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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.

Type

Journal article

Journal

Gastroenterology

Publication Date

04/2002

Volume

122

Pages

854 - 866

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Carrier Proteins, Child, Child, Preschool, Crohn Disease, Female, Genetic Predisposition to Disease, Genotype, HLA-A Antigens, HLA-DQ Antigens, Humans, Intracellular Signaling Peptides and Proteins, Linkage Disequilibrium, Male, Middle Aged, Nod2 Signaling Adaptor Protein, Phenotype, Polymorphism, Genetic, Proteins, Survival Analysis