Skip to main content

Advertisement

SpringerLink
Log in

Immunogenetics of Kawasaki disease

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Kawasaki disease (KD) is a medium vessel vasculitis that affects young children. Despite extensive research over the last 50 years, the etiology of KD remains an enigma. Seasonal change in wind patterns was shown to have correlation with the epidemics of KD in Japan. Occurrence of disease in epidemiological clusters, seasonal variation, and a very low risk of recurrence suggest that KD is triggered by an infectious agent. The identification of oligoclonal IgA response in the affected tissues suggests an antigen-driven inflammation. The recent identification of a viral antigen in the cytoplasm of bronchial ciliated epithelium also favors infection as the main trigger for KD. Pointers that suggest a genetic basis of KD include a high disease prevalence in North-East Asian populations, a high risk among siblings, and familial occurrence of cases. Dysregulated innate and adaptive immune responses are evident in the acute stages of KD. In addition to the coronary wall inflammation, endothelial dysfunction and impaired vascular remodeling contribute to the development of coronary artery abnormalities (CAAs) and thrombosis. Genetic aberrations in certain intracellular signaling pathways involving immune effector functions are found to be associated with increased susceptibility to KD and development of coronary artery abnormalities (CAAs). Several susceptible genes have been identified through genome-wide association studies (GWAS) and linkage studies (GWLS). The genes that are studied in KD can be classified under 4 major groups—enhanced T cell activation (ITPKC, ORAI1, STIM1), dysregulated B cell signaling (CD40, BLK, FCGR2A), decreased apoptosis (CASP3), and altered transforming growth factor beta signaling (TGFB2, TGFBR2, MMP, SMAD). The review aims to highlight the role of several genetic risk factors that are linked with the increased susceptibility to KD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

KD:

Kawasaki disease

IVIg:

Intravenous immunoglobulin

CAA:

Coronary artery aneurysms

SNP:

Single-nucleotide polymorphism

LD:

Linkage disequilibrium

TGF-β:

Transforming growth factor β

GWAS:

Genome-wide association studies

ITPKC:

Inositol 1,4,5-trisphosphate 3-kinase C

CASP3:

Caspase-3

NFAT1:

Nuclear factor of activated T cells

CRP:

C-reactive protein

ESR:

Erythrocyte sedimentation rate

CAMK2D:

Calcium/calmodulin-dependent protein kinase (CaM Kinase) II delta

References

  1. Kawasaki T (1967) Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi 16:178–222

    CAS  PubMed  Google Scholar 

  2. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H (1974) A new infantile acute febrile mucocutaneous lymph node syndrome (MCLS) prevailing in Japan. Pediatrics 54:271–276

    CAS  PubMed  Google Scholar 

  3. Son MB, Newburger JW (2011) Kawasaki disease. In: Kliegman, Stanton, St. Geme, Schor, Behrman A (eds) Nelson textbook of pediatrics. Elsevier Saunders, Philadelphia, pp 862–867

    Google Scholar 

  4. Newburger JW, Takahashi M, Gerber MA et al (2004) 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 110:2747–2771

    PubMed  Google Scholar 

  5. Newburger JW, Takahashi M, Gerber MA et al (2004) 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. Pediatrics 114:1708–1733

    PubMed  Google Scholar 

  6. Takeuchi S, Yanagawa H, Kawasaki T et al (1983) An outbreak of Kawasaki disease in Miyako Island in Okinawa prefecture. Pediatr Int 25:436–437

    Google Scholar 

  7. Yeung RS (2010) Kawasaki disease: update on pathogenesis. Curr Opin Rheumatol 22:551–560

    PubMed  Google Scholar 

  8. Holman RC, Curns AT, Belay ED, et al (2003) Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics112:495–501

  9. Kao AS, Getis A, Brodine S, Burns JC (2008) Spatial and temporal clustering of Kawasaki syndrome cases. Pediatr Infect Dis J 27:981–985

    PubMed  PubMed Central  Google Scholar 

  10. Wu MH, Lin MT, Chen HC et al (2017) Postnatal risk of acquiring Kawasaki disease: a nationwide birth cohort database study. J Pediatr 180:80

    PubMed  Google Scholar 

  11. Makino N, Nakamura Y, Yashiro M, Ae R, Tsuboi S, Aoyama Y, Kojo T, Uehara R, Kotani K, Yanagawa H (2015) Descriptive epidemiology of Kawasaki disease in Japan, 2011–2012: from the results of the 22nd nationwide survey. J Epidemiol 25:239–245

    PubMed  Google Scholar 

  12. Singh S, Vignesh P, Burgner D (2015) The epidemiology of Kawasaki disease: a global update. Arch Dis Child 100:1084–1088

    PubMed  Google Scholar 

  13. Lai W, Mertens L, Cohen MS, Geva T (2016) Echocardiography in pediatric and congenital heart disease: from fetus to adult, second edition. John Wiley & Sons

