Abstract
Kawasaki disease (KD) is an acute self-limited vasculitis of infants and children that manifests as fever and signs of mucocutaneous inflammation. Coronary artery aneurysms develop in approximately 15–25% of untreated children. Although the etiology of KD is largely unknown, epidemiologic data suggest the importance of genetic factors in the susceptibility to KD. In order to identify genetic variants that influence KD susceptibility, we performed a genome-wide association study (GWAS) using Affymetrix SNP array 6.0 in 186 Korean KD patients and 600 healthy controls; 18 and 26 genomic regions with one or more sequence variants were associated with KD and KD with coronary artery lesions (CALs), respectively (p < 1 × 10−5). Of these, one locus on chromosome 1p31 (rs527409) was replicated in 266 children with KD and 600 normal controls (odds ratio [OR] = 2.90, 95% confidence interval [CI] = 1.85–4.54, P combined = 1.46 × 10−6); and a PELI1 locus on chromosome 2p13.3 (rs7604693) was replicated in 86 KD patients with CALs and 600 controls (OR = 2.70, 95% CI = 1.77–4.12, P combined = 2.00 × 10−6). These results implicate a locus in the 1p31 region and the PELI1 gene locus in the 2p13.3 region as susceptibility loci for KD and CALs, respectively.
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Abbreviations
- CAL:
-
Coronary artery lesion
- CI:
-
Confidence interval
- GWAS:
-
Genome-wide association study
- HWE:
-
Hardy–Weinberg equilibrium
- IBS:
-
Identity-by-state
- KD:
-
Kawasaki disease
- KKDGC:
-
Korean Kawasaki Disease Genetics Consortium
- LD:
-
Linkage disequilibrium
- MAF:
-
Minor allele frequency
- nsSNP:
-
Nonsynonymous SNP
- OR:
-
Odds ratio
- SNP:
-
Single nucleotide polymorphism
References
Björkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT, Freeman MW (2004) Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 10:416–421
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:e1000319
Burns JC, Glodé MP (2004) Kawasaki syndrome. Lancet 364:533–554
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 Taiwan children. Hum Mol Genet 19:1147–1151
Durongpisitkul K, Gururaj VJ, Park JM, Martin CF (1995) The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 96:1057–1061
Fujita Y, Nakamura Y, Sakata K, Hara N, Kobayashi M, Nagai M, Yanagawa H, Kawasaki T (1989) Kawasaki disease in families. Pediatrics 84:666–669
Harada F, Sada M, Kamiya T, Yanase Y, Kawasaki T, Sasazuki T (1986) Genetic analysis of Kawasaki syndrome. Am J Hum Genet 39:537–539
Hollestelle SC, De Vries MR, Van Keulen JK, Schoneveld AH, Vink A, Strijder CF, Van Middelaar BJ, Pasterkamp G, Quax PH, De Kleijn DP (2004) Toll-like receptor 4 is involved in outward arterial remodeling. Circulation 109:393–398
Holman RC, Curns AT, Belay ED, Steiner CA, Schonberger LB (2003) Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics 112:495–501
Holman RC, Curns AT, Belay ED, Steiner CA, Effler PV, Yorita KL, Miyamura J, Forbes S, Schonberger LB, Melish M (2005) Kawasaki syndrome in Hawaii. Pediatr Infect Dis J 24:429–433
Huang Y, Shah V, Liu T, Keshvara L (2005) Signaling through disabled 1 requires phosphoinositide binding. Biochem Biophys Res Commun 331:1460–1468
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 10–21-year follow-up study of 594 patients. Circulation 94:1379–1385
Lee KY, Han JW, Lee JS (2007) Kawasaki disease may be a hyperimmune reaction of genetically-susceptible children to variants of normal environmental flora. Med Hypotheses 69:642–651
Lehman TJ, Mahnovski V (1988) Animal models of vasculitis. Lessons we can learn to improve our understanding of Kawasaki disease. Rheum Dis Clin North Am 14:479–487
Michelsen KS, Doherty TM, Shah PK, Arditi M (2004a) TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol 173:5901–5907
Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004b) Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci USA 101:10679–10684
Moynagh PN (2009) The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling. Trends Immunol 30:33–42
