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

doi:doi:10.1038/sj.gene.6364032

Genes and Immunity (2004) 5, 8–15. doi:10.1038/sj.gene.6364032

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

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.

M J Carter¹, S Jones¹, N J Camp⁴, A Cox², J Mee², B Warren³, G W Duff², A J Lobo¹ and F S di Giovine²

¹The Gastroenterology and Liver Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK
²Division Of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK
³Histopathology Department, John Radcliffe Hospital, Oxford, UK
⁴Genetic Epidemiology, University of Utah Medical School, UT, USA

Correspondence: Dr MJ Carter, Flat 9, 156 Haverstock Hill, Belsize Park, London NW3 2AT, UK. E-mail: Martyn.J.Carter@btinternet.com

Received 7 March 2003; Revised 24 September 2003; Accepted 26 September 2003.

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Abstract

Association studies have identified the interleukin-1 receptor antagonist gene allele 2(IL-1RN midast 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 midast 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 midast 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.