  14. Singh S, Sharma D, Bhattad S et al (2014) Recent advances in Kawasaki disease-Proceedings of the 3rd Kawasaki Disease Summit, Chandigarh, 2014 Indian. J Pediatr 83:47–52

    Google Scholar 

  15. Kawasaki T (1995) General review and problems in Kawasaki disease. Jpn Heart J 36:1–12

    CAS  PubMed  Google Scholar 

  16. Petty R, Laxer R, Lindsley C, Wedderbur L (2015) Textbook of pediatric rheumatology 7th Edition. Elsevier Saunders, pp 467–483

  17. Singh S, Kawasaki T (2009) Kawasaki disease- an Indian perspective. Indian Pediatr 46:563–571

    PubMed  Google Scholar 

  18. Hirata S, Nakamura Y, Yanagawa H (2001) Incidence rate of recurrent Kawasaki disease and related risk factors: from the results of nationwide surveys of Kawasaki disease in Japan. Acta Paediatr 90:40–44

    CAS  PubMed  Google Scholar 

  19. Nishio H, Kanno S, Onoyama S et al (2011) NOD1 ligands induce site-specific vascular inflammation. Arterioscler Thromb Vasc Biol 31:1093–1099

    CAS  PubMed  Google Scholar 

  20. Motomura Y, Kanno S, Asano K et al (2015) Identification of pathogenic cardiac CD11c1 macrophages in NOD1-mediated acute coronary arteritis. Arterioscler Thromb Vasc Biol 35:1423–1433

    CAS  PubMed  Google Scholar 

  21. Ye F, Foell D, Hirono KI, Vogl T, Rui C, Yu X, Watanabe S, Watanabe K, Uese K, Hashimoto I, Roth J, Ichida F, Miyawaki T (2004) Neutrophil-derived S100A12 is profoundly upregulated in the early stage of acute Kawasaki disease. Am J Cardiol 94:840–844

    CAS  PubMed  Google Scholar 

  22. Ebihara T, Endo R, Kikuta H, Ishiguro N, Ma X, Shimazu M, Otoguro T, Kobayashi K (2005) Differential gene expression of S100 protein family in leukocytes from patients with Kawasaki disease. Eur J Pediatr 164:427–431

    CAS  PubMed  Google Scholar 

  23. Hoshina T, Kusuhara K, Ikeda K et al (2008) High mobility group box 1 (HMGB1) and macrophage migration inhibitory factor (MIF) in Kawasaki disease. Scand J Rheumatol 37:445–449

    CAS  PubMed  Google Scholar 

  24. Foell D, Ichida F, Vogl T, Yu X, Chen R, Miyawaki T, Sorg C, Roth J (2003) S100A12 (EN-RAGE) in monitoring Kawasaki disease. Lancet 361:1270–1272

    CAS  PubMed  Google Scholar 

  25. Komatsu H, Tateno A (2007) Failure to distinguish systemic-onset juvenile idiopathic arthritis from incomplete Kawasaki disease in an infant. J Paediatr Child Health 43:707–709

    PubMed  Google Scholar 

  26. Dong S, Bout-Tabaku S, Texter K et al (2015) Diagnosis of systemic-onset juvenile idiopathic arthritis after treatment for presumed Kawasaki disease. J Pediatr 166:1283–1288

    PubMed  Google Scholar 

  27. Kuijpers TW, Wiegman A, van Lier RA, Roos MT, Wertheim-van Dillen P, Pinedo S, Ottenkamp J (1999) Kawasaki disease: a maturational defect in immune responsiveness. J Infect Dis 180:1869–1877

    CAS  PubMed  Google Scholar 

  28. Furukawa S, Matsubara T, Yabuta K (1992) Mononuclear cell subsets and coronary artery lesions in Kawasaki disease. Arch Dis Child 67:706–708

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Y, Wang W, Gong F et al (2013) Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease. Arthritis Rheum 65:805–814

    CAS  PubMed  Google Scholar 

  30. Furuno K, Yuge T, Kusuhara K, Takada H, Nishio H, Khajoee V, Ohno T, Hara T (2004) CD251CD41 regulatory T cells in patients with Kawasaki disease. J Pediatr 145:385–390

    CAS  PubMed  Google Scholar 

  31. Olivito B, Taddio A, Simonini G et al (2010) Defective FOXP3 expression in patients with acute Kawasaki disease and restoration by intravenous immunoglobulin therapy. Clin Exp Rheumatol 28:93–97

    PubMed  Google Scholar 

  32. Jia S, Li C, Wang G, Yang J, Zu Y (2010) The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease. Clin Exp Immunol 162:131–137

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Takahashi K, Oharaseki T, Yokouchi Y (2011) Pathogenesis of Kawasaki disease. Clin Exp Immunol 164:20–22

    PubMed  PubMed Central  Google Scholar 

  34. Rowley AH, Shulman ST (2010) Pathogenesis and management of Kawasaki disease. Expert Rev Anti-Infect Ther 8:197–203

    PubMed  PubMed Central  Google Scholar 

  35. Rowley AH, Shulman ST (2018) The epidemiology and pathogenesis of Kawasaki disease. Front Pediatr 6:374

    PubMed  PubMed Central  Google Scholar 

  36. Harnden A, Mayon-White R, Perera R et al (2009) Kawasaki disease in England: ethnicity, deprivation, and respiratory pathogens. Pediatr Infect Dis J 28:21–24

    PubMed  Google Scholar 

  37. Holman RC, Christensen KY, Belay ED et al (2010) Racial/ethnic differences in the incidence of Kawasaki syndrome among children in Hawaii. Hawaii Med J 69:194–197

    PubMed  PubMed Central  Google Scholar 

  38. Fujita Y, Nakamura Y, Sakata K et al (1989) Kawasaki disease in families. Pediatrics 84:666–669

    CAS  PubMed  Google Scholar 

  39. Singh S, Aulakh R, Bhalla AK, Suri D, Manojkumar R, Narula N, Burns JC (2011) Is Kawasaki disease incidence rising in Chandigarh, North India? Arch Dis Child 96:137–140

    PubMed  Google Scholar 

  40. Onouchi Y (2009) Molecular genetics of Kawasaki disease. Pediatr Res 65:46–54

    Google Scholar 

  41. Matsuda I, Hattori S, Nagata N, Fruse A, Nambu H (1977) HLA antigens in mucocutaneous lymph node syndrome. Am J Dis Child 131:1417–1418

    CAS  PubMed  Google Scholar 

  42. Kato S, Kimura M, Tsuji K, Kusakawa S, Asai T, Juji T, Kawasaki T (1978) HLA antigens in Kawasaki disease. Pediatrics 61:252–255

    CAS  PubMed  Google Scholar 

  43. Krensky AM, Berenberg W, Shanley K et al (1981) HLA antigens in mucocutaneous lymph node syndrome in New England. Pediatrics 67:741–743

    CAS  PubMed  Google Scholar 

  44. Krensky AM, Grady S, Shanley KM, Berenberg W, Yunis EJ (1983) Epidemic and endemic HLA-B and DR associations in mucocutaneous lymph node syndrome. Hum Immunol 6:75–77

    CAS  PubMed  Google Scholar 

  45. Shimizu C, Kim J, Eleftherohorinou H, Wright VJ, Hoang LT, Tremoulet AH, Franco A, Hibberd ML, Takahashi A, Kubo M, Ito K, Tanaka T, Onouchi Y, Coin LJM, Levin M, Burns JC, Shike H (2019) International Kawasaki Disease Genetic Consortium. HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease. Hum Immunol 80:731–738

    CAS  PubMed  Google Scholar 

  46. Maury CP, Salo E, Pelkonen P (1989) Elevated circulating tumor necrosis factor-alpha in patients with Kawasaki disease. J Lab Clin Med 113:651–654

    CAS  PubMed  Google Scholar 

  47. Kamizono S, Yamada A, Higuchi T, Kato H, Itoh K (1999) Analysis of tumor necrosis factor-alpha production and polymorphisms of the tumor necrosis factor-alpha gene in individuals with a history of Kawasaki disease. Pediatr Int 41:341–345

    CAS  PubMed  Google Scholar 

  48. Quasney MW, Bronstein DE, Cantor RM et al (2001) Increased frequency of alleles associated with elevated tumor necrosis factor-alpha levels in children with Kawasaki disease. Pediatr Res 49:686–690

    CAS  PubMed  Google Scholar 

  49. Breunis WB, Biezeveld MH, Geissler J, Ottenkamp J, Kuipers IM, Lam J, Hutchinson A, Welch R, Chanock SJ, Kuijpers TW (2006) Vascular endothelial growth factor gene haplotypes in Kawasaki disease. Arthritis Rheum 54:1588–1594

    CAS  PubMed  Google Scholar 

  50. Niu T, Chen X, Xu X (2002) Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications. Drugs 62:977–993

    CAS  PubMed  Google Scholar 

  51. Wu SF, Chang JS, Peng CT et al (2004) Polymorphism of angiotensin-1 converting enzyme gene and Kawasaki disease. Pediatr Cardiol 25:529–533

    PubMed  Google Scholar 

  52. Shim YH, Kim HS, Sohn S, Hong YM (2006) Insertion/deletion polymorphism of angiotensin converting enzyme gene in Kawasaki disease. J Korean Med Sci 21:208–211

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Nishimura S, Zaitsu M, Hara M, Yokota G, Watanabe M, Ueda Y, Imayoshi M, Ishii E, Tasaki H, Hamasaki Y (2003) A polymorphism in the promoter of the CD14 gene (CD14/-159) is associated with the development of coronary artery lesions in patients with Kawasaki disease. J Pediatr 143:357–362

    CAS  PubMed  Google Scholar 

  54. Biezeveld MH, Geissler J, Weverling GJ, Kuipers IM, Lam J, Ottenkamp J, Kuijpers TW (2006) Polymorphisms in the mannose-binding lectin gene as determinants of age-defined risk of coronary artery lesions in Kawasaki disease. Arthritis Rheum 54:369–376

