Immunochip Analysis Identification of 6 Additional Susceptibility Loci for Crohn's Disease in Koreans

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by persistent inflammation, often granulomatous, which affects all layers of the bowel wall. Being a complex disease, both genetic susceptibility and environmental factors are likely to be involved in the pathogenesis of CD. The current working hypothesis is that CD arises as a consequence of dysregulated mucosal immune responses to the gut flora in genetically susceptible individuals.1 Recent studies from China, Japan, and Korea have shown that the incidence of inflammatory bowel disease (IBD) is rapidly increasing in these countries.2–5 Despite identifying more than 140 susceptibility loci to CD in Caucasian through genome-wide association studies (GWASs) and meta-anal-yses,6–12 the heritability of CD has not been fully explained.12 Recent GWASs in Japanese and Korean populations identified several more CD susceptibility loci that are not significant in Caucasian populations.13,14 These include 2 intergenic regions on chromosomes 4p14 and 10q25, the ATG16L2-FCHSD2 region on chromosome 11q13 and the SLC25A15-ELF1-WBP4 region on chromosome 13q14. The lack of an association of the well-established Caucasian CD susceptibility genes, NOD215–17 and ATG16L1,18–20 in Asian populations suggests that there are differences in genetic susceptibility to CD between Asian and Western populations.15–20 Furthermore, reports on the role of IL23R in Asian CD have been inconsistent.18–21 However, more recent studies suggest that there is association with CD at IL23R, at least in the Korean population, although the association is with a different variant (Gly149Arg) not present in Caucasian, the well-documented Caucasian-associated single-nucleotide polymorphism (SNP) (Arg381Gln) was monomorphic in the Korean population.14,21 The CD association of TNFSF15 has been confirmed in Asian and Caucasian cohorts.6,22–24 Collectively, these findings emphasized the importance of genetic studies across different ethnicities. Full details of the design and content of the ImmunoChip (Illumina, San Diego, CA) array have been previously described.25,26 Briefly, the ImmunoChip consists of all known SNPs from the 1000 Genomes Project (February 2010 release) and private resequencing efforts for 186 loci previously identified as showing association with 12 immune-mediated diseases including CD. For each disease, ∼3000 SNPs were selected from available GWAS data for deep replication and to cover strong candidate genes. The ImmunoChip was designed based on SNPs identified in individuals of European origin and non-European variation that may be underrepresented. This platform provides an opportunity to identify new CD associations with loci implicated in other autoimmune diseases and permits fine-mapping experiments. In this study, we used the ImmunoChip to identify additional susceptibility loci for CD in Koreans and expand our knowledge of the genetic architecture of CD in this population.