Skip to main content
SpringerLink
Log in

Common Variants in the CRP Promoter are Associated with a High C-Reactive Protein Level in Kawasaki Disease

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

Abstract

Kawasaki disease (KD) is an acute self-limiting form of vasculitis that afflicts infants and children and manifests as fever and signs of mucocutaneous inflammation. Children with KD show various laboratory inflammatory abnormalities, such as elevations in their white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). We here performed a genome-wide association study (GWAS) of 178 KD patients to identify the genetic loci that influence 10 important KD laboratory markers: WBC count, neutrophil count, platelet count, CRP, ESR, hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication (p < 1 × 10−5). Of these, only 2 SNPs (rs12068753 and rs4786091) demonstrated a significant association with the CRP level in replication study of 473 KD patients (p < 0.05). The SNP located at the CRP locus (rs12068753) demonstrated the most significant association with CRP in KD patients (beta = 4.73 and p = 1.20 × 10−6 according to the stage 1 GWAS; beta = 3.65 and p = 1.35 × 10−8 according to the replication study; beta = 3.97 and p = 1.11 × 10−13 according to combined analysis) and explained 8.1 % of the phenotypic variation observed. However, this SNP did not demonstrate any significant association with CRP in the general population (beta = 0.37 and p = 0.1732) and only explained 0.1 % of the phenotypic variation in this instance. Furthermore, rs12068753 did not affect the development of coronary artery lesions or intravenous immunoglobulin resistance in KD patients. These results indicate that common variants in the CRP promoter can play an important role in the CRP levels in 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. Beiser AS, Takahashi M, Baker AL, Sundel RP, Newburger JW (1998) A predictive instrument for coronary artery aneurysms in Kawasaki disease. Am J Cardiol 81:1116–1120

    Article  CAS  PubMed  Google Scholar 

  2. Benjamin EJ, Dupuis J, Larson MG, Lunetta KL, Booth SL, Govindaraju DR, Kathiresan S, Keaney JF Jr, Keyes MJ, Lin JP, Meigs JB, Robins SJ, Rong J, Schnabel R, Vita JA, Wang TJ, Wilson PW, Wolf PA, Vasan RS (2007) Genome-wide association with select biomarker traits in the Framingham heart study. BMC Med Genet 8(Suppl 1):S11

    Article  PubMed Central  PubMed  Google Scholar 

  3. Blake GJ, Ridker PM (2001) Novel clinical markers of vascular wall inflammation. Circ Res 89:763–771

    Article  CAS  PubMed  Google Scholar 

  4. Burns JC, Glodé MP (2004) Kawasaki syndrome. Lancet 364:533–554

    Article  PubMed  Google Scholar 

  5. Burns JC, Mason WH, Glode MP, Shulman ST, Melish ME, Meissner C, Bastian J, Beiser AS, Meyerson HM, Newburger JW (1991) Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease. United States Multicenter Kawasaki Disease Study Group. J Pediatr 118:680–686

    Article  CAS  PubMed  Google Scholar 

  6. Cho YS, Chen CS, Hu C, Long J, Ong RTH, Sim X, Takeuchi F, Wu Y, Go MJ, Yamauchi T, Chang YC, Kwak SH, Ma RCW, Yamamoto K, Adair LS, Aung T, Cai Q, Chang LC, Chen YT, Gao Y, Hu FB, Kim HL, Kim S, Kim YJ, Lee JJM, Lee NR, Li Y, Liu JJ, Lu W, Nkamura J, Nakashima E, Ng DPK, Tay WT, Tsai FJ, Wong TY, Yokota M, Zheng W, Zhang R, Wang C, So WY, Ohnaka K, Ikegami H, Hara K, Cho YM, Cho NH, Chang TJ, Bao Y, Hedman AK, Morris AP, McCarthy MI, DIAGRAM Consortium, MuTHER Consortium, Takayanagi R, Park KS, Jia W, Chuang LM, Chan JCN, Maeda S, Kadowski T, Lee JY, Wu JY, Teo YY, Tai ES, Shu XO, Mohlke KL, Kato N, Han BG, Seielstad M (2012) Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 44:67–72

