Pediatric Cardiology

, Volume 40, Issue 3, pp 483–488 | Cite as

Identification of the TIFAB Gene as a Susceptibility Locus for Coronary Artery Aneurysm in Patients with Kawasaki Disease

  • Young-Chang Kwon
  • Jae-Jung Kim
  • Jeong Jin Yu
  • Sin Weon Yun
  • Kyung Lim Yoon
  • Kyung-Yil Lee
  • Hong-Ryang Kil
  • Gi Beom Kim
  • Myung-Ki Han
  • Min Seob Song
  • Hyoung Doo Lee
  • Kee Soo Ha
  • Sejung Sohn
  • Young Mi Hong
  • Gi Young Jang
  • Jong-Keuk LeeEmail author
  • Korean Kawasaki Disease Genetics Consortium
Original Article


Kawasaki disease (KD) is a self-limiting systemic vasculitis of unknown etiology. KD is often complicated by coronary artery aneurysms (CAAs), which develop in about 20–25% of untreated children and 3–5% of children treated with intravenous immunoglobulin therapy. To identify the risk loci for CAA susceptibility in patients with KD, we performed a genome-wide association study (GWAS) using our previous Illumina HumanOmni1-Quad BeadChip data (296 KD patients) and a new replication study in an independent sample set (713 KD patients) by grouping KD patients without CAA (control) versus KD patients with extremely large aneurysms (diameter ≥ 5 mm) (case). Among 44 candidate single -nucleotide polymorphisms (SNPs) selected from the initial GWAS data (33 cases vs. 215 controls), a SNP (rs899162) located 7 kb upstream of the TIFAB gene on chromosome five was replicated in an independent sample (12 cases vs. 532 controls). In the combined analysis (45 cases vs. 747 controls), the SNP (rs899162) showed a highly significant association with CAA formation (diameter ≥ 5 mm) in patients with KD (odds ratio = 3.20, 95% confidence interval = 2.02–5.05, Pcombined = 1.95 × 10−7). These results indicate that the TIFAB gene may act as a CAA susceptibility locus in patients with KD.


Kawasaki disease Coronary artery aneurysm TRAF-interacting protein with FHA domain-containing protein B Single-nucleotide polymorphism Genome-wide association study 



We thank all of our patients and their families for participating in this study. The following authors also participated in this study as members of the Korean Kawasaki Disease Genetics Consortium: In-Sook Park, Soo-Jong Hong, and Kwi-Joo Kim (Department of Pediatrics, Asan Medical Center, Seoul, Korea); Hyo-Kyoung Nam and Jung-Hye Byeon (Department of Pediatrics, Korea University Hospital, Seoul, Korea); Jung-Woo Rhim (Department of Pediatrics, The Catholic University of Korea, St. Mary’s Hospital, Daejeon, Korea); Dong Soo Kim (Department of Pediatrics, Yonsei University College of Medicine, Severance Children’s Hospital, Seoul, Korea); and Jae-Moo Lee and Jong-Duk Kim (Seoul Clinical Laboratories, Seoul, Korea). This study was supported by a Grant from the Ministry of Health and Welfare of the Republic of Korea (HI15C1575).

Compliance with Ethical Standards

Conflict of interest

The authors have no conflict of interest to declare.

Supplementary material

246_2018_1992_MOESM1_ESM.docx (83 kb)
Supplementary material 1 (DOCX 83 KB)
246_2018_1992_MOESM2_ESM.docx (73 kb)
Supplementary material 2 (DOCX 72 KB)


