent Proteins, Haplotypes, HeLa Cells, Humans, Interleukin-10, Luminescent Agents, Mice, Polymorphism, Single Nucleotide, Receptors, Interleukin-10, STAT1 Transcription Factor, STAT3 Transcription Factor, Transfection, Hela Cells, 1107 Immunology, 3105 Genetics, 3204 Immunology

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.