    CAS  PubMed  Google Scholar 

  55. Ouchi K, Suzuki Y, Shirakawa T et al (2003) Polymorphism of SLC11A1 (formerly NRAMP1) gene confers susceptibility to Kawasaki disease. J Infect Dis 187:326–329

    CAS  PubMed  Google Scholar 

  56. Wang W, Lou J, Zhong R et al (2014) The roles of Ca2+/NFAT signalling genes in Kawasaki disease: single- and multiple-risk genetic variants. Sci Rep 4:5208

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Peng Q, Chen C, Zhang Y et al (2012) Single-nucleotide polymorphism rs2290692 in the 3'UTR of ITPKC associated with susceptibility to Kawasaki disease in a Han Chinese population. Pediatr Cardiol 33:1046–1053

    PubMed  Google Scholar 

  58. Kuo HC, Yu HR, Juo SHH et al (2011) CASP3 gene single-nucleotide polymorphism (rs72689236) and Kawasaki disease in Taiwanese children. J Hum Genet 56:161–165

    CAS  PubMed  Google Scholar 

  59. Khor CC, Davila S, Breunis WB, Lee YC, Shimizu C, Wright VJ, Yeung RS, Tan DE, Sim KS, Wang JJ, Wong TY, Pang J, Mitchell P, Cimaz R, Dahdah N, Cheung YF, Huang GY, Yang W, Park IS, Lee JK, Wu JY, Levin M, Burns JC, Burgner D, Kuijpers TW, Hibberd ML, Hong Kong–Shanghai Kawasaki Disease Genetics Consortium, Korean Kawasaki Disease Genetics Consortium, Taiwan Kawasaki Disease Genetics Consortium, International Kawasaki Disease Genetics Consortium, US Kawasaki Disease Genetics Consortium, Blue Mountains Eye Study (2011) Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet 43:1241–1246

    CAS  PubMed  Google Scholar 

  60. Lin MT, Wang JK, Yeh JI, Sun LC, Chen PL, Wu JF, Chang CC, Lee WL, Shen CT, Wang NK, Wu CS, Yeh SZ, Chen CA, Chiu SN, Wu MH (2011) Clinical implication of the C allele of the ITPKC gene SNP rs28493229 in Kawasaki disease: association with disease susceptibility and BCG scar reactivation. Pediatr Infect Dis J 30:148–152

    PubMed  Google Scholar 

  61. Onouchi Y, Gunji T, Burns JC, Shimizu C, Newburger JW, Yashiro M, Nakamura Y, Yanagawa H, Wakui K, Fukushima Y, Kishi F, Hamamoto K, Terai M, Sato Y, Ouchi K, Saji T, Nariai A, Kaburagi Y, Yoshikawa T, Suzuki K, Tanaka T, Nagai T, Cho H, Fujino A, Sekine A, Nakamichi R, Tsunoda T, Kawasaki T, Nakamura Y, Hata A (2008) ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet 40:35–42

    CAS  PubMed  Google Scholar 

  62. Yan Y, Ma Y, Liu Y, Hu H, Shen Y, Zhang S, Ma Y, Tao D, Wu Q, Peng Q, Yang Y (2013) Combined analysis of genome-wide-linked susceptibility loci to Kawasaki disease in Han Chinese. Hum Genet 132(6):669–680

    CAS  PubMed  Google Scholar 

  63. Onouchi Y, Suzuki Y, Suzuki H (2013) ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease. Pharmacogenomics J 13(1):52–59

    CAS  PubMed  Google Scholar 

  64. Chi H, Huang FY, Chen MR, Chiu NC, Lee HC, Lin SP, Chen WF, Lin CL, Chan HW, Liu HF, Huang LM, Lee YJ (2010) ITPKC gene SNP rs28493229 and Kawasaki disease in Taiwanese children. Hum Mol Genet 19:1147–1151

    CAS  PubMed  Google Scholar 

  65. Onouchi Y, Fukazawa R, Yamamura K et al (2016) Variations in ORAI1 gene associated with Kawasaki disease. PLoS One 11:e0145486

    PubMed  PubMed Central  Google Scholar 

  66. Kuo HC, Lin YJ, Juo SH, Hsu YW, Chen WC, Yang KD, Liang CD, Yang S, Chao MC, Yu HR, Wang S, Lin LY, Chang WC (2011) Lack of association between ORAI1/CRACM1 gene polymorphisms and Kawasaki disease in the Taiwanese children. J Clin Immunol 31:650–655

    CAS  PubMed  Google Scholar 

  67. Duan J, Lou J, Zhang Q et al (2014) A genetic variant rs1801274 in FCGR2A as a potential risk marker for Kawasaki disease: a case-control study and meta-analysis. PLoS One 9:e103329

    PubMed  PubMed Central  Google Scholar 

  68. Lou J, Zhong R, Shen N, et al (2015) Systematic confirmation study of GWAS-identified genetic variants for Kawasaki disease in a Chinese population Sci Rep 5:8194

