Abstract
Genetic susceptibility is an important contributor to the pathogenesis of Crohn's disease (CD). We investigated multiple CD susceptibility genes in an Australian paediatric onset CD cohort. Newly diagnosed paediatric onset CD patients (n = 72) and controls (n = 98) were genotyped for 34 single nucleotide polymorphisms (SNPs) in 18 genetic loci. Gene-gene interaction analysis, gene-disease phenotype analysis and genetic risk profiling were performed for all SNPs and all genes. Of the 34 SNPs analysed, four polymorphisms on three genes (NOD2, IL23R, and region 3p21) were significantly associated with CD status (p<0.05). All three CD specific paediatric polymorphisms on PSMG1 and TNFRSF6B showed a trend of association with p<0.1. An additive gene-gene interaction involving TLR4, PSMG1, TNFRSF6B and IRGM was identified with CD. Genes involved in microbial processing (TLR4, PSMG1, NOD2) were significantly associated either at the individual level or in gene-gene interactive roles. Colonic disease was significantly associated with disease SNP rs7517847 (IL23R) (p<0.05) and colonic and ileal/colonic disease was significantly associated with disease SNP rs125221868 (IBD5) and SLC22A4 & SLC22A4/5 variants (p<0.05). We were able to demonstrate genetic association of several genes to CD in a paediatric onset cohort. Several of the observed associations have not been reported previously in association with paediatric CD patients. Our findings demonstrate that CD genetic susceptibility in paediatric patients presents as a complex interaction between numerous genes.
Highlights
Crohn’s disease (CD) is a chronic relapsing inflammatory disease occurring anywhere in the gastrointestinal tract, it most commonly affects the small intestine [1]
Four single nucleotide polymorphisms (SNPs) variants present on NOD2, IL23R and on a 3p21 chromosomal region were significantly associated with our CD population
These SNPs have been reported previously, but no studies have investigated their interaction in a paediatric CD cohort
Summary
Crohn’s disease (CD) is a chronic relapsing inflammatory disease occurring anywhere in the gastrointestinal tract, it most commonly affects the small intestine [1]. CD is a major cause of morbidity throughout the world with an escalating epidemic of CD recorded globally in children and adults during the past few decades [2]. A worldwide study reported an incidence per 100,000 population as low as 0.3 in China to as high as 20.2 cases in Canada [2]. A ten-fold increase in the incidence of paediatric CD over a 31 year period was reported from the Royal Children’s Hospital (RCH) in Melbourne, Australia [3]. 30 new cases of CD in children (age 2–16 years) are diagnosed and treated at the RCH each year compared with approximately 3 new cases reported annually in 1975. European studies report a similar dramatic increase in the incidence of paediatric CD [4,5]. It is widely accepted that CD is mediated by a dysfunctional immunological response of T-lymphocytes which is primarily induced in genetically susceptible individuals by the presence of an environmental stimulus [6,7]
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