Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2017; 23(27): 4897-4909
Published online Jul 21, 2017. doi: 10.3748/wjg.v23.i27.4897
Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease
Zhenwu Lin, Zhong Wang, John P Hegarty, Tony R Lin, Yunhua Wang, Sue Deiling, Rongling Wu, Neal J Thomas, Joanna Floros
Zhenwu Lin, Yunhua Wang, Neal J Thomas, Joanna Floros, CHILD Research, Department of Pediatrics, the Pennsylvania State University, College of Medicine, Hershey, PA 17033, United States
Zhong Wang, Rongling Wu, Division of Biostatistics, Department of Public Health Science, the Pennsylvania State University, College of Medicine, Hershey, PA 17033, United States
John P Hegarty, Tony R Lin, Sue Deiling, Department of Surgery, the Pennsylvania State University, College of Medicine, Hershey, PA 17033, United States
Joanna Floros, Department of Obstetrics and Gynecology, the Pennsylvania State University, College of Medicine, Hershey, PA 17033, United States
Zhenwu Lin, Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 17033, United States
Author contributions: Lin Z and Wang Z contributed equally to this work; Lin Z designed the experimental approach and was responsible for troubleshooting, data collection and organization and the overall supervision of the project and he worked with the statistician for data analysis, manuscript writing and submission, and the response to reviewers; Wang Z and Wu R contributed to the data analysis and presentation of the results, manuscript writing and revision; Hegarty JP was involved in grant writing, preliminary data preparation and genotype analysis; Lin TR contributed to IL-10 genotype and genotyping data analysis (adult IBD and youth IBD), as well as of IL-10 gene expression in patients with different genotype; Wang Y performed genotype analysis by PCR, gel electrophoresis, genotype scoring, and prepared the data sheet for analysis; Deiling S contributed to clinical sample collection and documentation; Thomas NJ was involved in study subject recruitment, clinical sample collection and manuscript writing; Floros J was involved in experimental design, management of the research team, oversight of the project, data collection and presentation, manuscript writing, final critical reading before submission, response to reviewers and revising the manuscript for resubmission.
Supported by a Children Miracle Network Research Grant, No. 132698 to Lin Z (P.I.) and Thomas NJ (Co-P.I.) (2011-2013), and Floros J (P.I.) (2013-2014).
Institutional review board statement: All study protocols were approved by the Penn State University College of Medicine Institutional Review Board, Study ID: PRAMS020105-A Jane 8, 2016. ATCC Material transfer agreement (MTA) Aug 28, 2012.
Conflict-of-interest statement: No conflict of interest exists for all authors.
Data sharing statement: Data will be shared freely to whoever requests them via contact of Zhenwu Lin (
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Zhenwu Lin, PhD, Senior Research Scientist, Department of Pediatrics, the Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, United States.
Telephone: +1-717-2198591 Fax: +1-717-5310215
Received: November 27, 2016
Peer-review started: November 28, 2016
First decision: January 19, 2017
Revised: February 18, 2017
Accepted: June 1, 2017
Article in press: June 1, 2017
Published online: July 21, 2017
Processing time: 235 Days and 6.6 Hours

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.

Keywords: Pediatric inflammatory bowel disease, Interleukin-10, HO1, Single nucleotide polymorphism, IL10-STAT3 pathway, Epistatic interaction

Core tip: Inflammatory bowel disease (IBD) affects not only adults, but also children and newborn infants. Of the 163 genes currently associated with risk for development of IBD, only a few have been studied in pediatric patients. In this study, we found that one interleukin (IL)-10 genetic variation, rs304496, is associated with risk for pediatric IBD. IL-10 restricts excessive immune responses during intestinal inflammation. We also demonstrated epistatic interactions between genetic variants within the IL-10/STAT3 signaling pathway that contribute to a higher associated risk for pediatric IBD. These findings emphasize the importance of the IL-10 pathway in a subgroup of IBD patients.