Association of an IGHV3-66 gene variant with Kawasaki disease

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

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.