Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.
Hoggart C., Shimizu C., Galassini R., Wright VJ., Shailes H., Bellos E., Herberg JA., Pollard AJ., O'Connor D., Choi SW., Seaby EG., Menikou S., Hibberd M., Sallah N., Burgner D., Brogan P., Patel H., Kim J., Tremoulet AH., Salo E., van Stijn D., Kuijpers T., Burns JC., Levin M., International Kawasaki Disease Genetics Consortium None., UK Kawasaki Disease Genetics Consortium None., EUCLIDS Consortium None.
Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.