Skip to main content
SpringerLink
Log in

Genetic Polymorphism of SMAD5 is Associated With Kawasaki Disease

  • Original Article
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

Mothers against decapentaplegic homolog (SMAD) proteins are intracellular mediators of members of the transforming growth factor-β (TGF-β) superfamily, which are activated by bone morphogenetic proteins (BMPs). On activation, SMAD5 forms heterometric SMAD complexes, which are translated to the nucleus where they regulate gene transcription. TGF-β induces T cell activation and cardiovascular disease, two important features of Kawasaki disease (KD), whereas BMP is associated with coronary artery disease. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) of SMAD5 may be associated with KD and coronary arterial lesions (CALs). Genotyping for 15 SNPs of the SMAD5 gene (rs3764941, rs10085013, rs6596284, rs7356756, rs13179769, rs13166063, rs1109158, rs4585442, rs4146185, rs12719481, rs6865297, rs3206634, rs6871224, rs1057898, and rs7031) was performed by direct sequencing of 105 KD patients and 303 healthy adult controls. We also compared the allele frequencies between a CAL group (n = 31) and a normal coronary group (n = 74). Results showed that among the 15 SNPs, rs3206634 was significantly associated with KD in a recessive model (odds ratio = 2.31, p = 0.019), whereas there was no association between any of the 15 SNPs and CALs. These findings may be used as a risk factors development of KD or for future generations of therapeutic treatments for 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

Similar content being viewed by others

References

  1. Andrabi S, Bekheirnia MR, Robbins-Furman P, Lewis RA, Prior TW, Potocki L (2011) SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction. Am J Med Genet A 155A:1165–1169

    Article  PubMed  Google Scholar 

  2. Arj-Ong S, Thakkinstian A, McEvoy M, Attia J (2010) A systematic review and meta-analysis of tumor necrosis factor α-308 polymorphism and Kawasaki disease. Pediatr Int 52:527–532

    Article  PubMed  Google Scholar 

  3. Arjunan K, Daniels SR, Meyer RA, Schwartz DC, Barron H, Kaplan S (1986) Coronary artery caliber in normal children and patients with Kawasaki disease but without aneurysms: an echocardiographic and angiographic study. J Am Coll Cardiol 8:1119–1124

    Article  CAS  PubMed  Google Scholar 

  4. Attisano L, Lee-Hoeflich ST (2001) The SMADS. Genome Biol 2:REVIEWS3010

  5. Bharathy S, Xie W, Yingling JM, Reiss M (2008) Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-SMADs and invasive phenotype. Cancer Res 68:1656–1666

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Burgner D, Davila S, Breunis WB, Ng SB, Li Y, Bonnard C et al (2009) A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet. doi:10.1371/journal.pgen.1000319

    PubMed Central  PubMed  Google Scholar 

  7. Burns JC, Kushner HI, Bastian JF, Shike H, Shimizu C, Matsubara T et al (2000) Kawasaki disease: a brief history. Pediatrics 06:E27

    Article  Google Scholar 

  8. Burns JC, Shimizu C, Gonzalez E, Kulkarni H, Patel S, Shike H et al (2005) Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease. J Infect Dis 192:344–349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Chu MP, Wang D, Zhang YY, Li BQ, Zhou AH, Chen XW et al (2012) Pachyman treatment improves CD4+CD25+Treg counts and serum interleukin 4 and interferon γ levels in a mouse model of Kawasaki disease. Mol Med Rep 5(5):1237–1240

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  12. Euler-Taimor G, Heger J (2006) The complex pattern of SMAD signaling in the cardiovascular system. Cardiovasc Res 69:15–25

    Article  CAS  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  14. Huang FY, Chang TY, Chen MR, Chiu NC, Chi H, Lee HC et al (2008) Genetic polymorphisms in the CD40 ligand gene and Kawasaki disease. J Clin Immunol 28:405–410

    Article  CAS  PubMed  Google Scholar 

  15. Huang WC, Huang LM, Chang IS, Chang LY, Chiang BL, Chen PJ et al (2009) Epidemiologic features of Kawasaki disease in Taiwan, 2003–2006. Pediatrics 123:e401–e405

    Article  PubMed  Google Scholar 

  16. Kariyazono H, Ohno T, Khjoee V, Ihara K, Kusuhara K, Kinukawa N et al (2004) Association of vascular endothelial growth factor (VEGF) and VEGF receptor gene polymorphism with coronary artery lesions of Kawasaki disease. Pediatr Res 56:953–959

    Article  CAS  PubMed  Google Scholar 

  17. Kuo HC, Onouchi Y, Hsu YW, Chen WC, Huang JD, Huang YH et al (2011) Polymorphisms of transforming growth factor-β signaling pathway and Kawasaki disease in the Taiwanese population. J Hum Genet 56:840–845

    Article  CAS  PubMed  Google Scholar 

  18. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H et al (2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355:788–798

    Article  CAS  PubMed  Google Scholar 

  19. Miyazono K, Kamiya Y, Morikawa M (2010) Bone morphogenetic protein receptors and signal transduction. J Biochem 147:35–51

