Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease

Clive Hoggart ,Victoria J Wright ,Harsita Patel ,Adriana H Tremoulet ,Andrew J Pollard ,Jethro Herberg ,Daniel O’connor ,Diana Van Stijn ,Jane C Burns ,Shing Wan Choi ,Chisato Shimizu ,Hannah Shailes ,Eeva Salo ,Taco W Kuijpers ,Martin L Hibberd ,Paul Brogan ,David Burgner ,Jihoon Kim ,Eleanor G Seaby ,Evangelos Bellos ,Neneh Sallah ,Rachel Galassini ,Stephanie Menikou ,Michael Levin

doi:10.1038/s41431-021-00838-5

Abstract

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.

Highlights

Kawasaki disease (KD) is the leading cause of acquired heart disease in children in developed countries [1]
Introduction of effective treatment with intravenous immunoglobulin (IVIG) reduces the incidence of coronary artery aneurysm (CAA), aneurysm formation continues to occur in a significant proportion of children
Summary level data of CASP3 and BLK/FAM167A susceptibility loci were available from two genome-wide association study (GWAS) of Japanese subjects [12, 21] and were meta-analysed with our European meta-analysis results

Summary

Introduction

Kawasaki disease (KD) is the leading cause of acquired heart disease in children in developed countries [1]. Introduction of effective treatment with intravenous immunoglobulin (IVIG) reduces the incidence of coronary artery aneurysm (CAA), aneurysm formation continues to occur in a significant proportion of children. Most of the patients who develop CAA, including those who are diagnosed in the first 10 days of the illness, have evidence of coronary artery (CA) dilatation or CAA at initial presentation [3]. Others who go on to develop CAA may have inadequate response to IVIG and other agents and represent a group of patients with “resistant KD” who have a severe inflammatory process often poorly responsive to anti-inflammatory agents [5]

Methods

Discussion

Conclusion