  69. Taniuchi S, Masuda M, Teraguchi M, Ikemoto Y, Komiyama Y, Takahashi H, Kino M, Kobayashi Y (2005) Polymorphism of Fc gamma RIIa may affect the efficacy of gamma-globulin therapy in Kawasaki disease. J Clin Immunol 25:309–313

    CAS  PubMed  Google Scholar 

  70. Ji YX, Zhang HY, Lin SX (2013) Single nucleotide polymorphism of FCGR2A gene in Han Chinese children with Kawasaki disease. Zhongguo Dang Dai Er Ke Za Zhi 15:196–200

    CAS  PubMed  Google Scholar 

  71. Kwon YC, Kim JJ, Yun SW et al (2017) Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease. PLoS One 12:e0184248

    PubMed  PubMed Central  Google Scholar 

  72. Chatzikyriakidou A, Aidinidou L, Giannopoulos A, Papadopoulou-Legbelou K, Kalinderi K, Fidani L (2015) Absence of association of FCGR2A gene polymorphism rs1801274 with Kawasaki disease in Greek patients. Cardiol Young 25:681–683

    PubMed  Google Scholar 

  73. Peng Q, Chen CH, Wu Q et al (2013) Meta-analyses of the associations of genome-wide association study- linked gene loci with Kawasaki disease. Zhonghua Er Ke Za Zhi 51:571–577

    PubMed  Google Scholar 

  74. Lin L, Wang SY, Yang SB, Xiao FC (2015) Association between the FCGR2A gene H131R polymorphism and risk of Kawasaki disease: a meta-analysis. Genet Mol Res 14:6256–6264

    CAS  PubMed  Google Scholar 

  75. Onouchi Y, Ozaki K, Burns JC et al (2012) A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet 44:517–521

    CAS  PubMed  Google Scholar 

  76. Biezeveld M, Geissler J, Merkus M, Kuipers IM, Ottenkamp J, Kuijpers T (2007) The involvement of Fc gamma receptor gene polymorphisms in Kawasaki disease. M Clin Exp Immunol 147(1):106–111

    CAS  PubMed  Google Scholar 

  77. Cheng SC, Cheng YY, Wu JL (2014) Association between gene polymorphism of CD40 gene and coronary artery lesion in Kawasaki disease. Zhongguo Dang Dai Er Ke Za Zhi 16(10):1025–1028

    CAS  PubMed  Google Scholar 

  78. Jin XQ, Liu P, Zhang QP (2015) Genetic susceptibility in children with incomplete Kawasaki disease. Zhongguo Dang Dai Er Ke Za Zhi 17(7):663–667

    CAS  PubMed  Google Scholar 

  79. Lee YC, Kuo HC, Chang JS, Chang LY, Huang LM, Chen MR, Liang CD, Chi H, Huang FY, Lee ML, Huang YC, Hwang B, Chiu NC, Hwang KP, Lee PC, Chang LC, Liu YM, Chen YJ, Chen CH, Taiwan Pediatric ID Alliance, Chen YT, Tsai FJ, Wu JY (2012) Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat Genet 44:522–525

    CAS  PubMed  Google Scholar 

  80. Kuo HC, Chao MC, Hsu YW et al (2012) CD40 gene polymorphisms associated with susceptibility and coronary artery lesions of Kawasaki disease in the Taiwanese population. Sci World J 2012:520865

    Google Scholar 

  81. Chang CJ, Kuo HC, Chang JS et al (2013) Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility. PLoS One 8:e72037

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Onouchi Y, Ozaki K, Burns JC et al (2010) Common variants in CASP3 confer susceptibility to Kawasaki disease. Hum Mol Genet 19:2898–2906

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Tsai FJ, Lee YC, Chang JS, Huang LM, Huang FY, Chiu NC, Chen MR, Chi H, Lee YJ, Chang LC, Liu YM, Wang HH, Chen CH, Chen YT, Wu JY (2011) Identification of novel susceptibility loci for Kawasaki disease in a Han Chinese population by a genome-wide association study. PLoS One 6:e16853

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Peng Q, Chen CH, Wu Q et al (2013) Association of new functional SNP rs72689236 ofCASP3 with Kawasaki disease: a meta-analysis. Zhongguo Dang Dai Er Ke Za Zhi 15:477–483

    CAS  PubMed  Google Scholar 

  85. Choi YM, Shim KS, Yoon KL, Han MY, Cha SH, Kim SK, Jung JH (2012) Transforming growth factor beta receptor II polymorphisms are associated with Kawasaki disease. Korean J Pediatr 55(1):18–23

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kuo HC, Hsu YW, Wu CM et al (2013) A replication study for association of ITPKC and CASP3 two-locus analysis in IVIG unresponsiveness and coronary artery lesion in Kawasaki disease. PLoS One 8:e69685

