ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease

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 investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg−1 (n=70) or 1 g kg−1 daily for 2 days (n=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=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg−1), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=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=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.

[1]  S. Koike,et al.  Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome. , 1975, The Journal of pediatrics.

[2]  I-Chun Lin,et al.  ITPKC Single Nucleotide Polymorphism Associated with the Kawasaki Disease in a Taiwanese Population , 2011, PloS one.

[3]  K. Durongpisitkul,et al.  Immunoglobulin Failure and Retreatment in Kawasaki Disease , 2003, Pediatric Cardiology.

[4]  N. Shirai,et al.  [Pathology of Kawasaki disease]. , 2008, Nihon rinsho. Japanese journal of clinical medicine.

[5]  R. Holman,et al.  Analysis of Potential Risk Factors Associated With Nonresponse to Initial Intravenous Immunoglobulin Treatment Among Kawasaki Disease Patients in Japan , 2008, The Pediatric infectious disease journal.

[6]  J. Burns,et al.  Increased Incidence and Severity of Kawasaki Disease Among Filipino-Americans in San Diego County , 2011, The Pediatric infectious disease journal.

[7]  H L Shah.  Two dimensional echocardiography. , 1980, Indian heart journal: teaching series.

[8]  R. Amin,et al.  Initial Intravenous γ‐Globulin Treatment Failure in Iranian Children with Kawasaki Disease , 2005 .

[9]  Tomio Kobayashi,et al.  Prediction of Intravenous Immunoglobulin Unresponsiveness in Patients With Kawasaki Disease , 2006, Circulation.

[10]  Yoshikazu Nakamura,et al.  Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition) , 2005, Pediatrics international : official journal of the Japan Pediatric Society.

[11]  Yoshihiro Onouchi,et al.  Molecular Genetics of Kawasaki Disease , 2009, Pediatric Research.

[12]  Yusuke Nakamura,et al.  ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms , 2008, Nature Genetics.

[13]  T. Matsuishi,et al.  Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. , 2006, The Journal of pediatrics.

[14]  Yusuke Nakamura,et al.  Common variants in CASP3 confer susceptibility to Kawasaki disease. , 2010, Human molecular genetics.

[15]  K. Nishigaki,et al.  Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008)--digest version. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[16]  M Takahashi,et al.  A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. , 1991, The New England journal of medicine.

[17]  S. Kurotobi,et al.  Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment , 2006, European Journal of Pediatrics.

[18]  T. Kawasaki,et al.  [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children]. , 1967, Arerugi = [Allergy].

[19]  A. Hata,et al.  Cyclosporin A Treatment for Kawasaki Disease Refractory to Initial and Additional Intravenous Immunoglobulin , 2011, The Pediatric infectious disease journal.

[20]  Ravi S. Misra,et al.  Proteolytic Regulation of Nuclear Factor of Activated T (NFAT) c2 Cells and NFAT Activity by Caspase-3* , 2006, Journal of Biological Chemistry.

[21]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[22]  D. Sherry,et al.  Initial intravenous gammaglobulin treatment failure in Kawasaki disease. , 2000, Pediatrics.

[23]  Yusuke Nakamura,et al.  A genomewide linkage analysis of Kawasaki disease: evidence for linkage to chromosome 12 , 2006, Journal of Human Genetics.

[24]  Chien-Fu Huang,et al.  CASP3 gene single-nucleotide polymorphism (rs72689236) and Kawasaki disease in Taiwanese children , 2011, Journal of Human Genetics.

[25]  J. Newburger,et al.  Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group. , 1998, The Pediatric infectious disease journal.

[26]  Y. Arakaki,et al.  [Two-dimensional echocardiography of coronary artery in Kawasaki disease (MCLS): detection, changes in acute phase, and follow-up observation of the aneurysm (author's transl)]. , 1981, Journal of Edugeography.

[27]  Y. Hamashima,et al.  Pathology of Kawasaki disease: I. Pathology and morphogenesis of the vascular changes. , 1979, Japanese circulation journal.