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Identification of SAMD9L as a susceptibility locus for intravenous immunoglobulin resistance in Kawasaki disease by genome-wide association analysis

Abstract

Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10–20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P= 1.39 × 10−5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P= 5.30 × 10−6). These results provide new insights into the mechanism of IVIG response in KD.

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Acknowledgements

We thank all patients and their families for participating in this study. This work was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (HI15C1575) and a grant from the Korea Center for Disease Control and Prevention (2014-ER7402–00). The following authors participated in this work as members of Japan Kawasaki Disease Genome Consortium: Masaru Terai (Chiba Kaihin Municipal Hospital, Chiba, Japan), Kumi Yasukawa (Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan), Tomohiro Suenaga (Department of Pediatrics, Wakayama Medical University, Wakayama, Japan), Takafumi Honda (Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan), Akihito Honda (Department of Pediatrics, Asahi General Hospital, Asahi, Japan), Hironobu Kobayashi (Department of Pediatrics, Asahi General Hospital Asahi, Japan), Kouji Higashi (Department of Cardiology, Chiba Children’s Hospital Chiba, Japan), Takashi Takeuchi (Department of Pediatrics, Wakayama Medical University, Wakayama, Japan), Junichi Sato (Department of Pediatrics, Funabashi Municipal Medical Center, Funabashi, Japan), Shoichi Shibuta (Department of Pediatrics, Kinan Hospital, Tanabe, Japan), Masakazu Miyawaki (Department of Pediatrics, Kinan Hospital, Tanabe, Japan), Ko Oishi (Department of Pediatrics, Hashimoto Municipal Hospital, Hashimoto, Japan), Hironobu Yamaga (Department of Pediatrics, Naga Hospital, Kinokawa, Japan), Noriyuki Aoyagi (Department of Pediatrics, Wakayama Rosai Hospital, Wakayama, Japan), Megumi Yoshiyama (Department of Pediatrics, Hidaka General Hospital, Gobo, Japan), and Ritsuko Miyashita (Department of Pediatrics, Izumiotsu Municipal Hospital, Izumiotsu, Japan).

The Korean Kawasaki Disease Genetics Consortium

Jeong Jin Yu3, In-Sook Park18, Soo-Jong Hong18, Kwi-Joo Kim18, Jong-Keuk Lee1, Jae-Jung Kim1, Young Mi Hong12, Sejung Sohn12, Gi Young Jang11, Kee Soo Ha11, Hyo-Kyoung Nam11, Jung-Hye Byeon11, Sin Weon Yun2, Myung-Ki Han8, Kyung-Yil Lee5, Ja-Young Hwang5, Jung-Woo Rhim5, Min Seob Song9, Hyoung Doo Lee10, Dong Soo Kim19, Kyung Lim Yoon4, Hong-Ryang Kil6, Gi Beom Kim7, Jae-Moo Lee20, Jong-Duk Kim20

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Correspondence to Jong-Keuk Lee.

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The names of the members of the Korean Kawasaki Disease Genetics Consortium are mentioned below Acknowledgements.

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