Genetic Variants Assessing Crohn’s Disease Pattern in Pediatric Inflammatory Bowel Disease Patients by a Clinical Exome Survey

Abstract

Background: Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn’s disease (CD) and ulcerative colitis (UC). Recent discoveries have brought much attention to the genetic predisposition of patients with IBD. Here we evaluate the interaction between IBD genetic risk factors susceptibility and CD occurrence in an IBD pediatric patient population, performing a clinical exome survey. Methods: From February 2018 to April 2019, we collected blood samples from 7 pediatric patients with IBD concerns from several collaborating health centers and/or hospitals. Blood samples were processed by extracting and sequencing DNA for a clinical exome survey. Shophia-DDM-v3-4 platform allowed sequenced reads alignment on hg19 genome as well as genetic variant calling. Both IBD risk and pathogenic genetic variants covered by at least 20 reads were selected for subjacent analysis. Results: Normality and Bartlett tests of both risk and pathogenic genetic variants suggested random and heterogeneous distribution of these variants in this group of IBD pediatric patients. P value clustering analysis by processing 157 IBD risk factors revealed genetic heterogeneity in IBD population and suggested two pathways influencing IBD development. In particular, (1) genetic variants associated with autoimmune and (2) metabolic diseases and CD risk factors (rs2066844 and rs2241880 single nucleotide polymorphism variants, respectively, of genes NOD2 and ATG16L) were identified in distinct clusters of IBD patients ( P < .05). Moreover, the heterogeneous distribution of the following variants rs10065172 (IRGM), rs1805010 (IL4R), rs5030737 (MBL2), and rs33995883 (LRRK2) in this group of IBD patients was consistent with their random distribution in that population. Conclusion: Our study revealed specific genetic variants linked to CD susceptibility, autoimmune and/or innate immunodeficiency as well as to metabolic defects, as favoring factors of IBD, suggesting the valuable role of next generation sequencing (NGS) approaches in IBD molecular diagnostic procedures.

An insight into genetic landscape of inflammatory bowel disease

“…21 In a paediatric population, the gene clusters of NOD2 and autophagy-related 16 like 1 (ATG16L) demonstrated variants (rs2066844 and rs2241880), as strong risk factors for CD. 22 In a Malaysian cohort, polymorphisms in the autophagy-related 16 like 2 (ATG16L2) gene and long intergenic non-protein coding ribonucleic acid (RNA) 8234 (LINC00824) were shown to have a high risk of CD development. 23 A study assessed the contribution of gene variants to the IBD among Arab Muslims, Ashkenazi Jews, and the Druze population.…”

Pediatric Inflammatory Bowel Disease

“…IBDs are multifactorial diseases that depend on the complex interplay between host genotype, environment, microbiome, and immune system. [1][2][3][4][5] The incidence of pediatric IBD (PIBD) has increased rapidly during the past decades, especially in countries where the incidence used to be low. 6 On the basis of 2 large US claims databases, the prevalence of PIBD more than doubled from 33 per 100 000 population in 2007 to 77 in 2016.…”

“…Combined genome wide association studies data from >25 000 patients have revealed >200 loci that increase the risk for either CD, UC, or (for the majority of loci) both. 1,82,83 The candidate genes that map to these loci are involved in a diverse array of cellular functions, including the response to cellular stress, epithelial barrier integrity, and the innate immune response to bacterial molecules. 84 This extensive body of research suggests that IBD pathogenesis may originate from dysfunction in 1 of a great many interconnected and codependent molecular pathways that operate in conjunction to maintain immune homeostasis in the intestinal tract.…”