Functional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis

doi:10.1016/S0016-5085(99)70338-0

Gastroenterology

Volume 117, Issue 4, October 1999, Pages 806-813

https://doi.org/10.1016/S0016-5085(99)70338-0 Get rights and content

Abstract

Background & Aims: The role of the interleukin (IL)-1 receptor antagonist (IL-1ra) in predisposing an individual to inflammatory bowel disease (IBD) is controversial. This study aimed to determine the association between intron 2 IL-1ra polymorphism and IBD by performing a multiethnic case-control study and to assess its functional significance. Methods: A total of 236 patients with ulcerative colitis (UC), 196 patients with Crohn's disease (CD), and 338 ethnically matched control patients treated at LAC-USC and Cedars-Sinai Medical Centers and the University of Milan Medical Center were genotyped for a variable length polymorphism in intron 2 of the IL-1ra gene (IL-1RN). Total IL-1ra protein production rates in peripheral blood mononuclear cells (PBMCs) were correlated with carriage of allele 2 of the IL-1RN gene (IL-1RN*2). Results: In the LAC-USC group, UC patients (n = 60) had an increased frequency of at least 1 copy of IL-1RN*2 compared with controls (n = 129) (70% vs. 33%; P < 0.01; odds ratio [OR], 4.7). The frequency of IL-1RN*2 carriage in the Cedars-Sinai group was 59% in UC, 45% in CD, and 42% in controls (P < 0.01; OR, 2.0). A significant difference was observed only in the Jewish subgroup (P = 0.003; OR, 5.0). The association was not detected in UC or CD patients treated at the University of Milan. The ORs of 4.7 and 5.0 appear to be the highest reported in any UC population for any genetic markers. Further, carriage of IL-1RN*2 was associated with decreased production of total IL-1ra protein in cultured PBMCs from both UC patients and controls. Conclusions: These results provide further evidence that IL-1ra is important in the predisposition to UC, there may be genetic or pathogenetic heterogeneity between different ethnic groups, and UC and CD are genetically distinct diseases.

GASTROENTEROLOGY 1999;117:806-813

Section snippets

Patients treated at LAC-USC Medical Center

Sixty unrelated patients with UC (33 men, 27 women) treated at the clinical IBD Center, Los Angeles County–University of Southern California (LAC-USC) Medical Center, were evaluated. This patient population was 80% Spanish-Caucasian, 15% white-Caucasian, and 5% African-American (Table 1). None of the patients in this study had known Jewish ancestry. The diagnosis of UC was documented by clinical, endoscopic, and histological criteria. Informed consent was obtained from each patient, and the

Patients treated at LAC-USC Medical Center

The carriage rate (number of individuals who have at least 1 copy of the allele) of IL-1RN*2 was increased from 33% in the control population to 70% in the UC group (P < 0.001, Figure 1).

. Carriage of allele 2 in patients from LAC-USC Medical Center and ethnically matched controls. IL-1ra genotypes were determined by PCR using specific oligonucleotide primers flanking the VNTR in intron 2 of the IL-1ra gene (IL-1RN*2). Results are reported as the percentage of probands with at least 1 copy of

Discussion

Recent studies from our laboratory have provided evidence that insufficient production of the anti-inflammatory cytokine IL-1ra may be an important contributing factor during chronic intestinal inflammation and that an imbalance between IL-1 and IL-1ra may contribute to the pathogenesis of IBD.²⁹ However, the mechanisms of this imbalance are not fully understood.³⁰ In the present study, we attempted to investigate the hypothesis that the amount of IL-1ra an individual can produce is genetically

Acknowledgements

The authors thank Oscar Tejeda and Daniel L. Coulter for their contribution to this work.

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Citation Excerpt :
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^☆: Address requests for reprints to: Fabio Cominelli, M.D., Ph.D., Division of Gastroenterology and Hepatology, University of Virginia Health Sciences Center, Multistory Building, 2nd Floor, P.O. Box 10033, Charlottesville, Virginia 22906. e-mail: [email protected]; fax: (804) 243-6405.

^☆☆: Supported by National Institutes of Health grants DK46763, DK43211, DK42191, and DK45740 and the Crohn's and Colitis Foundation of America.

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Alimentary TractFunctional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis☆,☆☆

Abstract

Section snippets

Patients treated at LAC-USC Medical Center

Patients treated at LAC-USC Medical Center

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Cell

Cell

Genetic aspects of idiopathic inflammatory bowel disease

Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews

Gut

Familial occurrence of inflammatory bowel disease

N Engl J Med

Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking

Gut

Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA class II) and subclinical (anti-neutrophil cytoplasmic antibodies (ANCA) markers

J Clin Invest

An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele

Proc Natl Acad Sci USA

Ter williger JD, Lathrop GM, Bell JI, Jewell DP. Two stage genomewide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7, and 12

Nat Genet

Mapping of a susceptibility locus for Crohn's disease on chromosome 16

Nature

Susceptibility locus for inflammatory bowel disease on chromosome 16 has a role in Crohn's disease, but not in ulcerative colitis

Hum Mol Genet

Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease

J Immunol

Alimentary Tract
Functional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis☆,☆☆