  7. Dajani AS, Taubert KA, Gerber MA, Shulman ST, Ferrieri P, Freed M, Takahashi M, Bierman FZ, Karchmer AW, Wilson W et al (1993) Diagnosis and therapy of Kawasaki disease in children. Circulation 87:1776–1780

    Article  CAS  PubMed  Google Scholar 

  8. Doumatey AP, Chen G, Tekola Ayele F, Zhou J, Erdos M, Shriner D, Huang H, Adeleye J, Balogun W, Fasanmade O, Johnson T, Oli J, Okafor G, Amoah A, Eghan BA, Agyenim-Boateng K, Acheampong J, Adebamowo C, Gerry NP, Christman MF, Adeyemo A, Rotimi CN (2012) C-reactive protein (CRP) promoter polymorphisms influence circulating CRP levels in a genome-wide association study of African Americans. Hum Mol Genet 21:3063–3072

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF, Erdmann J, Braund P, Engert JC, Bennett D, Coin L, Ashby D, Tzoulaki I, Brown IJ, Mt-Isa S, McCarthy MI, Peltonen L, Freimer NB, Farrall M, Ruokonen A, Hamsten A, Lim N, Froguel P, Waterworth DM, Vollenweider P, Waeber G, Jarvelin MR, Mooser V, Scott J, Hall AS, Schunkert H, Anand SS, Collins R, Samani NJ, Watkins H, Kooner JS (2009) Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302:37–48

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Harada K (1991) Intravenous gamma globulin treatment in Kawasaki disease. Acta Paediatr Jpn 33:805–810

    Article  CAS  PubMed  Google Scholar 

  11. Honkanen VE, McCrindle BW, Laxer RM, Feldman BM, Schneider R, Silverman ED (2003) Clinical relevance of the risk factors for coronary artery inflammation in Kawasaki disease. Pediatr Cardiol 24:122–126

    Article  CAS  PubMed  Google Scholar 

  12. Hunter DJ, Altshuler D, Rader DJ (2008) From Darwin’s finches to canaries in the coal mine–mining the genome for new biology. N Engl J Med 358:2760–2763

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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 129:487–495

    Article  PubMed  Google Scholar 

  15. Koren G, Lavi S, Rose V, Rowe R (1986) Kawasaki disease: review of risk factors for coronary aneurysms. J Pediatr 108:388–392

    Article  CAS  PubMed  Google Scholar 

  16. 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, Chen YT, Tsai FJ, Wu JY, Taiwan Pediatric ID Alliance (2012) Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat Genet 44(5):522–525

    Article  CAS  PubMed  Google Scholar 

  17. Melzer D, Perry JR, Hernandez D, Corsi AM, Stevens K, Rafferty I, Lauretani F, Murray A, Gibbs JR, Paolisso G, Rafiq S, Simon-Sanchez J, Lango H, Scholz S, Weedon MN, Arepalli S, Rice N, Washecka N, Hurst A, Britton A, Henley W, van de Leemput J, Li R, Newman AB, Tranah G, Harris T, Panicker V, Dayan C, Bennett A, McCarthy MI, Ruokonen A, Jarvelin MR, Guralnik J, Bandinelli S, Frayling TM, Singleton A, Ferrucci L (2008) A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4:e1000072

    Article  PubMed Central  PubMed  Google Scholar 

  18. Mori M, Imagawa T, Yasui K, Kanaya A, Yokota S (2000) Predictors of coronary artery lesions after intravenous gamma globulin treatment in Kawasaki disease. J Pediatr 137:177–180

    Article  CAS  PubMed  Google Scholar 

  19. Morikawa Y, Ohashi Y, Harada K, Asai T, Okawa S, Nagashima M, Katoh T, Baba K, Furusho K, Okuni M, Osano M (2000) Coronary risks after high dose gamma globulin in children with Kawasaki disease. Pediatr Int 42:464–469

    Article  CAS  PubMed  Google Scholar 

  20. Naitza S, Porcu E, Steri M, Taub DD, Mulas A, Xiao X, Strait J, Dei M, Lai S, Busonero F, Maschio A, Usala G, Zoledziewska M, Sidore C, Zara I, Pitzalis M, Loi A, Virdis F, Piras R, Deidda F, Whalen MB, Crisponi L, Concas A, Podda C, Uzzau S, Scheet P, Longo DL, Lakatta E, Abecasis GR, Cao A, Schlessinger D, Uda M, Sanna S, Cucca F (2012) A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. PLoS Genet 8:e1002480

