Susceptibility to severe ulcerative colitis is associated with polymorphism in the central MHC gene IKBL

doi:10.1053/gast.2000.20258

Gastroenterology

Volume 119, Issue 6, December 2000, Pages 1491-1495

https://doi.org/10.1053/gast.2000.20258 Get rights and content

Abstract

Background & Aims: IKBL gene lies telomeric of the tumor necrosis factor cluster in the central major histocompatibility complex and carries a structural polymorphism at position +738. In the Spanish white population, we found the IKBL + 738(C) allele in haplotypes carrying either HLA-DRB1*1501 or -DRB1*0103. Because these HLA class II alleles may confer susceptibility to ulcerative colitis, we investigated an association between IKBL + 738(C) and this disease. Methods: DNA-based techniques were used to type individual alleles of HLA-DRB1 and IKBL+738. The frequencies of these alleles were compared among ethnically matched populations comprising 155 patients and 298 controls. Results: IKBL + 738(C) allele was exclusively increased in patients with extensive and/or intractable disease. HLA-DRB1*0103 was the only HLA-DRB1 allele to be significantly increased in frequency in patients with UC compared with controls. It was found in patients with extensive and distal disease. In the HLA-DRB1*0103–negative population, patients with extensive disease still had a significant association with IKBL+738(C). The difference between the 2 groups of patients was statistically significant (13.7% vs. 1.7% in patients with distal disease; odds ratio, 9.25; P = 0.01). Conclusions: HLA-DRB1*0103 is associated with susceptibility to ulcerative colitis, and IKBL + 738(C) marks a propensity to extensive and more severe disease.

GASTROENTEROLOGY 2000;119:1491-1495

Section snippets

Patients and controls

The study group consisted of 155 adult unrelated white, Spanish patients with definitive UC ascertained at San Carlos University Hospital (Madrid). Many of them had been included in previously reported studies on HLA class II association with UC,2, 10 although the cohort of patients has been considerably enlarged. The diagnosis was documented by conventional endoscopic, histologic, and clinical criteria. Disease extent was defined by the most proximal extent of the disease found by colonoscopy.

Results

The frequency distribution of the IKBL + 738(C) allele in patients with UC and controls is shown in Table 1.A statistically significant increase of the IKBL + 738(C) allele was observed in UC patients (16.8% vs. 6.7% in controls; odds ratio [OR], 2.80; P < 0.001). When patients were grouped according to the extent of the disease or the response to treatment, IKBL + 738(C) was associated only with those with extensive disease and/or with severe disease refractory to medical therapy (Table 1).

Discussion

The genetic contribution to the pathogenesis of UC remains largely unclear. While genomewide searches have identified several loci in linkage with the disease,18, 19, 20, 21 case-control studies have shown an association between UC and HLA class II genes, especially DRB1*01031, 3, 6, 7, 8, 9, 10 and DRB1*15.2, 5, 8, 9 Association with DRB1*0103 has proved to be the stronger, and all studies testing for DRB1*0103 in UC have resulted in a significant association,1, 3, 6, 7, 8, 9, 10 whereas DR2

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^☆: Address requests for reprints to: Emilio Gómez de la Concha, M.D., Department of Immunology, Hospital Universitario San Carlos, 28040 Madrid, Spain. e-mail: [email protected]; fax: (34) 913303182.

^☆☆: Supported by the Spanish Fondo de Investigaciones Sanitarias grant 97/0188.

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Alimentary TractSusceptibility to severe ulcerative colitis is associated with polymorphism in the central MHC gene IKBL☆,☆☆

Abstract

Section snippets

Patients and controls

Results

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Am J Hum Genet

Gastroenterology

Gastroenterology

Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease

Lancet

Positive and negative associations of distinct HLA-DR2 subtypes with ulcerative colitis

Clin Exp Immunol

Associations between HLA-DR alleles and subsets of ulcerative colitis defined by extent of colitis (abstr)

Gastroenterology

Genetic markers in clinically well defined patients with ulcerative colitis (UC)

Clin Exp Immunol

HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis

Gut

Amino acid polymorphism at residue 71 in HLA-DR beta chain plays a critical role in susceptibility to ulcerative colitis

Dig Dis Sci

Immunogenetics of cytokines. Relevance for future research in inflammatory bowel disease

Scan J Gastroenterol

Alimentary Tract
Susceptibility to severe ulcerative colitis is associated with polymorphism in the central MHC gene IKBL☆,☆☆