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

Abstract

AIMTo study the genetic association and epistatic interaction of the interleukin (IL)-10 and IL-10/STAT3 pathways in pediatric inflammatory bowel disease (IBD).METHODSA 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.RESULTSThe 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).CONCLUSIONThese 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.

Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis

“…This method can decompose the overall genetic effect into its underlying components and test the significance of each component, gaining insight into the mechanisms of how SNPs affect disease. It has been used in our previous studies in human inflammatory bowel diseases (IBD) that included both case-control and case-trios studies, and targeting SNPs in one gene and in multiple genes of a metabolic pathway ( 140 , 141 ). Because this method is powerful and helps understand genetic contribution to a disease via interactions of genes in a metabolic pathway or gene network, we used it in the present study.…”

Interpretable network-guided epistasis detection

“…In the past, several genetic studies studying epistasis on IBD have been conducted [14,25,26,30,33,45]. We compared them to our results at the gene level, the minimal functional unit at which we expect genetic studies to converge.…”

“…Possible explanations include a large number of common variants with small effects, rare variants with large effects not covered in GWAS, unaccounted gene-environment interactions, and genetic interactions [29]. In this article we explore the latter, called epistasis, which has been linked to IBD in the past [14,26,30,33,45,53]. Often, two types of epistasis are described: biological and statistical epistasis [31].…”

The absence of interleukin 10 affects the morphology, differentiation, granule content and the production of cryptidin-4 in Paneth cells in mice

“…For example, mutations in the leader sequence of IL-10 protein and IL-10-1082A/G polymorphism are related with the severity of CD [13][14]. Moreover, the presence of IL-10 polymorphisms as rs304496 and IL-10 epistatic interaction with genes of STAT3 signaling pathway, has been related with the risk of pediatric IBD [15].…”