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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Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi. 1967;16:178–222. Note: An English translation was published in Pediat Infect Dis J. 2002;21:1–38
Kato H, Koike S, Yamamoto M, Ito Y, Yano E. Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome. J Pediatr. 1975;86:892–8.
Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, et al. Long-term consequences of Kawasaki disease: a 10- to 21-year follow-up study of 594 patients. Circulation. 1996;94:1379–85.
Bayers S, Shulman ST, Paller AS. Kawasaki disease: part II. Complications and treatment. J Am Acad Dermatol. 2013;69:513.e1–8.
Burns JC, Capparelli EV, Brown JA, Newburger JW, Glode MP. Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group. Pediatr Infect Dis J. 1998;17:1144–8.
Sittiwangkul R, Pongprot Y, Silvilairat S, Phornphutkul C. Management and outcome of intravenous gammaglobulin-resistant Kawasaki disease. Singapore Med J. 2006;47:780–4.
Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113:2606–12.
Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149:237–40.
Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, et al. Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr. 2007;166:131–7.
Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr. 2008;153:117–21.
Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747–71.
McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99.
Onouchi Y, Suzuki Y, Suzuki H, Terai M, Yasukawa K, Hamada H, et al. ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease. Pharmacogenomics J. 2013;13:52–59.
Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y. A high-throughput SNP typing system for genome-wide association studies. J Hum Genet. 2001;46:471–7.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.
Li CF, MacDonald JR, Wei RY, Ray J, Lau K, Kandel C, et al. Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse. BMC Genomics. 2007;8:92.
Wang Q, Zhai YY, Dai JH, Li KY, Deng Q, Han ZG. SAMD9L inactivation promotes cell proliferation via facilitating G1-S transition in hepatitis B virus-associated hepatocellular carcinoma. Int J Biol Sci. 2014;10:807–16.
Lemos de Matos A, Liu J, McFadden G, Esteves PJ. Evolution and divergence of the mammalian SAMD9/SAMD9L gene family. BMC Evol Biol. 2013;13:121.
Asou H, Matsui H, Ozaki Y, Nagamachi A, Nakamura M, Aki D, et al. Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome. Biochem Biophys Res Commun. 2009;383:245–51.
Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A, et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell. 2013;24:305–17.
Chen DH, Below JE, Shimamura A, Keel SB, Matsushita M, Wolff J, et al. Ataxia-Pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98:1146–58.
Tesi B, Davidsson J, Voss M, Rahikkala E, Holmes TD, Chiang SCC, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129:2266–79.
Martin JE, Assassi S, Diaz-Gallo LM, Broen JC, Simeon CP, Castellvi I, et al. A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Hum Mol Genet. 2013;22:4021–9.
Weng KP, Hsieh KS, Ho TY, Huang SH, Lai CR, Chiu YT, et al. IL-1B polymorphism in association with initial intravenous immunoglobulin treatment failure in Taiwanese children with Kawasaki disease. Circ J. 2010;74:544–51.
Shrestha S, Wiener HW, Olson AK, Edberg JC, Bowles NE, Patel H, et al. Functional FCGR2B gene variants influence intravenous immunoglobulin response in patients with Kawasaki disease. J Allergy Clin Immunol. 2011;128:677–80.
Shrestha S, Wiener H, Shendre A, Kaslow RA, Wu J, Olson A, et al. Role of activating FcγR gene polymorphisms in Kawasaki disease susceptibility and intravenous immunoglobulin response. Circ Cardiovasc Genet. 2012;5:309–16.
Makowsky R, Wiener HW, Ptacek TS, Silva M, Shendre A, Edberg JC, et al. FcγR gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response. Pharmacogenet Genomics. 2013;23:455–62.
Portman MA, Wiener HW, Silva M, Shendre A, Shrestha S. DC-SIGN gene promoter variants and IVIG treatment response in Kawasaki disease. Pediatr Rheumatol Online J. 2013;11:32.
Kuo HC, Wong HS, Chang WP, Chen BK, Wu MS, Yang KD, et al. Prediction for intravenous immunoglobulin resistance by using weighted genetic risk score identified from genome-wide association study in Kawasaki disease. Circ Cardiovasc Genet. 2017;10:pii e001625.
Shimizu C, Eleftherohorinou H, Wright VJ, Kim J, Alphonse MP, Perry JC, et al. Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities. Circ Cardiovasc Genet. 2016;9:559–68.
Jaggi P, Wang W, Dvorchik I, Printz B, Berry E, Kovalchin JP, et al. Patterns of fever in children after primary treatment for Kawasaki disease. Pediatr Infect Dis J. 2015;34:1315–8.
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
Conflict of interest
The authors declare that they have no conflict of interest.
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The names of the members of the Korean Kawasaki Disease Genetics Consortium are mentioned below Acknowledgements.