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Interaction of Crohn's disease susceptibility genes in an Australian paediatric cohort
Josef Wagner1, Winnie H Sim, Justine A Ellis
1Enteric Virus Group, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. josef.wagner@mcri.edu.au
Insights
Genetic susceptibility plays a key role in Crohn's disease (CD) pathogenesis. This study identified significant gene associations and interactions in Australian pediatric CD patients, revealing complex genetic underpinnings.
Area of Science:
- Genetics
- Gastroenterology
- Pediatrics
Background:
- Genetic susceptibility is a significant factor in Crohn's disease (CD) development.
- Understanding the genetic basis of pediatric CD is crucial for early diagnosis and treatment.
- Previous studies have identified several CD susceptibility genes, but their roles in early-onset disease require further investigation.
Purpose of the Study:
- To investigate multiple CD susceptibility genes in an Australian pediatric CD cohort.
- To identify specific single nucleotide polymorphisms (SNPs) and gene-gene interactions associated with pediatric CD.
- To explore the relationship between genetic factors and disease phenotypes in young CD patients.
Main Methods:
- Genotyping of 34 single nucleotide polymorphisms (SNPs) in 18 genetic loci in 72 pediatric CD patients and 98 controls.
- Performing gene-gene interaction analysis, gene-disease phenotype analysis, and genetic risk profiling.
- Analyzing associations between specific SNPs, genes, and CD status, including disease location.
Main Results:
- Four polymorphisms in three genes (NOD2, IL23R, 3p21) were significantly associated with CD status (p<0.05).
- An additive gene-gene interaction was identified involving TLR4, PSMG1, TNFRSF6B, and IRGM.
- Genes involved in microbial processing (TLR4, PSMG1, NOD2) showed significant individual or interactive associations with CD.
- Specific SNPs and variants were associated with colonic or ileal/colonic disease, with some novel findings in pediatric CD.
Conclusions:
- This study demonstrates significant genetic associations with Crohn's disease in a pediatric onset cohort.
- Several identified genetic associations have not been previously reported in pediatric CD patients.
- Pediatric CD genetic susceptibility arises from a complex interplay of multiple genes and their interactions.
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.
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