Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease.
OBJECTIVE
The clinical manifestations of Crohn's disease (CD) are diverse, ranging from fibrostenosing small-bowel disease to colon-predominant inflammation. These distinctions may represent genetic, immunologic, and microbial heterogeneity. NOD2 gene mutations in CD have been described recently and may alter innate immune responses. We hypothesized that NOD2 mutations may be associated with distinct phenotypic expressions of CD.


METHODS
Two cohorts of consecutively identified patients referred to an inflammatory bowel disease center (n = 142 collected between 1993 and 1996; n = 59 collected between 1999 and 2001) were genotyped for 3 single nucleotide variants of NOD2-R675W, G881R, and 3020insC-and phenotyped for disease behavior, disease location, and serum immune markers.


RESULTS
Univariate analysis showed that CD-associated NOD2 variants were significantly associated with fibrostenosing disease in each cohort (P = 0.049 and P = 0.002, respectively). When both cohorts were analyzed together, the association between NOD2 variants and fibrostenosing disease was more significant (P = 0.001). These relationships were observed in both Jews and non-Jews. Forty-six percent of patients with fibrostenosing disease carried at least 1 of these alleles, compared with only 23.5% of patients without fibrostenosing disease (odds ratio, 2.8; 95% confidence interval, 1.6-5.2). Multivariate and conditioning analyses showed a primary association between NOD2 allelic variants and fibrostenosing disease, but not with small-bowel disease.


CONCLUSIONS
In this description of a genotype/phenotype correlation in CD patients and NOD2 variants, data suggest that variation in this gene contributes to the occurrence of fibrostenotic CD of the small bowel.
Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. Maria.Abreu@cshs.org
Maria T
MT
Abreu
Kent D
KD
Taylor
Ying-Chao
YC
Lin
Tieu
T
Hang
Joanne
J
Gaiennie
Carol J
CJ
Landers
Eric A
EA
Vasiliauskas
Lori Y
LY
Kam
Micha
M
Rojany
Konstantinos A
KA
Papadakis
Jerome I
JI
Rotter
Stephan R
SR
Targan
Huiying
H
Yang
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003251:Constriction, Pathologic; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007422:Intestines / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein