Abstract
Kawasaki disease (KD) is a dominant cause of acquired heart disease in children due to frequent complicating coronary artery lesions (CALs). Genome-wide association study and linkage analysis have recently identified 6 susceptibility loci at genome-wide significance of P < 5.0 × 10−8 in subjects of Japanese, Taiwanese and European. In present study, we analysed the variants of 6 single nucleotide polymorphisms (SNPs) in the genetic loci to investigate their potential effect on KD susceptibility and outcomes in Han Chinese population. As a result, the risk alleles of rs1801274 and rs2254546 were observed significant effect on KD with higher frequencies in 358 patients than those in 815 controls. The significant role of rs1801274, rs2857151 and rs2254546 in KD was found in the multi-variable logistic regression analysis of the SNPs. Two 2-locus and one 3-locus combinations of the SNPs showed significant effect on KD with stronger association with KD relative to comparable single SNP or 2-locus combinations. Significant susceptibility to CALs was found in KD patients with high-risk genotypes at both rs1801274 and rs2857151. The meta-analyses first revealed significant risk for CALs in KD patients carrying risk allele of rs11340705, and the association of rs28493229 with KD was not observed in the Han Chinese. In conclusion, the findings demonstrated that 5 of the 6 genetic loci influence the risk for KD and 3 of them may be involved in secondary CALs formation in Han Chinese. The additive effects of 3 multi-locus combinations on KD/CALs imply that some loci may participate together in certain unknown gene networks related to KD/CALs. Further function studies of the genetic loci are helpful for better understanding the pathophysiology of KD.
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Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y, Asaumi Y, Kitazawa J, Takayanagi H, Penninger JM, Matsumoto M, Nitta T, Takahama Y, Inoue J (2008) The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29(3):423–437. doi:10.1016/j.immuni.2008.06.015
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR,Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T,Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ; NIDDK IBD Genetics Consortium, Libioulle C, Sandor C,Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P,Van Gossum A,Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E;Belgian-French IBD Consortium; Wellcome Trust Case Control Consortium, Cardon LR,Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA,Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ (2008). Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40(8):955–962. doi:10.1038/ng.175
Burgner D, Davila S, Breunis WB, Ng SB, Li Y, Bonnard C, Ling L, Wright VJ, Thalamuthu A, Odam M, Shimizu C, Burns JC, Levin M, Kuijpers TW, Hibberd ML; International Kawasaki Disease Genetics Consortium (2009) A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet 5(1):e1000319. doi:10.1371/journal.pgen.1000319
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(6):1147–1151. doi:10.1093/hmg/ddp586
Cook DH, Antia A, Attie F, Gersony WM, Kamiya T, Kato H, Kusakawa S, Rowe RD, Takao A, Van der Hauwaert L (1989) Results from an international survey of Kawasaki disease in 1979–82. Can J Cardiol 5(8):389–394
Du ZD, Zhao D, Du J, Zhang YL, Lin Y, Liu C, Zhang T, Beijing Kawasaki Research Group (2007) Epidemiologic study on Kawasaki disease in Beijing from 2000 through 2004. Pediatr Infect Dis J 26(5):449–451. doi:10.1097/01.inf.0000261196.79223.18
Dymecki SM, Zwollo P, Zeller K, Kuhajda FP, Desiderio SV (1992) Structure and developmental regulation of the B-lymphoid tyrosine kinase gene blk. J Biol Chem 267(7):4815–4823
Fujita Y, Nakamura Y, Sakata K, Hara N, Kobayashi M, Nagai M, Yanagawa H, Kawasaki T (1989) Kawasaki disease in families. Pediatrics 84(4):666–669
Harley IT, Kaufman KM, Langefeld CD, Harley JB, Kelly JA (2009) Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet 10(5):285–290. doi:10.1038/nrg2571
Hibbs ML, Bonadonna L, Scott BM, McKenzie IFC, Hogarth PM (1988) Molecular cloning of a human immunoglobulin G Fc receptor. Proc Nat Acad Sci 85(7):2240–2244
Huang WC, Huang LM, Chang IS, Chang LY, Chiang BL, Chen PJ, Wu MH, Lue HC, Lee CY, Kawasaki Disease Research Group (2009) Epidemiologic features of Kawasaki disease in Taiwan, 2003–2006. Pediatrics 123(3):e401–e405. doi:10.1542/peds.2008-2187
Iezzi G, Sonderegger I, Ampenberger F, Schmitz N, Marsland BJ, Kopf M (2009) CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells. Proc Natl Acad Sci USA 106(3):876–881. doi:10.1073/pnas.0810769106
Jacobson EM, Huber AK, Akeno N, Sivak M, Li CW, Concepcion E, Ho K, Tomer Y (2007) A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression. Genes Immun 8(3):205–214. doi:10.1038/sj.gene.6364375
Kato H, Koike S, Yamamoto M, Ito Y, Yano E (1975) Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome. J Pediatr 86(6):892–898
Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, Kazue T, Eto G, Yamakawa R (1996) Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 94(6):1379–1385. doi:10.1161/01.CIR.94.6.1379
Kawasaki T (1967) Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi 16(3):178–222