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. 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

    Article  PubMed  Google Scholar 

  22. Okada Y, Takahashi A, Ohmiya H, Kumasaka N, Kamatani Y, Hosono N, Tsunoda T, Matsuda K, Tanaka T, Kubo M, Nakamura Y, Yamamoto K, Kamatani N (2011) Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus. Hum Mol Genet 20:1224–1231

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Reiner AP, Barber MJ, Guan Y, Ridker PM, Lange LA, Chasman DI, Walston JD, Cooper GM, Jenny NS, Rieder MJ, Durda JP, Smith JD, Novembre J, Tracy RP, Rotter JI, Stephens M, Nickerson DA, Krauss RM (2008) Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet 82:1193–1201

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ridker PM, Pare G, Parker A, Zee RY, Danik JS, Buring JE, Kwiatkowski D, Cook NR, Miletich JP, Chasman DI (2008) Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study. Am J Hum Genet 82:1185–1192

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Ross R (1999) Atherosclerosis–an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  28. Wu Y, McDade TW, Kuzawa CW, Borja J, Li Y, Adair LS, Mohlke KL, Lange LA (2012) Genome-wide association with C-reactive protein levels in CLHNS: evidence for the CRP and HNF1A loci and their interaction with exposure to a pathogenic environment. Inflammation 35:574–583

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all of our patients and their families for participating in this study. This work was supported by a grant from the Ministry of Health & Welfare of the Republic of Korea (Grant No. A010384).

Conflict of interests

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Asan Institute for Life Sciences, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 138-736, Korea

    Jae-Jung Kim & Jong-Keuk Lee

  2. Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea

    Sin Weon Yun

  3. Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Jeong Jin Yu

  4. Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea

    Kyung Lim Yoon

  5. Department of Pediatrics, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Korea

    Kyung-Yil Lee

  6. Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea

    Hong-Ryang Kil

  7. Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea

    Gi Beom Kim

  8. Department of Pediatrics, Gangneung Asan Hospital, University of Ulsan, Gangneung, Korea

    Myung Ki Han

  9. Department of Pediatrics, Inje University Paik Hospital, Busan, Korea

    Min Seob Song

  10. Department of Pediatrics, Pusan National University Hospital, Busan, Korea

    Hyoung Doo Lee

  11. Department of Pediatrics, Korea University Hospital, Seoul, Korea

    Jung Hye Byeon & Gi Young Jang

  12. Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea

    Saejung Sohn & Young Mi Hong

Authors
  1. Jae-Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sin Weon Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeong Jin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyung Lim Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyung-Yil Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong-Ryang Kil
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gi Beom Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Myung Ki Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Min Seob Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hyoung Doo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jung Hye Byeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Saejung Sohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Young Mi Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Gi Young Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jong-Keuk Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Korean Kawasaki Disease Genetics Consortium

Corresponding author

Correspondence to Jong-Keuk Lee.

Additional information

The members of Korean Kawasaki Disease Genetics Consortium are provided in the Appendix.

These authors Young Mi Hong, Gi Young Jang, and Jong-Keuk Lee are equally contributed to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 7977 kb)

Korean Kawasaki Disease Genetics Consortium

Korean Kawasaki Disease Genetics Consortium

Jeong-Jin Yoo, In-Sook Park, 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, Jung-Woo Rhim (Department of Pediatrics, The Catholic University of Korea, 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); Kyung Lim Yoon (Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea); Hong-Ryang Kil (Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea); Gi Beom Kim (Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea); Jae-Moo Lee, Jong-Duk Kim (Seoul Clinical Laboratories, Seoul, Korea).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, JJ., Yun, S.W., Yu, J.J. et al. Common Variants in the CRP Promoter are Associated with a High C-Reactive Protein Level in Kawasaki Disease. Pediatr Cardiol 36, 438–444 (2015). https://doi.org/10.1007/s00246-014-1032-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-014-1032-1

Keywords

Search

Navigation