Defining complex contributions of NOD2/CARD15 gene mutations, age at onset, and tobacco use on Crohn's disease phenotypes.
BACKGROUND
Multiple factors, particularly IBD family history, tobacco use, age at diagnosis and recently, NOD2 mutant genotypes may influence Crohn's disease (CD) heterogeneity.


METHODS
We performed a multicenter retrospective record analysis of 275 unrelated patients with CD. Age at diagnosis, IBD family history, Jewish ethnicity, tobacco use at diagnosis, surgical history, disease site and clinical behavior were correlated with genotypes for NOD2 mutations, and all risk factors were assessed for independent influence on outcomes of disease site, behavior and surgery free survival.


RESULTS
Risk of ileal disease was increased for CD patients with two NOD2 mutations (Odds Ratio, O.R. 10.1), a smoking history (O.R. 2.25 per pack per day at diagnosis) or a younger age at diagnosis (O.R. 0.97 per each increased year). Presence of ileal disease (O.R. 4.8) and carrying one or two NOD2 mutations (O.R. 1.9 and 3.5, respectively) were independent risk factors for stricturing or non-perianal fistulizing behavior. Ileal disease, youthful onset and smoking at diagnosis (but not NOD2 mutations) were risk factors for early surgery.


CONCLUSIONS
Carrying two NOD2 mutations predicts youthful onset, ileal disease involvement, and development of stricturing or non-perianal fistulizing complications. Smoking and early onset independently influence ileal site and time to surgery.
Brant
Steven R
SR
The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Dept. of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, U.S.A. sbrant@mail.jhmi.edu
Picco
Michael F
MF
Achkar
Jean-Paul
JP
Bayless
Theodore M
TM
Kane
Sunanda V
SV
Brzezinski
Aaron
A
Nouvet
Franklin J
FJ
Bonen
Denise
D
Karban
Amir
A
Dassopoulos
Themistocles
T
Karaliukas
Reda
R
Beaty
Terri H
TH
Hanauer
Stephen B
SB
Duerr
Richard H
RH
Cho
Judy H
JH
D000328:Adult; D017668:Age of Onset; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007077:Ileal Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D007585:Jews; D008297:Male; D053473:Nod2 Signaling Adaptor Protein; D016017:Odds Ratio; D010641:Phenotype; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein