1. Association of an IGHV3-66 gene variant with Kawasaki disease.
- Author
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Johnson TA, Mashimo Y, Wu JY, Yoon D, Hata A, Kubo M, Takahashi A, Tsunoda T, Ozaki K, Tanaka T, Ito K, Suzuki H, Hamada H, Kobayashi T, Hara T, Chen CH, Lee YC, Liu YM, Chang LC, Chang CP, Hong YM, Jang GY, Yun SW, Yu JJ, Lee KY, Kim JJ, Park T, Lee JK, Chen YT, and Onouchi Y
- Subjects
- Adult, Alleles, B-Lymphocytes metabolism, Computer Simulation, Datasets as Topic, Follow-Up Studies, Gene Expression Regulation, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Japan epidemiology, Leukocytes metabolism, Linkage Disequilibrium, Models, Genetic, Mucocutaneous Lymph Node Syndrome epidemiology, Polymorphism, Single Nucleotide, Republic of Korea epidemiology, Taiwan epidemiology, Transcription, Genetic, Genes, Immunoglobulin Heavy Chain, Genome-Wide Association Study, Mucocutaneous Lymph Node Syndrome genetics
- 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.- Published
- 2021
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