Nakamura Y, Yashiro M, Uehara R, Oki I, Kayaba K, Yanagawa H (2008) Increasing incidence of Kawasaki disease in Japan: nationwide survey. Pediatr Int 50:287–290
Newburger JW, Fulton DR (2004) Kawasaki disease. Curr Opin Pediatr 16:508–514
Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, Glode MP, Mason WH, Reddy V, Sanders SP et al (1986) The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 315:341–347
Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics (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
Nickerson DA, Tobe VO, Taylor SL (1997) PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res 25:2745–2751
Nigro V, Okazaki Y, Belsito A, Piluso G, Matsuda Y, Politano L, Nigro G, Ventura C, Molinari AM, Acampora D, Nishimura M, Hayashizaki Y, Puca GA (1997) Identification of the Syrian hamster cardiomyopathy gene. Hum Mol Genet 6:601–607
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
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 19:2898–2906
Park YW, Han JW, Park IS, Kim CH, Cha SH, Ma JS, Lee JS, Kwon TC, Lee SB, Kim CH, Lee HJ, Yun YS (2007) Kawasaki disease in Korea, 2003–2005. Pediatr Infect Dis J 26:821–823
Park YW, Han JW, Hong YM, Ma JS, Cha SH, Kwon TC, Lee SB, Kim CH, Lee JS, Kim CH (2010) Epidemiological Features of Kawasaki disease in Korea, 2006–2008. Pediatr Int. doi:10.1111/j.1442-200X.2010.03178.x
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Rosenkranz ME, Schulte DJ, Agle LM, Wong MH, Zhang W, Ivashkiv L, Doherty TM, Fishbein MC, Lehman TJ, Michelsen KS, Arditi M (2005) TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease. Circulation 112:2966–2973
Rowley AH, Shulman ST, Spike BT, Mask CA, Baker SC (2001) Oligoclonal IgA response in the vascular wall in acute Kawasaki disease. J Immunol 166:1334–1343
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386
Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16:3–9
Uehara R, Yashiro M, Nakamura Y, Yanagawa H (2003) Kawasaki disease in parents and children. Acta Paediatr 92:694–697
Acknowledgments
We thank all patients with Kawasaki disease and their families for participating in this study. We also thank Dr. Kyunga Kim and Dr. Sang-Hoon Moon for statistical and bioinformatics support, respectively. This work was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (A010384).
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The authors declare no conflict of interest.
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Details of the Korean Kawasaki Disease Genetics Consortium are given in the Appendix.
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Appendix: Korean Kawasaki Disease Genetics Consortium
Appendix: Korean Kawasaki Disease Genetics Consortium
In-Sook Park, Jeong-Jin Yoo, Soo-Jong Hong, Kwi-Joo Kim (Department of Pediatrics, Asan Medical Center, Seoul, Korea); Jong-Keuk Lee, Jae-Jung Kim, Young-Mi Park (Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea); Young Mi Hong, Saejung Sohn (Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea); Gi Young Jang, Kee-Soo Ha, Hyo-Kyoung Nam, Jung-Hye Byeon (Department of Pediatrics, Korea University Hospital, Seoul, Korea); Sin Weon Yun (Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea); Myung Ki Han (Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea); Kyung-Yil Lee, Ja-Young Hwang, Jung-Woo Rhim (Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary’s Hospital, Daejeon, Korea); Min Seob Song (Department of Pediatrics, Inje University Paik Hospital, Busan, Korea); Hyoung Doo Lee (Department of Pediatrics, Pusan National University Hospital, Busan, Korea); Dong Soo Kim (Department of Pediatrics, Yonsei University College of Medicine, Severance Children’s Hospital, Seoul, Korea); Jae-Moo Lee (Seoul Clinical Laboratories, Seoul, Korea).
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Kim, JJ., Hong, Y.M., Sohn, S. et al. A genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for Kawasaki disease. Hum Genet 129, 487–495 (2011). https://doi.org/10.1007/s00439-010-0937-x
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DOI: https://doi.org/10.1007/s00439-010-0937-x