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Background

IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease IBD. However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown.

Methodology-Principal Findings

We analyzed IL12B gene variants regarding association with Crohn-s disease CD and ulcerative colitis UC. Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region rs3212227, rs17860508, rs10045431, rs6887695. Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD p = 0.035; OR 1.15 95% CI 1.01–1.31 including a trend for rs6887695 for association with CD OR 1.41; 0.99–1.31, p = 0.066 and UC OR 1.18 0.97–1.43, p = 0.092. CD patients, who were homozygous C-C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele p = 6.8×10−5; OR = 2.84, 95% CI 1.66–4.84, while C-C homozygous UC patients had less often extensive colitis than G allele carriers p = 0.029; OR = 0.36, 95% CI 0.14–0.92. In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694 in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 p<0.05 but there was no epistasis between IL23R and IL12B variants.

Conclusions-Significance

The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants.



Autor: Jürgen Glas , Julia Seiderer , Johanna Wagner, Torsten Olszak, Christoph Fries, Cornelia Tillack, Matthias Friedrich, Florian Be

Fuente: http://plos.srce.hr/



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