Abstract
In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10−9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10−10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.
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Acknowledgements
This study was supported by grants from the Millennium Project, from the Japan Kawasaki Disease Research Center (2015 to YM, and 2018 and 2019 to YO), and from the Japan Agency for Medical Research and Development (JP18ek0410039 to TH). This study was also supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (HI15C1575 to JKL). We are grateful to the KD patients and their family members as well as the medical staff taking care of the patients. We also thank Ms. Yoshie Kikuchi for her technical assistance.
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JKL, JYW, YTC, and YO supervised the study. JKL, JYW, and YO conceived the study. JYW, TAJ, TT, JKL, and YO designed the study. TAJ, YM, JKL, JYW, and YO wrote the manuscript. AH, HS, HH, TH, and Japan Kawasaki Disease Genome Consortium collected Japanese samples. YMH, GYJ, SWY, JJY, KYL, and Korean Kawasaki Disease Genetics Consortium collected Korean samples. Taiwan Kawasaki Disease Genetics Consortium and Taiwan Pediatric ID Alliance collected Taiwanese samples. YML coordinated the multi-center collaboration in Taiwan as the project manager and collected samples and clinical information. MK performed GWAS assays for the Japanese samples. AT performed statistical analyses for the Japanese GWAS data. DY and TP performed statistical analyses for the Korean GWAS data. JJK conducted a follow-up study (Stage 2) for the Korean samples. CHC performed statistical analyses for the Taiwanese GWAS data and followed-up meta-analyses for the Taiwanese data. YCL supervised the GWAS and replication genotyping pipeline, performed the data analyses. LCC performed statistical analyses for the Taiwanese GWAS data and followed-up meta-analyses for the Taiwanese data. CPC performed genotyping and direct sequencing of Taiwanese samples. TAJ, DY, and CHC conducted the whole-genome imputation. TAJ performed P value simulation and meta-analyses. KO, TT, and KI performed genotyping and direct sequencing of the Japanese samples. YM and YO performed the NGS data analyses for the IGH repertoires.
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Members of the Korean Kawasaki Disease Genetics Consortium, Taiwan Kawasaki Disease Genetics Consortium, Taiwan Pediatric ID Alliance, Japan Kawasaki Disease Genome Consortium are listed in the Supplementary information.
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Johnson, T.A., Mashimo, Y., Wu, JY. et al. Association of an IGHV3-66 gene variant with Kawasaki disease. J Hum Genet 66, 475–489 (2021). https://doi.org/10.1038/s10038-020-00864-z
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DOI: https://doi.org/10.1038/s10038-020-00864-z
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