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kuo HC, Onouchi Y, Hsu YW, Chen WC, Huang JD, Huang YH, Yang YL, Chao MC, Yu HR, Juan YS, Kuo CM, Yang KD, Huang JS, Chang WC (2011) Polymorphisms of transforming growth factor-β signaling pathway and Kawasaki disease in the Taiwanese population. J Hum Genet 56(12):840–845

    CAS  PubMed  Google Scholar 

  88. Peng Q, Deng Y, Yang X et al (2016) Genetic variants of ADAM17 are implicated in the pathological process of Kawasaki disease and secondary coronary artery lesions via the TGF-β/SMAD3 signaling pathway. Eur J Pediatr 175(5):705–713

    CAS  PubMed  Google Scholar 

  89. Shi CP, Zhang HY (2013) Association of single nucleotide polymorphism in TGFBR2 gene with Kawasaki disease and coronary artery lesions. Zhongguo Dang Dai Er Ke Za Zhi 15(9):767–770

    CAS  PubMed  Google Scholar 

  90. Ban JY, Kim SK, Kang SW, Yoon KL, Chung JH (2010) Association between polymorphisms of matrix metalloproteinase 11 (MMP-11) and Kawasaki disease in the Korean population. Life Sci 86:756–759

    CAS  PubMed  Google Scholar 

  91. Park JA, Shin KS, Kim YW (2005) Polymorphism of matrix metalloproteinase-3 promoter gene as a risk factor for coronary artery lesions in Kawasaki disease. J Korean Med Sci 20(4):607–611

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ikeda K, Ihara K, Yamaguchi K, Muneuchi J, Ohno T, Mizuno Y, Hara T (2008) Genetic analysis of MMP gene polymorphisms in patients with Kawasaki disease. Pediatr Res 63(2):182–185

    CAS  PubMed  Google Scholar 

  93. Hong YM, Jin HS, Park IS, Hong SJ (2008) Association of the matrix metalloproteinase-3 (-439C/G) promoter polymorphism with Kawasaki disease in Korean children. Heart Vessel 23:341–347

    Google Scholar 

  94. Kim JJ, Park YM, Yoon D, Lee KY, Seob Song M, Doo Lee H, Kim KJ, Park IS, Nam HK, Weon Yun S, Ki Han M, Mi Hong Y, Young Jang G, Lee JK, Korean Kawasaki Disease Genetics Consortium (2013) Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis. J Hum Genet 58:521–525

    CAS  PubMed  Google Scholar 

  95. Huang YC, Lin YJ, Chang JS et al (2010) Single nucleotide polymorphism rs2229634 in the ITPR3 gene is associated with the risk of developing coronary artery aneurysm in children with Kawasaki disease. Int J Immunogenet 37(6):439–443

    CAS  PubMed  Google Scholar 

  96. Burgner D, Davila S, Breunis WB et al (2009) A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet 5:e1

    Google Scholar 

  97. Kim JJ, Hong YM, Sohn S, Jang GY, Ha KS, Yun SW, Han MK, Lee KY, Song MS, Lee HD, Kim DS, Lee JE, Shin ES, Jang JH, Lee YS, Kim SY, Lee JY, Han BG, Wu JY, Kim KJ, Park YM, Seo EJ, Park IS, Lee JK, Korean Kawasaki Disease Genetics Consortium (2011) A genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for Kawasaki disease. Hum Genet 129(5):487–495

    PubMed  Google Scholar 

  98. Barrett KE, Barman SM, Boitano S et al (2011) Overview of cellular physiology in medical physiology. In: Barrett KE, Barman SM, Boitano S, Brooks H (eds) Ganong’s review of medical physiology

  99. Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5:472–484

    CAS  PubMed  Google Scholar 

  100. Onouchi Y, Tamari M, Takahashi A, Tsunoda T, Yashiro M, Nakamura Y, Yanagawa H, Wakui K, Fukushima Y, Kawasaki T, Nakamura Y, Hata A (2007) A genome-wide linkage analysis for Kawasaki disease: evidence for linkage to chromosome 12. J Hum Genet 52:179–190

    CAS  PubMed  Google Scholar 

  101. Kuo HC, Yang KD, Juo SH et al (2011) ITPKC single nucleotide polymorphism associated with the Kawasaki disease in a Taiwanese population. PLoS One 6:e17370

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Lou J, Xu S, Zou L et al (2012) A functional polymorphism, rs28493229, in ITPKC and risk of Kawasaki disease: an integrated meta-analysis. Mol Biol Rep 39:11137–11144

    CAS  PubMed  Google Scholar 

  103. Kuo HC, Hsu YW, Lo MH et al (2014) Single-nucleotide polymorphism rs7251246 in ITPKC is associated with susceptibility and coronary artery lesions in Kawasaki disease. PLoS One 9:e91118

    PubMed  PubMed Central  Google Scholar 

  104. Ho S, Clipstone N, Timmermann L, Northrop J, Graef I, Fiorentino D, Nourse J, Crabtree GR (1996) The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol 80:S40–S45

    CAS  PubMed  Google Scholar 

  105. McCarl CA, Khalil S, Ma J et al (2010) Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. J Immunol 185:5845–5858

