Association of interleukin-1 receptor-associated kinase M (IRAK-M) and inflammatory bowel diseases.
OBJECTIVE
Inflammatory bowel diseases (IBD) have a complex genetic background. The interleukin receptor associated kinase-M (IRAK-M) is a NF-kappaB-mediated, negative regulator of Toll-like receptor (TLR) signaling. A functional mutation in a negative regulator might induce impaired endotoxin tolerance and increased inflammatory responses. IRAK-M is situated on chromosome 12q14, a susceptibility locus for IBD, which makes it a good candidate gene. The objective of the study was to analyze a large cohort of IBD patients for the association between IBD and IRAK-M.


METHODS
A total of 542 patients with IBD (309 Crohn's disease (CD), 233 ulcerative colitis (UC)) and 305 controls were studied. Two single nucleotide polymorphisms (V147I and V270I) and six microsatellite markers were evaluated using association analysis and the haplotype sharing statistic. Results were stratified for CARD15 mutations R702W, G908R and 1007fsinsC.


RESULTS
No significant differences in IRAK-M allele frequencies were observed between IBD, UC, CD or subgroups of CD or UC and controls. Five out of 36 UC patients (13.9%) with an IBD-associated CARD15 mutation were carriers versus 2/167 (1.2%) in non-carriers (OR 13.1, 95% CI 1.0-164.5). No interaction was observed for CD.


CONCLUSIONS
No evidence was found to suggest an association between IBD, CD, UC or subsets of CD and UC and IRAK-M. However, an interaction was found between IRAK-M and CARD15 in UC patients. In CARD15 mutant patients, the production of IRAK-M upon stimulation might be impaired. Further studies are needed to determine whether an impaired negative regulation of the TLR-signaling pathway might be partly responsible for the development of IBD.
Weersma
Rinse K
RK
Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. R.K.Weersma@int.umcg.nl
Oostenbrug
Liekele E
LE
Nolte
Ilja M
IM
Van Der Steege
Gerrit
G
Oosterom
Elvira
E
Van Dullemen
Hendrik M
HM
Kleibeuker
Jan H
JH
Dijkstra
Gerard
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002881:Chromosomes, Human, Pair 12; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D053473:Nod2 Signaling Adaptor Protein; D053592:Interleukin-1 Receptor-Associated Kinases