Genetic epistasis of IL23/IL17 pathway genes in Crohn's disease.
BACKGROUND
The IL23/IL17 pathway is pivotal in the development of chronic mucosal inflammation seen in Crohn's disease (CD). Genetic variants in the IL23R and IL12B have been associated with CD susceptibility. We investigated 10 genes within the IL23/IL17 pathway in a case-control study of 763 CD cases and 254 healthy controls.


METHODS
We identified a novel association in haplotypes in IL17A (empirical P = 0.02), IL17RA (P = 0.001), IL17RD (P = 0.001), IL12RB1 (P = 0.003), and IL12RB2 (P = 0.001) as well as confirming the association with IL12B variants (P = 0.003).


RESULTS
The cumulative risk for carrying an increased number of CD risk haplotypes from genes in this pathway rises to an odds ratio of 4.3 for carrying 5 risk haplotypes. We have previously demonstrated an association between this cohort and IL23R haplotypes. Pairwise analyses suggest that there is statistical interaction between variants in IL17A and IL23R (P = 0.047) and between variants in IL17RA and IL23R (P = 0.036). Furthermore, a significant association between CD and the widely replicated IL23R variants is only seen in the presence of IL17A or IL17RA variants.


CONCLUSIONS
These data support the investigation of pathways implicated in CD pathogenesis in order to identify further susceptibility genes and also suggest that important gene-gene interaction is present in CD susceptibility.(Inflamm Bowel Dis 2009).
McGovern
Dermot P B
DP
Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Rotter
Jerome I
JI
Mei
Ling
L
Haritunians
Talin
T
Landers
Carol
C
Derkowski
Carrie
C
Dutridge
Deb
D
Dubinsky
Marla
M
Ippoliti
Andy
A
Vasiliauskas
Eric
E
Mengesha
Emebet
E
King
Lily
L
Pressman
Sheila
S
Targan
Stephan R
SR
Taylor
Kent D
KD
D016022:Case-Control Studies; D003424:Crohn Disease / Q000453:epidemiology* / Q000235:genetics*; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D007585:Jews / Q000235:genetics / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics*; D053707:Receptors, Interleukin-12 / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000235:genetics*; D012307:Risk Factors
C508438:IL12RB1 protein, human; C508717:IL17A protein, human; C109985:IL17RA protein, human; C515500:IL23R protein, human; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053722:Receptors, Interleukin-17