Gastroenterology

Gastroenterology

Volume 122, Issue 4, April 2002, Pages 854-866
Gastroenterology

Rapid Communications
The molecular classification of the clinical manifestations of Crohn's disease☆,☆☆

https://doi.org/10.1053/gast.2002.32413Get rights and content

Abstract

Background & Aims: Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients. Methods: A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms. Results: We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease. Conclusions: The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.

GASTROENTEROLOGY 2002;122:854-866

Section snippets

Participants

A total of 244 white patients with Crohn's disease were recruited from a single tertiary referral center. Diagnosis of Crohn's disease was based on standard clinical, radiologic, endoscopic, and histologic criteria. Phenotypic details were obtained on 2 occasions by retrospective case-note review between January and May 2001 by 2 investigators (T.A. and A.d.S). Any interobserver variation was resolved by discussion (Table 1 and Figure 1).

. Anatomic location of disease in 244 patients with Crohn's

Results

A total of 244 patients with Crohn's disease and 354 control subjects were studied (Table 1). The mean age at presentation was 28.0 years and median duration of follow-up was 16.2 years. There was no significant difference in age, sex, or smoking history between patients and controls. Forty-eight (19.7%) reported a family history of Crohn's disease in a first- or second-degree relative. More than 1 site was involved in 68.8% of patients (Figure 1). Exclusively ileal, colonic, and perianal

Discussion

This study reports significant genetic associations with clinical manifestations of Crohn's disease by using a large and rigorously phenotyped cohort. Patients were ethnically homogeneous, from a single British referral center, and had been followed-up for a median time of 16 years. Clinical data collection was complete for all individuals. The most powerful finding was that NOD2/CARD15 polymorphisms are strong predictors of ileal disease, but are not associated with perianal or colonic

Acknowledgements

The authors thank the patients that participated in this study. The authors acknowledge the contributions of Heather Holt and Sue Goldthorpe for organization and collection of blood specimens, Matthew Neville for details of novel HLA class III polymorphisms, and Robert Walton for allowing us to use the OXCHECK samples.

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    ☆

    Address requests for reprints to: Tariq Ahmad, Gastroenterology Unit, Gibson Laboratories, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6QX, United Kingdom. e-mail: [email protected]; fax: (44) 0-1865-790792.

    ☆☆

    Supported by a grant from the National Association of Crohn's and Colitis (NACC, UK) (to T.A.) and the Institute G. Toniolo di Studi Superiori (to A.A.).

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