  1. 1.
    McCrindle BW, Rowley AH, Newburger JW et al (2017) Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation 135:e927–e999CrossRefGoogle Scholar
  2. 2.
    Burns JC, Glodé MP (2004) Kawasaki syndrome. Lancet 364:533–544CrossRefGoogle Scholar
  3. 3.
    Burns JC (2007) The riddle of Kawasaki disease. N Engl J Med 356:659–661CrossRefGoogle Scholar
  4. 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. Am Heart Assoc Circ 110(17):2747–2771Google Scholar
  5. 5.
    Kato H, Sugimura T, Akagi T et al (1996) Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 94:1379–1385CrossRefGoogle Scholar
  6. 6.
    Takahashi K, Oharaseki T, Naoe S et al (2005) Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr Int 47:305–310CrossRefGoogle Scholar
  7. 7.
    Brown TJ, Crawford SE, Cornwall ML et al (2001) CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease. J Infect Dis 184:940–943CrossRefGoogle Scholar
  8. 8.
    Yilmaz A, Rowley A, Schulte DJ et al (2007) Activated myeloid dendritic cells accumulate and co-localize with CD3+ T cells in coronary artery lesions in patients with Kawasaki disease. Exp Mol Pathol 83:93–103CrossRefGoogle Scholar
  9. 9.
    Rowley AH, Shulman ST, Mask CA et al (2000) IgA plasma cell infiltration of proximal respiratory tract, pancreas, kidney, and coronary artery in acute Kawasaki disease. J Infect Dis 182:1183–1191CrossRefGoogle Scholar
  10. 10.
    Liang CD, Kuo HC, Yang KD et al (2009) Coronary artery fistula associated with Kawasaki disease. Am Heart J 157:584–588CrossRefGoogle Scholar
  11. 11.
    Ruan Y, Ye B, Zhao X (2013) Clinical characteristics of Kawasaki syndrome and the risk factors for coronary artery lesions in China. Pediatr Infect Dis J 32:e397–e402CrossRefGoogle Scholar
  12. 12.
    Friedman KG, Gauvreau K, Hamaoka Okamoto A et al (2016) Coronary artery aneurysms in Kawasaki disease: risk factors for progressive disease and adverse cardiac events in the US population. J Am Heart Assoc 5:e003289–e003219CrossRefGoogle Scholar
  13. 13.
    Ha KS, Jang G, Lee J et al (2013) Incomplete clinical manifestation as a risk factor for coronary artery abnormalities in Kawasaki disease: a meta-analysis. Eur J Pediatr 172:343–349CrossRefGoogle Scholar
  14. 14.
    Maric LS, Knezovic I, Papic N et al (2015) Risk factors for coronary artery abnormalities in children with Kawasaki disease: a 10-year experience. Rheumatol Int 35:1053–1058CrossRefGoogle Scholar
  15. 15.
    Song D, Yeo Y, Ha K et al (2009) Risk factors for Kawasaki disease-associated coronary abnormalities differ depending on age. Eur J Pediatr 168:1315–1321CrossRefGoogle Scholar
  16. 16.
    Burns JC, Capparelli EV, Brown JA et al (1998) Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group. Pediatr Infect Dis J 17:1144–1148CrossRefGoogle Scholar
  17. 17.
    Callinan LS, Tabnak F, Holman RC et al (2012) Kawasaki syndrome and factors associated with coronary artery abnormalities in California. Pediatr Infect Dis J 31:894–898CrossRefGoogle Scholar
  18. 18.
    Lin YJ, Chang JS, Liu X et al (2015) Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan. Sci Rep 5:14762CrossRefGoogle Scholar
  19. 19.
    Kuo HC, Li SC, Guo MMH et al (2016) Genome-wide association study identifies novel susceptibility genes associated with coronary artery aneurysm formation in Kawasaki disease. PLoS ONE 11:e0154943–e0154916CrossRefGoogle Scholar
  20. 20.
    Kim JJ, Park YM, Yoon D et al (2013) Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis. J Hum Genet 58:521–525CrossRefGoogle Scholar
  21. 21.
    Kim JJ, Yun SW, Yu JJ et al (2017) A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease. J Hum Genet 62:1023–1029CrossRefGoogle Scholar
  22. 22.
    Lee JK, Hong YM, Jang GY et al (2015) Consortium-based genetic studies of Kawasaki disease in Korea: Korean Kawasaki Disease Genetics Consortium. Korean Circ J 45:443–448CrossRefGoogle Scholar
  23. 23.
    Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575CrossRefGoogle Scholar
  24. 24.
    R Core Team (2016) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  25. 25.
    Matsumura T, Semba K, Azuma S et al (2004) TIFAB inhibits TIFA, TRAF-interacting protein with a forkhead-associated domain. Biochem Biophys Res Commun 317(1):230–234CrossRefGoogle Scholar
  26. 26.
    Matsumura T, Kawamura-Tsuzuku J, Yamamoto T et al (2009) TRAF-interacting protein with a forkhead-associated domain B (TIFAB) is a negative regulator of the TRAF6-induced cellular functions. J Biochem 146:375–381CrossRefGoogle Scholar
  27. 27.
    Varney ME, Niederkorn M, Konno H et al (2015) Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med 212:1967–1985CrossRefGoogle Scholar
  28. 28.
    Masuda M, Senju S, Fujii SI et al (2002) Identification and immunocytochemical analysis of DCNP1, a dendritic cell-associated nuclear protein. Biochem Biophys Res Commun 290:1022–1029CrossRefGoogle Scholar
  29. 29.
    Suda K, Kishimoto S, Takahashi T et al (2013) Circulating myeloid dendritic cells is decreased in the acute phase of Kawasaki disease. J Clin Exp Cardiol 4:272Google Scholar
  30. 30.
    Westra HJ, Peters MJ, Esko T et al (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45:1238–1243CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Young-Chang Kwon
    • 1
  • Jae-Jung Kim
    • 1
  • Jeong Jin Yu
    • 2
  • Sin Weon Yun
    • 3
  • Kyung Lim Yoon
    • 4
  • Kyung-Yil Lee
    • 5
  • Hong-Ryang Kil
    • 6
  • Gi Beom Kim
    • 7
  • Myung-Ki Han
    • 8
  • Min Seob Song
    • 9
  • Hyoung Doo Lee
    • 10
  • Kee Soo Ha
    • 11
  • Sejung Sohn
    • 12
  • Young Mi Hong
    • 12
  • Gi Young Jang
    • 11
  • Jong-Keuk Lee
    • 1
    Email author
  • Korean Kawasaki Disease Genetics Consortium
  1. 1.Asan Institute for Life Sciences, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  2. 2.Department of Pediatrics, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  3. 3.Department of PediatricsChung-Ang University HospitalSeoulSouth Korea
  4. 4.Department of PediatricsKyung Hee University Hospital at GangdongSeoulSouth Korea
  5. 5.Department of Pediatrics, Daejeon St. Mary’s HospitalThe Catholic University of KoreaDaejeonSouth Korea
  6. 6.Department of PediatricsChungnam National University HospitalDaejeonSouth Korea
  7. 7.Department of PediatricsSeoul National University Children’s HospitalSeoulSouth Korea
  8. 8.Department of Pediatrics, Gangneung Asan HospitalUniversity of UlsanGangneungSouth Korea
  9. 9.Department of PediatricsInje University Paik HospitalBusanSouth Korea
  10. 10.Department of PediatricsPusan National University HospitalBusanSouth Korea
  11. 11.Department of PediatricsKorea University HospitalSeoulSouth Korea
  12. 12.Department of PediatricsEwha Womans University HospitalSeoulSouth Korea

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