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Sogkas G, Vögtle T, Rau E, Gewecke B, Stegner D, Schmidt RE, Nieswandt B, Gessner JE (2015) ORAI1 controls C5a-induced neutrophil recruitment in inflammation. Eur J Immunol 45:2143–2153

    CAS  PubMed  Google Scholar 

  107. Prakriya M, Feske S, Gwack Y et al (2006) ORAI1 is an essential pore subunit of the CRAC channel. Nature 443:230–233

    CAS  PubMed  Google Scholar 

  108. Wu W, Misra RS, Russell JQ, Flavell RA, Rincón M, Budd RC (2006) Proteolytic regulation of nuclear factor of activated T (NFAT) c2 cells and NFAT activity by caspase-3. J Biol Chem 281:10682–10690

    CAS  PubMed  Google Scholar 

  109. Chang WC, Lee CH, Hirota T et al (2012) ORAI1 genetic polymorphisms associated with the susceptibility of atopic dermatitis in Japanese and Taiwanese populations. PLoS One 7:e29387

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wei JC, Yen JH, Juo SH et al (2011) Association of ORAI1 haplotypes with the risk of HLA-B27 positive ankylosing spondylitis. PLoS One 6:e20426

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Yen JH, Chang CM, Hsu YW et al (2014) A polymorphism of ORAI1 rs7135617 is associated with susceptibility to rheumatoid arthritis. Mediat Inflamm 2014:834831

    Google Scholar 

  112. Chou YH, Juo SH, Chiu YC, Liu ME, Chen WC, Chang CC, Chang WP, Chang JG, Chang WC (2011) A polymorphism of the ORAI1 gene is associated with the risk and recurrence of calcium nephrolithiasis. J Urol 185:1742–1746

    CAS  PubMed  Google Scholar 

  113. Feske S, Gwack Y, Prakriya M et al (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185

    CAS  PubMed  Google Scholar 

  114. Thiha K, Mashimo Y, Suzuki H et al (2019) Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease. J Hum Genet 64:511–519

    CAS  PubMed  Google Scholar 

  115. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Veliçelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Brandman O, Liou J, Park WS, Meyer T (2007) STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131:1327–1339

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Hirota J, Furuichi T, Mikoshiba K (1999) Inositol 1,4,5-trisphosphate receptor type 1 is a substrate for caspase-3 and is cleaved during apoptosis in a caspase-3-dependent manner. J Biol Chem 274:34433–34437

    CAS  PubMed  Google Scholar 

  118. Woo M, Hakem R, Furlonger C, Hakem A, Duncan GS, Sasaki T, Bouchard D, Lu L, Wu GE, Paige CJ, Mak TW (2003) Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity. Nat Immunol 4:1016–1022

    CAS  PubMed  Google Scholar 

  119. Alam A, Cohen LY, Aouad S et al (1999) Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J Exp Med 190:1879–1890

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Kennedy NJ, Kataoka T, Tschopp J, Budd RC (1999) Caspase activation is required for T cell proliferation. J Exp Med 190:1891–1896

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Miossec C, Dutilleul V, Fassy F et al (1997) Evidence for CPP32 activation in the absence of apoptosis during T lymphocyte stimulation. J Biol Chem 272:13459–13462

    CAS  PubMed  Google Scholar 

  122. Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kägi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW, Mak TW (1998) Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev 12:806–819

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Tsujimoto H, Takeshita S, Nakatani K, Kawamura Y, Tokutomi T, Sekine I (2001) Delayed apoptosis of circulating neutrophils in Kawasaki disease. Clin Exp Immunol 126:355–364

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Onouchi Y, Tamari M, Takahashi A, Tsunoda T, Yashiro M, Nakamura Y, Yanagawa H, Wakui K, Fukushima Y, Kawasaki T, Nakamura Y, Hata A (2007) A genome wide linkage analysis of Kawasaki disease: evidence for linkage to chromosome 12. J Hum Genet 52:179–190

    CAS  PubMed  Google Scholar 

  125. Xie X, Shi X, Liu M (2018) The roles of genetic factors in Kawasaki disease: a systematic review and meta-analysis of genetic association studies. Pediatr Cardiol 39:207–225

    PubMed  Google Scholar 

  126. Bewarder N, Weinrich V, Budde P, Hartmann D, Flaswinkel H, Reth M, Frey J (1996) In vivo and in vitro specificity of protein tyrosine kinases for immunoglobulin G receptor (FcgammaRII) phosphorylation. Mol Cell Biol 16:4735–4743

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Tomer Y, Concepcion E, Greenberg DA (2002) A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves’ disease. Thyroid 12:1129–1135

    CAS  PubMed  Google Scholar 

  128. Jacobson EM, Concepcion E, Oashi T, Tomer Y (2005) A Graves’ disease associated Kozak sequence single-nucleotide polymorphism enhances the efficiency of CD40 gene translation: a case for translational pathophysiology. Endocrinology 146:2684–2691