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(12):1241–1246. doi:10.1038/ng.981
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. doi:10.1007/s00439-010-0937-x
Kuo HC, Yu HR, Juo SH, Yang KD, Wang YS, Liang CD, Chen WC, Chang WP, Huang CF, Lee CP, Lin LY, Liu YC, Guo YC, Chiu CC, Chang WC (2011) CASP3 gene single-nucleotide polymorphism (rs72689236) and Kawasaki disease in Taiwanese children. J Hum Genet 56(2):161–165. doi:10.1038/jhg.2010.154
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(5):522–525. doi:10.1038/ng.2227
Li XH, Li XJ, Li H, Xu M, Zhou M (2008) Epidemiological survey of Kawasaki disease in Sichuan province of China. J Trop Pediatr 54(2):133–136. doi:10.1093/tropej/fmm085
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(2):148–152. doi:10.1097/INF.0b013e3181f43a4e
Ma XJ, Yu CY, Huang M, Chen SB, Huang MR, Huang GY, Shanghai Kawasaki Research Group (2010) Epidemiologic features of Kawasaki disease in Shanghai from 2003 through 2007. Chin Med J (Engl) 123(19):2629–2634. doi:10.3760/cma.j.issn.0366-6999.2010.19.002
Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, Aoyama Y, Kotani K, Tsogzolbaatar EO, Yanagawa H (2012) Epidemiologic features of Kawasaki disease in Japan: results of the 2009–2010 nationwide survey. J Epidemiol 22(3):216–221. doi:10.2188/jea.JE20110126
Nemazee D, Weigert M (2000) Revising B cell receptors. J Exp Med 191(11):1813–1817. doi:10.1084/jem.191.11.1813
Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8(1):34–47. doi:10.1038/nri2206
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(1):35–42. doi:10.1038/ng.2007.59
Onouchi Y, Ozaki K, Buns JC, Shimizu C, Hamada H, Honda T, Terai M, Honda A, Takeuchi T, Shibuta S, Suenaga T, Suzuki H, Higashi K, Yasukawa K, Suzuki Y, Sasago K, Kemmotsu Y, Takatsuki S, Saji T, Yoshikawa T, Nagai T, Hamamoto K, Kishi F, Ouchi K, Sato Y, Newburger JW, Baker AL, Shulman ST, Rowley AH, Yashiro M, Nakamura Y, Wakui K, Fukushima Y, Fujino A, Tsunoda T, Kawasaki T, Hata A, Nakamura Y, Tanaka T (2010) Common variants in CASP3 confer susceptibility to Kawasaki disease. Hum Mol Genet 19(14):2898–2906. doi:10.1093/hmg/ddq176
Onouchi Y, Suzuki Y, Suzuki H, Terai M, Yasukawa K, Hamada H, Suenaga T, Honda T, Honda A, Kobayashi H, Takeuchi T, Yoshikawa N, Sato J, Shibuta S, Miyawaki M, Oishi K, Yamaga H, Aoyagi N, Iwahashi S, Miyashita R, Murata Y, Ebata R, Higashi K, Ozaki K, Sasago K, Tanaka T, Hata A (2011) ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease. Pharmacogenomics J. doi:10.1038/tpj.2011.45
Onouchi Y, Ozaki K, Burns JC, Shimizu C, Terai M, Hamada H, Honda T, Suzuki H, Suenaga T, Takeuchi T, Yoshikawa N, Suzuki Y, Yasukawa K, Ebata R, Higashi K, Saji T, Kemmotsu Y, Takatsuki S, Ouchi K, Kishi F, Yoshikawa T, Nagai T, Hamamoto K, Sato Y, Honda A, Kobayashi H, Sato J, Shibuta S, Miyawaki M, Oishi K, Yamaga H, Aoyagi N, Iwahashi S, Miyashita R, Murata Y, Sasago K, Takahashi A, Kamatani N, Kubo M, Tsunoda T, Hata A, Nakamura Y, Tanaka T; Japan Kawasaki Disease Genome Consortium; US Kawasaki Disease Genetics Consortium (2012) A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet 44(5):517–521. doi:10.1038/ng.2220
Park YW, Han JW, Hong YM, Ma JS, Cha SH, Kwon TC, Lee SB, Kim CH, Lee JS, Kim CH (2011) Epidemiological features of Kawasaki disease in Korea, 2006–2008. Pediatr Int 53(1):36–39. doi:10.1111/j.1442-200X.2010.03178.x
Peng Q, Chen C, Zhang Y, He H, Wu Q, Liao J, Li B, Luo C, Hu X, Zheng Z, Yang Y (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(7):1046–1053. doi:10.1007/s00246-012-0223-x
Purcell S, Cherny SS, Sham PC (2003) Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19(1):149–150. doi:10.1093/bioinformatics/19.1.149
Research Committee on Kawasaki Disease (1984) Report of subcommittee on standardization of diagnostic criteria and reporting of coronary artery lesions in Kawasaki Disease. Ministry of Health and Welfare, Tokyo
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(2):e16853. doi:10.1371/journal.pone.0016853
Uehara R, Yashiro M, Nakamura Y, Yanagawa H (2003) Kawasaki disease in parents and children. Acta Paediatr 92(6):694–697. doi:10.1111/j.1651-2227.2003.tb00602.x
Wallace CA, French JW, Kahn SJ, Sherry DD (2000) Initial intravenous gammaglobulin treatment failure in Kawasaki disease. Pediatrics 105(6):E78. doi:10.1542/peds.105.6.e78
Wasserman R, Li YS, Hardy RR (1995) Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. J Immunol 155(2):644–651
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This study was supported by the Health Department Program of Sichuan Province, China (No.120079), and the National Key Technologies R&D Program of China (No. 2006BAI05A10).
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Y. L. Yan and Y. Y. Ma contributed equally to this study and share first authorship.
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Yan, Y., Ma, Y., Liu, Y. et al. Combined analysis of genome-wide-linked susceptibility loci to Kawasaki disease in Han Chinese. Hum Genet 132, 669–680 (2013). https://doi.org/10.1007/s00439-013-1279-2
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DOI: https://doi.org/10.1007/s00439-013-1279-2