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Functional correlates of the interleukin-1 receptor antagonist gene polymorphism in the colonic mucosa in ulcerative colitis

Genes & Immunity volume 5, pages 8–15 (2004)Cite this article

Abstract

Association studies have identified the interleukin-1 receptor antagonist gene allele 2(IL-1RN*2) as a marker of susceptibility in ulcerative colitis (UC). This study investigated the significance of the IL-1RN genotype with respect to protein and mRNA expression in the colonic mucosa. Homogenates of rectal biopsies from 99 UC and 54 controls were assayed for cytokines IL-1ra, IL-1a and IL-1b using ELISA. IL1RN, IL1A and IL1B genotypes were determined using restriction-enzyme analysis. The ability of the two IL1RN alleles to generate steady-state mRNA accumulation was assessed in the colonic mucosa of seven heterozygous patients. Stepwise linear regression demonstrated that IL-1RN genotype (P=0.001), diagnosis (P<0.0001) and treatment (P<0.03) were independent factors associated with the IL-1ra protein level whilst IL1RN genotype (P=0.005) and macroscopic inflammatory grade (P<0.0001) were associated with the IL-1ra/ total IL-1 ratio. The IL1RN*2 correlated with reduced IL-1ra and IL-1ra/IL-1 ratio with a gene dosage effect. In heterozygous UC patients the ratio of allele 1 mRNA / allele 2 steady state mRNA was always greater than 1 (range: 1.2–3.1) (P=0.018). The IL-1RN*2 is associated with reduced levels of IL-1ra protein and IL-1RN mRNA in the colonic mucosa, providing a biologically plausible explanation for the observed association of the allele with the disease.

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Authors and Affiliations

  1. The Gastroenterology and Liver Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK

    M J Carter, S Jones & A J Lobo

  2. Division Of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK

    A Cox, J Mee, G W Duff & F S di Giovine

  3. Histopathology Department, John Radcliffe Hospital, Oxford, UK

    B Warren

  4. Genetic Epidemiology, University of Utah Medical School, UT, USA

    N J Camp

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  1. M J Carter
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Correspondence to M J Carter.

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This study was financially supported by a grant from The National Association of Colitis and Crohn's Disease and The Special Trustees of the Central Sheffield Hospitals. Dr Carter is a Digestive Disorders Foundation Research Training Fellow.

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Carter, M., Jones, S., Camp, N. et al. Functional correlates of the interleukin-1 receptor antagonist gene polymorphism in the colonic mucosa in ulcerative colitis. Genes Immun 5, 8–15 (2004). https://doi.org/10.1038/sj.gene.6364032

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