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Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease.

ABSTRACT: To study the genetic association and epistatic interaction of the interleukin (IL)-10 and IL-10/STAT3 pathways in pediatric inflammatory bowel disease (IBD).A total of 159 pediatric inflammatory IBD patients (Crohn's disease, n = 136; ulcerative colitis, n = 23) and 129 matched controls were studied for genetic association of selected single nucleotide polymorphisms (SNPs) of the IL-10 gene and the genes IL10RA, IL10RB, STAT3, and HO1, from the IL-10/STAT3 signaling pathway. As interactions between SNPs from different loci may significantly affect the associated risk for disease, additive (a) and dominant (d) modeling of SNP interactions was also performed to examine high-order epistasis between combinations of the individual SNPs.The results showed that IL-10 rs304496 was associated with pediatric IBD (P = 0.022), but no association was found for two other IL-10 SNPs, rs1800872 and rs2034498, or for SNPs in genes IL10RA, IL10RB, STAT3, and HO1. However, analysis of epistatic interaction among these genes showed significant interactions: (1) between two IL-10 SNPs rs1800872 and rs3024496 (additive-additive P = 0.00015, Bonferroni P value (Bp) = 0.003); (2) between IL-10RB rs2834167 and HO1 rs2071746 (dominant-additive, P = 0.0018, Bp = 0.039); and (3) among IL-10 rs1800872, IL10RB rs2834167, and HO1 rs2071746 (additive-dominant-additive, P = 0.00015, Bp = 0.005), as well as weak interactions among IL-10 rs1800872, IL-10 rs3024496, and IL-10RA (additive-additive-additive, P = 0.003; Bp = 0.099), and among IL10RA, IL10RB, and HO1 genes (additive-dominant-additive, P = 0.008, Bp = 0.287).These results indicate that both the IL-10 gene itself, and through epistatic interaction with genes within the IL-10/STAT3 signaling pathway, contribute to the risk of pediatric IBD.

SUBMITTER: Lin Z

PROVIDER: S-EPMC5526760 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease.

Lin Zhenwu Z Wang Zhong Z Hegarty John P JP Lin Tony R TR Wang Yunhua Y Deiling Sue S Wu Rongling R Thomas Neal J NJ Floros Joanna J

World journal of gastroenterology 20170701 27

<h4>Aim</h4>To study the genetic association and epistatic interaction of the interleukin (IL)-10 and IL-10/STAT3 pathways in pediatric inflammatory bowel disease (IBD).<h4>Methods</h4>A total of 159 pediatric inflammatory IBD patients (Crohn's disease, <i>n</i> = 136; ulcerative colitis, <i>n</i> = 23) and 129 matched controls were studied for genetic association of selected single nucleotide polymorphisms (SNPs) of the <i>IL-10</i> gene and the genes <i>IL10RA</i>, <i>IL10RB</i>, <i>STAT3</i>, ...[more]

PMID: 28785144

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Project description:BackgroundInflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn's disease pathogenesis, with deleterious variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription.MethodsTreatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a "complex" score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription.ResultsThirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (β = -0.702, P = 4.3 × 10-5) and increased NFKBIA (β = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (β = 0.8, P = 3.1475 × 10-8) and TXN (β = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (β = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (β = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients.ConclusionsData integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.

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Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease.

Publications

Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease.

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