Interaction of Crohn's Disease Susceptibility Genes in an Australian Paediatric Cohort

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.

... 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

... a higher rate of gene mutations compared with adult patients [12] . Three mutations were reported to be specifically associated with paediatric-onset inflammatory bowel disease. One of these (rs2836878) resides in a region that harbours no gene, but is most closely located to the proteasome assembly chaperone 1 gene ( PSMG1 ). The other two SNPs (rs4809330 and rs2315008) are located within a region containing several genes including the tumour necrosis factor receptor superfamily member 6B gene

... Three SNPs (rs2836878, rs2066845 and rs5743289 present on PSMG1 and NOD2 ) were found to deviate from Hardy Weinberg Equilibrium (HWE) at the P=0.05 level. However, these SNPs were retained in the analyses as in each case the deviation from HWE was observed in the cases only. Such distortions in case genotype frequency can be an indication of association [15] , [16] . Thus, alleles and genotypes from all SNPs were compared between the case and control phenotypic groups. Genotype and allele

... 3p21 n % n % rs9858542 GG 24 34 56 57 GA+AA 46 66 42 43 0.003* 2.56 (1.364.81) PSMG1 n % n % rs2836878 GG 32 46 55 59 AG+AA 38 54 38 41 0.089 1.72 (0.923.21) TNFRSF6B n % n % rs4809330 GG 40 56 42 43 AG+AA 31 44 56 57 0.083 1.72 (0.933.18 rs2315008 GG 40 56 42 43 GT+TT 30 44 56 57 0.068 1.78 (0.963.30) Four SNPs on three genes ( NOD2 , IL23R and 3p21 region) were significantly associated with paediatric onset Crohn's disease (CD) (p<0.05). Main NOD2 variants=SNP rs2066845, SNP rs2066844, rs5743293. Three SNPs on two paediatric specific CD susceptibility genes ( PSMG1 and TNFRSF6B ) showed a trend of association (p<0.1), X 2 =Pearson Chi Square analysis, F=Fisher's exact test analysis, OR=odds ratio, CI=confidence interval. a) Additive and genotypic logistic regression analyses At the individual level, allelic 2 and genotypic Fisher's comparisons of SNP rs2066845 ( NOD2 ) were highly significant at p<0.05 (p=0.00016, 0.0076 respectively). However, no minor allele homozygotes or heterozygotes

... patients had a single mutation in the NOD2 gene. Sixty six percent of CD patients had at least one disease associated allele of SNP 9858542 (3p21) compared to 43% in the control group (OR=2.56, 95% CI 1.364.81, p=0.003). Three SNPs on paediatric specific CD susceptibility genes (rs2836878 on PSMG1 and rs4809330 and rs2315008 on TNFRSF6B ) demonstrated some evidence of association at the p<0.1 level of significance. Fifty four percent of CD patients had at least one disease associated allele of SNP rs2836878 ( PSMG1 ) compared to 41% in the control group (p=0.089). Disease associated alleles of SNPs rs4809330 and rs2315008 ( TNFRSF6B ) were observed at lower frequency in CD (44%) patients compared to 57% in the control group (p=0.083 and p=0.068 for rs4809330 and rs2315008, respectively). Gene-gene interaction Several significant gene-gene interactions were detected for all three disease associated genes ( Tables S2a S2d ). There was an under-representation of wildtype allele combinations in CD

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Gene: PSMG1 - proteasome (prosome, macropain) assembly chaperone 1 - (NCBI)

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