    Article  CAS  PubMed  Google Scholar 

  20. Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, Aoyama Y et al (2012) Epidemiologic features of Kawasaki disease in Japan: results of the 2009–2010 nationwide survey. J Epidemiol 22:216–221

    Article  PubMed Central  PubMed  Google Scholar 

  21. Newburger JW, Burns JC (1999) Kawasaki disease. Vasc Med 4:187–202

    Article  CAS  PubMed  Google Scholar 

  22. Onouchi Y (2012) Genetics of Kawasaki disease: what we know and don’t know. Circ J 76:1581–1586

    Article  CAS  PubMed  Google Scholar 

  23. Onouchi Y, Gunji T, Burns JC, Shimizu C, Newburger JW, Yashiro M et al (2008) ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet 40:35–42

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E et al (2005) Mutations in transforming growth factor-β receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 112:513–520

    Article  CAS  PubMed  Google Scholar 

  25. Park YW, Han JW, Hong YM, Ma JS, Cha SH, Kwon TC et al (2011) Epidemiological features of Kawasaki disease in Korea, 2006–2008. Pediatr Int 53:36–39

    Article  PubMed  Google Scholar 

  26. Robinson PN, Arteaga-Solis E, Baldock C, Collod-Béroud G, Booms P, De Paepe A et al (2006) The molecular genetics of Marfan syndrome and related disorders. J Med Genet 43:769–787

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Ruiz-Ortega M, Rodríguez-Vita J, Sanchez-Lopez E, Carvajal G, Egido J (2007) TGF-beta signaling in vascular fibrosis. Cardiovasc Res 74:196–206

    Article  CAS  PubMed  Google Scholar 

  28. Shimizu C, Jain S, Davila S, Hibberd ML, Lin KO, Molkara D et al (2011) Transforming growth factor-beta signaling pathway in patients with Kawasaki disease. Circ Cardiovasc Genet 4:16–25

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Shirakawa T, Ikeda K, Nishimura S, Kuniba H, Nakashima K, Motomura H et al (2012) Lack of an association between E-selectin gene polymorphisms and risk of Kawasaki disease. Pediatr Int 54:455–460

    Article  CAS  PubMed  Google Scholar 

  30. Simonini G, Corinaldesi E, Massai C, Falcini F, Fanti F, De Martino M et al (2009) Macrophage migration inhibitory factor-173 polymorphism and risk of coronary alterations in children with Kawasaki disease. Clin Exp Rheumatol 27:1026–1030

    CAS  PubMed  Google Scholar 

  31. SMAD5 (http://www.ncbi.nlm.nih.gov/gene/4090)

  32. Sun Y, Zhou J, Liao X, Lü Y, Deng C, Huang P et al (2005) Disruption of SMAD5 gene induces mitochondria-dependent apoptosis in cardiomyocytes. Exp Cell Res 306:85–93

    Article  CAS  PubMed  Google Scholar 

  33. Tsuda E, Matsuo M, Naito H, Noguchi T, Nonogi H, Echigo S (2007) Clinical features in adults with coronary arterial lesions caused by presumed Kawasaki disease. Cardiol Young 17:84–89

    Article  PubMed  Google Scholar 

  34. Umans L, Cox L, Tjwa M, Bito V, Vermeire L, Laperre K et al (2007) Inactivation of SMAD5 in endothelial cells and smooth muscle cells demonstrates that SMAD5 is required for cardiac homeostasis. Am J Pathol 170:1460–1472

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Van de Laar I, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM et al (2011) Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 43:121–126

    Article  PubMed  Google Scholar 

  36. Wang CL, Wu YT, Liu CA, Kuo HC, Yang KD (2005) Kawasaki disease: infection, immunity and genetics. Pediatr Infect Dis J 24:998–1004

    Article  PubMed  Google Scholar 

  37. Wu SF, Chang JS, Peng CT, Shi YR, Tsai FJ (2004) Polymorphism of angiotensin-1 converting enzyme gene and Kawasaki disease. Pediatr Cardiol 25:529–533

    Article  PubMed  Google Scholar 

  38. Yasukawa K, Terai M, Shulman ST, Toyozaki T, Yajima S, Kohno Y et al (2002) Systemic production of vascular endothelial growth factor and fms-like tyrosine kinase-1 receptor in acute Kawasaki disease. Circulation 105:766–769

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the program of Kyung Hee University for young medical researchers in 2008 (KHU-20081238).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gandong-gu, Seoul, 137-727, Korea

    Ja Hyang Cho & Kyung Lim Yoon

  2. Department of Pediatrics, Kyung Hee University Medical Center, Seoul, Korea

    Mi Young Han & Sung Ho Cha

  3. Department of Clinical Pharmacology, Kyung Hee University School of Medicine, Seoul, Korea

    Joo Ho Jung

Authors
  1. Ja Hyang Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mi Young Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sung Ho Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joo Ho Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyung Lim Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyung Lim Yoon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, J.H., Han, M.Y., Cha, S.H. et al. Genetic Polymorphism of SMAD5 is Associated With Kawasaki Disease. Pediatr Cardiol 35, 601–607 (2014). https://doi.org/10.1007/s00246-013-0826-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-013-0826-x

Keywords

Search

Navigation