Regulatory Variants on the Leukocyte Immunoglobulin-Like Receptor Gene Cluster are Associated with Crohn’s Disease and Interact with Regulatory Variants for TAP2

Crohn's disease (CD) has a complex polygenic etiology with high heritability. We keep putting an effort to identify novel variants associated with susceptibility to CD through a genome-wide association study (GWAS) in large Korean populations.Genome-wide variant data from 902 Korean patients with CD and 72,179 controls were used to assess the genetic associations in a meta-analysis with previous Korean GWAS results from 1,621 patients with CD and 4,419 controls. Epistatic interactions between CD-risk variants of interest were tested using a multivariate logistic regression model with an interaction term.We identified two novel genetic associations with the risk of CD near ZBTB38 and within the leukocyte immunoglobulin-like receptor (LILR) gene cluster (P<5×10 -8), with highly consistent effect sizes between the two independent Korean cohorts. CD-risk variants in the LILR locus are known quantitative trait loci (QTL) for multiple LILR genes, of which LILRB2 directly interacts with various ligands including MHC class I molecules. The LILR lead variant exhibited a significant epistatic interaction with CD-associated regulatory variants for TAP2 involved in the antigen presentation of MHC class I molecules (P=4.11×10 -4), showing higher CD-risk effects of the TAP2 variant in individuals carrying more risk alleles of the LILR lead variant (OR=0.941, P=0.686 in non-carriers; OR=1.45, P=2.51×10 -4 in single-copy carriers; OR=2.38, P=2.76×10 -6 in two-copy carriers).This study demonstrated that genetic variants at two novel susceptibility loci and the epistatic interaction between variants in LILR and TAP2 loci confer risk of CD.