Clinical and molecular characteristics of isolated colonic Crohn's disease.
BACKGROUND
Clinical, serological, and molecular data support the existence of discrete subsets of Crohn's disease (CD) defined by location of disease. Little is known about the epidemiology and natural history of isolated CD of the colon (Montreal Classification L2) because most studies have not accurately distinguished it from ileocolonic disease. Our objectives were to describe the clinical features and natural history of isolated colonic CD in a rigorously characterized patient cohort and to investigate the association of polymorphisms in a number of genes with colonic location of disease and disease behavior.


METHODS
Patients with L2 disease were identified from a database of 675 CD patients. Only patients with a normal small bowel enema (70%), ileoscopy alone (30%), or both (20%) were included. Genotyping was performed using PCR-SSP or the iPLEX platform.


RESULTS
In all, 135 patients were classified with L2 disease. L2 disease was more common in women (74.0% versus 58.0%; P = 0.0004; odds ratio [OR] = 2.11, 95% confidence interval [CI] 1.36-3.26) and in never smokers (48.9% versus 36.9%; P = 0.008; OR = 1.64, 95% CI 1.09-2.45); 20.7% underwent colonic resection for severe disease. We confirmed that carriage of the HLA-DRB1*0103 allele is strongly associated with isolated colonic CD (14.9% versus 4.0%; P = 0.000016; OR 4.6, 95% CI 2.25-9.47) and report the novel association of this allele with time to first surgical event (log rank P = 0.001). There was no association with any of the known CD susceptibility loci (NOD2, IBD5, NOD1, IL23R, ATG16L1) and isolated colonic CD. A nonsynonymous polymorphism in MEKK1 (rs832582) was associated with CD susceptibility overall (15% versus 19%; P = 0.0083; OR = 1.28, 95% CI 1.07-1.54). The association was strongest in those patients not carrying a NOD2 mutation and had no effect on disease location.


CONCLUSIONS
This study describes the clinical features of isolated colonic CD and demonstrates the importance of the HLA region in determining the molecular basis of colonic inflammation.
Hancock
Laura
L
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. laurahancock@doctors.org.uk
Beckly
John
J
Geremia
Alessandra
A
Cooney
Rachel
R
Cummings
Fraser
F
Pathan
Saad
S
Guo
Changun
C
Warren
Bryan F
BF
Mortensen
Neil
N
Ahmad
Tariq
T
Jewell
Derek
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D018123:Receptors, Interleukin / Q000235:genetics; D015996:Survival Rate; D055815:Young Adult
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C515500:IL23R protein, human; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human