    CAS  PubMed  Google Scholar 

  129. Shimizu C, Eleftherohorinou H, Wright VJ et al (2016) Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities. Circ Cardiovasc Genet 9:559–568

    CAS  PubMed  Google Scholar 

  130. Blackshaw S, Sawa A, Sharp AH, Ross CA, Snyder SH, Khan AA (2000) Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death. FASEB J 14:1375–1379

    CAS  PubMed  Google Scholar 

  131. Oishi T, Iida A, Otsubo S, Kamatani Y, Usami M, Takei T, Uchida K, Tsuchiya K, Saito S, Ohnisi Y, Tokunaga K, Nitta K, Kawaguchi Y, Kamatani N, Kochi Y, Shimane K, Yamamoto K, Nakamura Y, Yumura W, Matsuda K (2008) A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population. J Hum Genet 53:151–162

    CAS  PubMed  Google Scholar 

  132. Gerber JS, Mosser DM (2001) Stimulatory and inhibitory signals originating from the macrophage Fcc receptors. Microbes Infect 3:131–139

    CAS  PubMed  Google Scholar 

  133. Nimmerjahn F, Ravetch JV (2008) Fcγ receptors as regulators of immune responses. Nature Rev Immunol 8:34–47

    CAS  Google Scholar 

  134. Ruiz-Ortega M, Rodriguez-Vita J, Sanchez-Lopez E et al (2007) TGF-beta signaling in vascular fibrosis. Cardiovasc Res 74:196–206

    CAS  PubMed  Google Scholar 

  135. Clark-Greuel JN, Connolly JM, Sorichillo E, Narula NR, Rapoport HS, Mohler ER 3rd, Gorman JH 3rd, Gorman RC, Levy RJ (2007) Transforming growth factor-beta1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. Ann Thorac Surg 83:946–953

    PubMed  Google Scholar 

  136. Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M (2008) SMAD3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 9:194–202

    CAS  PubMed  Google Scholar 

  137. Bujak M, Ren G, Kweon HJ, Dobaczewski M, Reddy A, Taffet G, Wang XF, Frangogiannis NG (2007) Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation 116:2127–2138

    CAS  PubMed  Google Scholar 

  138. Yoon KL (2015) Update of genetic susceptibility in patients with Kawasaki disease. Korean J Pediatr 58:84–88

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Shimizu C, Jain S, Davila S et al (2011) Transforming growth factor-β signaling pathway in patients with Kawasaki disease. Circ Cardiovasc Genet 4:16–25

    CAS  PubMed  Google Scholar 

  140. Cho JH, Han MY, Cha SH et al (2014) Genetic polymorphism of SMAD5 is associated with Kawasaki disease. Pediatr Cardiol 35:601–607

    PubMed  Google Scholar 

  141. Chang M, Jin W, Chang JH et al (2011) The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity. Nat Immunol 12:1002–1009

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Moynagh PN (2009) The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling. Trends Immunol 30:33–42

    CAS  PubMed  Google Scholar 

  143. Lehman TJ, Mahnovski V (1988) Animal models of vasculitis. Lessons we can learn to improve our understanding of Kawasaki disease. Rheum Dis Clin N Am 14:479–487

    CAS  Google Scholar 

  144. Kim JJ, Hong YM, Yun SW, Han MK, Lee KY, Song MS, Lee HD, Kim DS, Sohn S, Ha KS, Hong SJ, Kim KJ, Park IS, Jang GY, Lee JK, Korean Kawasaki Disease Genetics Consortium (2012) Assessment of risk factors for Korean children with Kawasaki disease. Pediatr Cardiol 33:513–520

    PubMed  Google Scholar 

  145. Li N, Timofeyev V, Tuteja D et al (2009) Ablation of a Ca2+-activated K+channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol 587:1087–1100

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Lee JK, Hong YM, Jang GY, Yun SW, Yu JJ, Yoon KL, Lee KY, Kil HR, Korean Kawasaki Disease Genetics Consortium (2015) Consortium-based genetic studies of Kawasaki disease in Korea: Korean Kawasaki disease genetics consortium. Korean Circ J 45:443–448

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We sincerely acknowledge Dr. Jane Burns, Professor and Director, Kawasaki Disease Research Centre, Department of Pediatrics, University of California, San Diego, USA, and Dr. Yoshihiro Onouchi, Associate Professor, Department of Public Health, Chiba University Graduate School of Medicine, Chiba, Japan, for critical review of the manuscript and useful suggestions for the improvement of the manuscript.

Author information

Authors and Affiliations

  1. Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Rajni Kumrah, Pandiarajan Vignesh, Amit Rawat & Surjit Singh

Authors
  1. Rajni Kumrah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pandiarajan Vignesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amit Rawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Surjit Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pandiarajan Vignesh.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumrah, R., Vignesh, P., Rawat, A. et al. Immunogenetics of Kawasaki disease. Clinic Rev Allerg Immunol 59, 122–139 (2020). https://doi.org/10.1007/s12016-020-08783-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-020-08783-9

Keywords

Search

Navigation