IL23R haplotypes provide a large population attributable risk for Crohn's disease.
BACKGROUND
The IL-23 pathway plays a pivotal role in the development of chronic mucosal inflammation seen in the inflammatory bowel diseases. Multiple studies have now established the contribution of the interleukin 23 receptor gene (IL23R) to Crohn's disease (CD) risk in general and of the IL23R R381Q variant in particular. The aim of this work was to estimate the total contribution of this gene to CD risk test using a haplotype approach.


METHODS
In all, 763 CD subjects and 254 controls were genotyped for single nucleotide polymorphisms in the IL23R gene using Illumina and ABI methods. Haplotypes were assigned using PHASEv2 and tested for association with CD by chi-square and permutation.


RESULTS
Haplotypes with both increased and decreased risk for CD were observed in 2 of the 4 observed blocks (Block 2 H1: 55.4% control, 64% CD, P = 0.019; H2: 64.5% control, 54.4% CD, P = 0.006; Block 3 H1: 55.8% control, 64.4% CD, P = 0.013; H2: 47.0% control, 36.6% CD, P = 0.001). The population attributable risk for these haplotypes was substantially larger than that estimated for the IL23R R381Q variant (Block 2 H1 and block 3 H1 approximately 20%, compared with approximately 4% for Block 3 H6, containing the variant).


CONCLUSIONS
These observations suggest that IL23R makes a substantial contribution to CD susceptibility, larger than that estimated from the population frequency of the R381Q variant. These observations also support the expectation that finding "hits" from genomewide association studies will be but an important chapter in the story of unraveling the genetic contribution to CD, rather than the final chapter that brings clarity to all the plot twists of a complicated story.
Taylor
Kent D
KD
Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. kent.taylor@cshs.org
Targan
Stephan R
SR
Mei
Ling
L
Ippoliti
Andrew F
AF
McGovern
Dermot
D
Mengesha
Emebet
E
King
Lily
L
Rotter
Jerome I
JI
D016022:Case-Control Studies; D015331:Cohort Studies; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015141:Los Angeles / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics*
C515500:IL23R protein, human; D018123:Receptors, Interleukin