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Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis.

ABSTRACT: To investigated the molecular cause of very early-onset ulcerative colitis (UC) in an 18-mo-old affected child.We analysed the interleukin-10 (IL10) receptor genes at the DNA and RNA level in the proband and his relatives. Beta catenin and tumor necrosis factor-? (TNF?) receptors were analysed in the proteins extracted from peripheral blood cells of the proband, his relatives and familial adenomatous polyposis (FAP) and PTEN hamartoma tumor syndrome (PHTS) patients. Samples were also collected from the proband's inflamed colorectal mucosa and compared to healthy and tumour mucosa collected from a FAP patient and patients affected by sporadic colorectal cancer (CRC). Finally, we examined mesalazine and azathioprine effects on primary fibroblasts stabilised from UC and FAP patients.Our patient was a compound heterozygote for the IL10RB E47K polymorphism, inherited from his father, and for a novel point mutation within the IL10RA promoter (the -413G->T), inherited from his mother. Beta catenin and tumour necrosis factor ? receptors-I (TNFRI) protein were both over-expressed in peripheral blood cells of the proband's relatives more than the proband. However, TNFRII was over-expressed only in the proband. Finally, both TNF?-receptors were shown to be under-expressed in the inflamed colon mucosa and colorectal cancer tissue compared to healthy colon mucosa. Consistent with this observation, mesalazine and azathioprine induced, in primary fibroblasts, IL10RB and TNFRII over-expression and TNFRI and TNF? under-expression. We suggest that ?-catenin and TNFRI protein expression in peripheral blood cells could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC.A synergistic effect of several variant alleles of the IL10 receptor genes, inherited in a Mendelian manner, is involved in UC onset in this young child.

SUBMITTER: Galatola M

PROVIDER: S-EPMC3870512 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis.

Galatola Martina M Miele Erasmo E Strisciuglio Caterina C Paparo Lorella L Rega Daniela D Delrio Paolo P Duraturo Francesca F Martinelli Massimo M Rossi Giovanni Battista GB Staiano Annamaria A Izzo Paola P De Rosa Marina M

World journal of gastroenterology 20131201 46

<h4>Aim</h4>To investigated the molecular cause of very early-onset ulcerative colitis (UC) in an 18-mo-old affected child.<h4>Methods</h4>We analysed the interleukin-10 (IL10) receptor genes at the DNA and RNA level in the proband and his relatives. Beta catenin and tumor necrosis factor-α (TNFα) receptors were analysed in the proteins extracted from peripheral blood cells of the proband, his relatives and familial adenomatous polyposis (FAP) and PTEN hamartoma tumor syndrome (PHTS) patients. S ...[more]

PMID: 24379584

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Project description:Background:The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). Method:To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. Results:HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). Conclusion:In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

Dataset Information

Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis.

Publications

Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis.

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