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Functional polymorphism in IL12B promoter site is associated with ulcerative colitis.
12 auth. A. Szperl, P. Saavalainen, R. Weersma, M. Lappalainen, P. Paavola‐Sakki, Leena Halme, ...
Ulcerative colitis (UC) is one of the two subtypes of inflammatory bowel disease (IBD). UC is a complex genetic disease that involves an abnormal immune response to the intestinal microflora causing ulceration of the epithelial barrier of the colon.…
Ulcerative colitis (UC) is one of the two subtypes of inflammatory bowel disease (IBD). UC is a complex genetic disease that involves an abnormal immune response to the intestinal microflora causing ulceration of the epithelial barrier of the colon. UC symptoms include bloody diarrhea, anemia, and abdominal pain. Twin studies and clustering of IBD in families indicate the presence of genetic factors that account for the development of the disease. Genome-wide association studies (GWAS) for UC have identified 30 loci with mostly immune-related genes such as IL23R, JAK2, STAT3, and IL12B. However, these common variants explain only part of the heritability due to their low effect size (odds ratios [OR] <2). Part of the missing heritability may thus lie in rare causative variants with a larger effect size. One of the UC-associated loci is the IL12B gene, encoding the IL12p40 homodimer protein produced by monocytes and dendritic cells. IL12p40 is the common subunit of two interleukins: IL12 and IL23. IL12 is responsible for T helper (Th) 1 differentiation and induces the production of interferon-c (IFNc), whereas IL23 is responsible for stabilizing the Th17 phenotype by promoting IL-17 production. A common GWAS associated SNP (rs10045431) in IL12B was not associated to UC in a Dutch population. Hence, we hypothesized that other variants in the IL12B gene that were not detected in the replication study due to their low frequency (rare variants) or simply because they were not tagged by the replication single nucleotide polymorphism (SNP) (due to low linkage disequilibrium, LD) might be causative for UC. As the expression of cytokines is likely to be regulated by variants in their regulatory and coding sequence, we genotyped a functional IL12B promoter variant previously associated with two other autoimmune diseases, systemic lupus erythematosus (SLE) and asthma. Further, to search for rare variants, we sequenced the coding part (including splice-sites) of the IL12B gene in 350 UC cases of Dutch origin. Table 1 shows the genotype distribution, allele frequency, and statistics of the IL12B promoter polymorphism, an insertion/deletion of 4 basepairs (rs41292470, previously reported as rs17860508), in both a Dutch and a Finnish cohort and in a combined analysis. We found moderate association of the GC allele with UC in Dutch (OR 1⁄4 0.86; 95% confidence interval [CI]: 0.76–1.31, P 1⁄4 0.025), whereas in the Finish population we observed a borderline significant association in the same direction (Table 1). The signal became more significant in a combined analysis (OR 1⁄4 0.85; 95% CI: 0.76–0.95, P 1⁄4 0.003). In the recessive model of inheritance the GC/GC genotype was associated with UC in Dutch (OR 1⁄4 0.77; 95% CI: 0.63–0.93, P 1⁄4 0.008) and combined analysis (OR 1⁄4 0.79; 95% CI: 0.67–0.94, P 1⁄4 0.008). The promoter variant did not appear to be in LD with the previously reported GWAS SNP (pairwise LD statistics (PLINK v1.07, r 0.037 and D0 0.285), this may explain why this association signal was not identified in our earlier replication study. Different genotypes of the IL12B promoter polymorphism have been linked with a broad spectrum of phenotypes. The CTCTAA/CTCTAA insertion genotype has been associated with increased mortality in children with cerebral malaria. Recently, the GC/GC genotype was associated with susceptibility for SLE in a Bulgarian cohort, whereas the heterozygous genotype has been correlated with severity of asthma in children. These studies and the present one indicate that genetic variation in IL12B plays an important role in the immune response in many diseases and the genotype of the promoter variant may influence different phenotypes. The IL12B promoter genotype has also been associated with differences in IL12 production by stimulated dendritic cells and higher transcriptional activity of IL12B. In contrast to previous studies, we did not see any correlation between the IL12B genotype and IL12 peripheral blood mRNA expression in 350 Dutch controls (Supporting Fig. 1). In this new study we used unstimulated cells, so it is possible that the IL12b mRNA levels were not high enough to identify differential expression. We cannot exclude the possibility of measuring different isoforms from the one measured in previous studies. This might happen due to different platforms used for the mRNA quantification. In search of causative rare variants for UC, we sequenced the coding parts, including splice sites, of IL12B in 350 Dutch UC cases. We identified four known SNPs (two intronic and two nonsynonymous, all reported in the dbSNP database) and two heterozygous, unknown variants (one nonsense and one splice-site) (Supporting Fig. 2). We genotyped all the variants in our Dutch UC cohort and controls and found very low frequencies of the variants exclusively in UC cases (Supporting Fig. 2). To investigate if there is a significant enrichment of rare variants in the UC Dutch cohort, we performed a pooled association test (Fisher’s exact test) for rare, potentially functional polymorphisms: the two Additional supporting information may be found in the online version of this article. Supported by a grant from the Netherlands Organization for Scientific Research (NWO-VICI grant 918.66.620 to C.W.) and by EU Marie Curie Excellence Grant (MEXT-CT-2005-025270. R.W. is supported by a clinical fellow grant (90700281)
Published in
Inflammatory Bowel Diseases
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3 | 2011 |
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