The molecular classification of the clinical manifestations of Crohn's disease.
OBJECTIVE
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.
Ahmad
Tariq
T
Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Oxford, United Kingdom. tariq.ahmad@ndm.ox.ac.uk
Armuzzi
Alessandro
A
Bunce
Mike
M
Mulcahy-Hawes
Kim
K
Marshall
Sara E
SE
Orchard
Timothy R
TR
Crawshaw
Jonathan
J
Large
Oliver
O
de Silva
Arjuna
A
Cook
Julia T
JT
Barnardo
Martin
M
Cullen
Sue
S
Welsh
Ken I
KI
Jewell
Derek P
DP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics; D016019:Survival Analysis
D002352:Carrier Proteins; D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011506:Proteins