Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

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Abstract

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10−11, odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10−9, OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10−12, OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings1. The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

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Figure 1: Regional association and linkage disequilibrium plots for regions on chromosomes 1 and 19 showing association with Kawasaki disease.

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Acknowledgements

We thank all the individuals with Kawasaki disease and their families for participating in this study. We are grateful to W.-Y. Meah, H.-B. Toh, X. Chen, K.-K. Heng, C.-H. Wong, P.-L. Ng, S.H.Y. Chen and J.-W. Tay for technical assistance, to J. Pancheri, N. Innocentini, D. Donati and S. Fernandez for subject data collection and to D. Scherrer for laboratory assistance. The authors acknowledge the contributions of The Kawasaki Syndrome Support Group (UK) for their assistance in recruitment of the UK collection. This study makes use of data generated by the Wellcome Trust Case Control Consortium 2. A full list of the investigators who contributed to the generation of this data is available from the WTCCC2 website (see URLs). This work was funded in part by internal funding from the Sainte-Justine Hospital research center (awarded to N.D.), by grants from the US National Institutes of Health, National Heart, Lung, Blood Institute (HL69413, awarded to J.C.B.), from the National Heart Foundation of Australia (to D.B.) and by the Agency for Science, Technology, and Research, Singapore. The Korean Kawasaki Disease Genetics Consortium was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (A010384). The Hong Kong Kawasaki Disease Genetics Consortium was supported by the Shun Tak District Min Yuen Tong. The Australian research activity was partly supported by the Victorian Government's Operational Infrastructure Support Program.

Author information

M.L., J.C.B., D.B., T.W.K. and M.L.H. are the principal investigators who conceived of and obtained funding for this project. C.C.K. and S.D. organized and supervised the GWAS and replication genotyping pipeline, devised the overall analysis plan and wrote the first draft of the manuscript with input from W.B.B., M.L., J.C.B., D.B., T.W.K., M.L.H., T.Y.W., J.-Y.W., J.-K.L. and Y.-F.C. C.C.K., S.D., W.B.B.,Y.-C.L., K.S.S., W.Y. and J.-Y.W. analyzed the data. W.B.B., C.S., V.J.W., R.S.M.Y., J.J.W., T.Y.W., P.M., R.C., N.D., Y.-F.C., G.-Y.H., W.Y., I.-S.P., J.-K.L. and J.-Y.W. coordinated and contributed subjects and database phenotype collections as lead investigators for their respective sample collections. D.E.K.T. and J.P. performed genotyping and DNA quality control analysis. All authors critically reviewed the manuscript revisions and contributed intellectually to the final manuscript.

Correspondence to Michael Levin or Jane C Burns or David Burgner or Taco W Kuijpers or Martin L Hibberd.

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A complete list of authors and affiliations appears at the end of this paper.

A complete list of authors and affiliations appears at the end of this paper.

A complete list of authors and affiliations appears at the end of this paper.

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