ORIGINAL ARTICLE ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease Y Onouchi 1 , Y Suzuki 2 , H Suzuki 3 , M Terai 4 , K Yasukawa 5 , H Hamada 4 , T Suenaga 3 , T Honda 4 , A Honda 6 , H Kobayashi 6 , T Takeuchi 3 , N Yoshikawa 3 , J Sato 7 , S Shibuta 8 , M Miyawaki 8 , K Oishi 9 , H Yamaga 10 , N Aoyagi 11 , S Iwahashi 12 , R Miyashita 13 , Y Murata 14 , R Ebata 5 , K Higashi 5 , K Ozaki 1 , K Sasago 2 , T Tanaka 1 and A Hata 2 1 Laboratory for Cardiovascular Diseases, Center for Genomic Medicine RIKEN, Yokohama, Kanagawa, Japan; 2 Department of Public Health, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan; 3 Department of Pediatrics, Wakayama Medical University, Wakayama, Wakayama, Japan; 4 Department of Pediatrics, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan; 5 Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan; 6 Department of Pediatrics, Asahi General Hospital, Asahi, Chiba, Japan; 7 Department of Pediatrics, Funabashi Municipal Medical Center, Funabashi, Chiba, Japan; 8 Department of Pediatrics, Social Insurance Kinan Hospital, Tanabe, Wakayama, Japan; 9 Department of Pediatrics, Hashimoto Municipal Hospital, Hashimoto, Wakayama, Japan; 10 Department of Pediatrics, Naga Hospital, Kinokawa, Wakayama, Japan; 11 Department of Pediatrics, Wakayama Rosai Hospital, Wakayama, Wakayama, Japan; 12 Department of Pediatrics, Hidaka General Hospital, Gobo, Wakayama, Japan; 13 Department of Pediatrics, Izumiotsu Municipal Hospital, Izumiotsu, Osaka, Japan and 14 Department of Pediatrics, Sendai City Hospital, Sendai, Miyagi, Japan Correspondence: Dr Y Onouchi, Laboratory for Cardiovascular Diseases, Center for Genomic Medicine RIKEN, 1-7-22, Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. E-mail: onouchi@src.riken.jp Received 30 January 2011; revised 6 September 2011; accepted 8 September 2011; published online 11 October 2011 Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5- trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki’s disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investi- gated 204 Japanese KD patients who received a single IVIG dose of 2 g kg À1 (n ¼ 70) or 1 g kg À1 daily for 2 days (n ¼ 134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P ¼ 0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg À1 ), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P ¼ 0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P ¼ 0.0031). Our findings strongly suggest the existence of genetic factors affecting patients’ responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation. The Pharmacogenomics Journal (2013) 13, 52–59; doi:10.1038/tpj.2011.45; published online 11 October 2011 Keywords: Kawasaki’s disease; ITPKC; CASP3; SNP; IVIG resistance; coronary artery lesion Introduction Kawasaki’s disease (KD; MIM611775) is an acute febrile illness characterized by high fever, polymorphous skin rash, bilateral conjunctivitis, erythema of the hands and feet, redness of the oral mucosa and cervical lymphadenopathy. 1 Pathologically, KD is a vasculitis of small and medium-sized arteries. 2 Coronary arteries are particularly affected and coronary artery lesions (CALs), such as aneurysms and dilatation, occur in 20–25% of untreated KD patients. 3 KD preferentially affects infants and children younger than 4 years of age and is the leading cause of acquired childhood cardiac disease in developed countries. Although KD has been postulated to be caused by some infectious trigger, the etiology of this disease remains unclear. Intravenous immunoglobulin (IVIG) therapy, introduced in the 1980s, is effective and has reduced the incidence of CAL to o5%; 4 however, around 10–20% of patients are resistant to this treatment and have a higher risk for CAL. 5–8 Therefore, unraveling the causes of resistance to IVIG and being able to predict patients’ responsiveness to IVIG therapy during the early stages of the disease before they develop CAL are urgent clinical issues. The Pharmacogenomics Journal (2013) 13, 52–59 & 2013 Macmillan Publishers Limited. All rights reserved 1470-269X/13 www.nature.com/tpj