Abstract 33: A Meta-analysis Of Three Genome-wide Association Studies Identifies A Novel Susceptibility Locus For Kawasaki Disease.

Abstract

Background: Although genome-wide association studies (GWAS) have conclusively identified several susceptibility genes / loci for Kawasaki disease (KD), a large part of the genetic etiology of this disease have not been unraveled and, above all, its marked predilection for East Asian populations have not been explained. Objective: To identify genetic variants commonly associated with KD in the East Asian populations, we conducted a meta-analysis of three GWASes from Japan, Korea and Taiwan. Methods: In the GWAS analyses, we genotyped 6322 subjects (1236 cases and 5086 controls) using either Illumina 550K or Affymetrix SNP 6.0 platforms and then imputed untyped genotypes using Impute2 or minimac software with 1000 Genomes Project’s East Asian population (JPT, CHB and CHS) reference haplotype data. We then performed a meta-analysis using a weighted-average method with inverse-variance weights and selected representative SNPs in 49 top associated loci, which were then genotyped in 4798 independent subjects (2151 cases and 2747 controls). Finally, we combined the data for the three GWASes and follow up studies in a meta-analysis. Results: SNPs within previously identified susceptibility loci showed significant association in the meta-analysis of the GWASes (ITPKC: rs28493229, P = 3.07 x 10-9; CASP3: rs2720377, P = 2.66 x 10-9; BLK: rs2736340, P = 1.23 x 10-16; CD40: rs1883832, P = 1.76 x 10-8; HLA class2: rs189914842, P = 4.57 x 10-11). In a meta-analysis of the three GWASes and follow-up studies, we observed a genome-wide significant level of association at a SNP in a chromosomal region different from the six known loci (P = 6.49 x 10-9). Conclusion: The meta-analysis of three GWAses and follow-up studies successfully identified a new SNP significantly associated with KD. Further investigation of the region where the SNP is located toward specification of the susceptibility gene, the responsible variant, as well as its effect on gene function is warranted. Acknowledgement: T.A.J., J.Y.W. and D.Y. equally contributed to this work and J.K.L., Y.T.C., and Y.O. are co-directing this project.