Genetic risk profiling and prediction of disease course in Crohn's disease patients.
OBJECTIVE
Clinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated.


METHODS
Complete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7-22). Fifty CD-associated polymorphisms were genotyped. Kaplan-Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time.


RESULTS
Homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60-18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13-69.78; P = .04 and OR, 0.56; 95% CI, 0.38-0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present.


CONCLUSIONS
CD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach.
Henckaerts
Liesbet
L
Department of Medicine, Gastroenterology Section, Catholic University of Leuven, Leuven, Belgium. liesbet.henckaerts@uzleuven.be
Van Steen
Kristel
K
Verstreken
Isabel
I
Cleynen
Isabelle
I
Franke
Andre
A
Schreiber
Stefan
S
Rutgeerts
Paul
P
Vermeire
Séverine
S
D000293:Adolescent; D000328:Adult; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D016172:DNA Fingerprinting; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012003:Rectal Fistula / Q000453:epidemiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D012737:Sex Factors; D055815:Young Adult; D012359:tRNA Methyltransferases
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human