Association of an IGHV3-66 gene variant with Kawasaki disease

• Published in: Journal of human genetics Vol. 66; no. 5; pp. 475 - 489
• Main Authors: Johnson, Todd A., Mashimo, Yoichi, Wu, Jer-Yuarn, Yoon, Dankyu, Hata, Akira, Kubo, Michiaki, Takahashi, Atsushi, Tsunoda, Tatsuhiko, Ozaki, Kouichi, Tanaka, Toshihiro, Ito, Kaoru, Suzuki, Hiroyuki, Hamada, Hiromichi, Kobayashi, Tohru, Hara, Toshiro, Chen, Chien-Hsiun, Lee, Yi-Ching, Liu, Yi-Min, Chang, Li-Ching, Chang, Chun-Ping, Hong, Young-Mi, Jang, Gi-Young, Yun, Sin-Weon, Yu, Jeong-Jin, Lee, Kyung-Yil, Kim, Jae-Jung, Park, Taesung, Lee, Jong-Keuk, Chen, Yuan-Tsong, Onouchi, Yoshihiro
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.05.2021; Nature Publishing Group
• Subjects: 45/43; 631/208/248/144; 631/250/249/2510; Adult; Alleles; B-Lymphocytes - metabolism; Biomedical and Life Sciences; Biomedicine; Chromosome 14; Computer Simulation; Coronary artery disease; Datasets as Topic; Follow-Up Studies; Gene Expression; Gene Expression Regulation; Gene Function; Gene Therapy; Genes, Immunoglobulin Heavy Chain; Genetic Predisposition to Disease; Genome-Wide Association Study; Heart diseases; High-Throughput Nucleotide Sequencing; Human Genetics; Humans; Immunoglobulins; Japan - epidemiology; Kawasaki disease; Leukocytes (mononuclear); Leukocytes - metabolism; Linkage Disequilibrium; Lymphocytes B; Models, Genetic; Molecular Medicine; Mucocutaneous lymph node syndrome; Mucocutaneous Lymph Node Syndrome - epidemiology; Mucocutaneous Lymph Node Syndrome - genetics; Peripheral blood mononuclear cells; Polymorphism, Single Nucleotide; Republic of Korea - epidemiology; Rheumatic fever; Rheumatic heart disease; Taiwan - epidemiology; Transcription, Genetic; Japan; Republic of Korea; Taiwan
• ISSN: 1434-5161; 1435-232X; 1435-232X
• DOI: 10.1038/s10038-020-00864-z

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.