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Association of SNP (rs1042579) in thrombomodulin gene and plasma thrombomodulin level in North Indian children with Kawasaki disease

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Abstract

Background

Kawasaki disease (KD) is the commonest systemic vasculitis in children. It predisposes to development of coronary artery abnormalities (CAAs). Thrombomodulin (THBD) gene polymorphism rs1042579 is associated with high risk of cerebrovascular diseases. However, association of THBD polymorphism (rs1042579) and plasma thrombomodulin (TM) levels with susceptibility to KD and CAAs remains unclear.

Methods and results

Polymorphism in THBD gene (rs1042579) was analysed in 50 KD patients and 50 age, gender and ethnicity matched controls using Sanger sequencing. Plasma TM levels were measured by ELISA.

Results

Mean plasma TM level (± SD) in KD patients was 2549.41 (± 853.18) pg/ml and in controls was 2298.03 (± 869.14) pg/ml; p = 0.042. Mean plasma TM levels in CC genotype was 2299.98 (± 834.88) pg/ml and in CT/TT genotype was 2837.96 (± 857.14) pg/ml; p = 0.005. Genotyping data did not reveal significant differences in patients with KD as compared to controls (p = 0.25), and in KD patients with and without CAAs (p = 0.407). Odds of finding T allele in cases were 2.07 times greater than in controls (p = 0.093).

Conclusions

This is the first study from India, and second in the world, that investigates association of THBD gene polymorphism with KD. This is also the first study to assess plasma TM levels in KD patients. Our data show that plasma TM levels were significantly higher in KD patients with CT/TT genotypes. Further, the polymorphism rs1042579 at exon 1 of THBD gene was found to be more common in KD patients than in controls although the difference was not statistically significant.

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References

  1. Sundel R, Petty RE (2016) Kawasaki disease. In: Petty RE, Lindsley CB, Laxer RM, Wedderburn L (eds) Cassidy’s textbook of pediatric rheumatology, 7th edn. Elsevier, Philadelphia

    Google Scholar 

  2. 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–e999

    Article  Google Scholar 

  3. Burgner D, Harnden A (2005) Kawasaki disease: what is the epidemiology telling us about the etiology? Int J Infect Dis 9:185–194

    Article  Google Scholar 

  4. Makino N, Nakamura Y, Yashiro M et al (2015) Descriptive epidemiology of Kawasaki disease in Japan, 2011–2012: from the results of the 22nd Nationwide Survey. J Epidemiol 25:239–245

    Article  Google Scholar 

  5. Holman RC, Belay ED, Christensen KY et al (2010) Hospitalizations for Kawasaki syndrome among children in the United States, 1997–2007. Pediatr Infect Dis J 29:483–488

    Article  Google Scholar 

  6. Holman RC, Christensen KY, Belay ED et al (2010) Racial/ethnic differences in the incidence of Kawasaki syndrome among children in Hawai‘i. Hawaii Med J 69(8):194–197

    PubMed  PubMed Central  Google Scholar 

  7. Singh S, Vignesh P, Burgner D (2015) The epidemiology of Kawasaki disease: a global update. Arch Dis Child 100:1084–1088

    Article  Google Scholar 

  8. Uehara R, Yashiro M, Nakamura Y et al (2011) Parents with a history of Kawasaki disease whose child also had the same disease. Pediatr Int 53:511–514

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Shimizu C, Oharaseki T, Takahashi K et al (2013) The role of TGF- β and myofibroblasts in the arteritis of Kawasaki disease. Hum Pathol 44:189–198

    Article  CAS  Google Scholar 

  11. Esmon CT (1989) The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 264:4743–4746

    Article  CAS  Google Scholar 

  12. Salomaa V, Matei C, Aleksic N et al (1999) Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities [ARIC] Study: a case-cohort study. Lancet 353:1729–1734

    Article  CAS  Google Scholar 

  13. Li Y-H, Chen J-H, Tsai W-C et al (2002) Synergistic effect of thrombomodulin promoter -33G/A polymorphism and smoking on the onset of acute myocardial infarction. Thromb Haemost 87:86–91

    Article  CAS  Google Scholar 

  14. Dogra R, Das R, Ahluwalia J et al (2013) Association of thrombomodulin gene polymorphisms and plasma thrombomodulin levels with acute myocardial infarction in north Indian patients. Clin Appl Thromb Hemost 19:637–643

    Article  CAS  Google Scholar 

  15. Shah SA, Ashavaid TF, Mankeshwar R et al (2012) Role of thrombomodulin gene in Indian population with coronary artery disease. Biomarkers 17:610–617

    Article  CAS  Google Scholar 

  16. Zhang S, Zhang Z, Zhang F et al (2014) Association between thrombomodulin polymorphisms and coronary artery disease risk: a meta-analysis. Med Sci Monit 20(1407–12):37

    CAS  Google Scholar 

  17. Wang H, Dong P (2015) Thrombomodulin -33G/A and Ala455Val polymorphisms are associated with the risk of coronary artery disease: a meta-analysis including 12 584 patients. Coron Artery Dis 26:72–77

    Article  Google Scholar 

  18. Xu J, Jin J, Tan S (2016) Association of thrombomodulin gene polymorphisms with susceptibility to atherosclerotic diseases: a meta-analysis. Ann Hum Genet 80:172–181

    Article  CAS  Google Scholar 

  19. Lu Y, Liu R, Zha L et al (2018) Association of thrombomodulin gene C1418T polymorphism with susceptibility to Kawasaki disease in Chinese children. Dis Markers 2018:1064380

    PubMed  PubMed Central  Google Scholar 

  20. Onouchi Y (2009) Molecular genetics of Kawasaki disease. Pediatr Res 65(5 Pt 2):46R-54R

    Article  Google Scholar 

  21. Onouchi Y, Suzuki Y, Suzuki H et al (2013) ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease. Pharmacogenomics J 13:52–59

    Article  CAS  Google Scholar 

  22. Chi H, Huang F-Y, Chen M-R et al (2010) ITPKC gene SNP rs28493229 and Kawasaki disease in Taiwanese children. Hum Mol Genet 19:1147–1151

    Article  CAS  Google Scholar 

  23. Peng Q, Chen C, Zhang Y et al (2012) Single-nucleotide polymorphism rs2290692 in the 3’UTR of ITPKC associated with susceptibility to Kawasaki disease in a Han Chinese population. Pediatr Cardiol 33:1046–1053

    Article  Google Scholar 

  24. Kuo H-C, Lin Y-J, Juo S-HH et al (2011) Lack of association between ORAI1/CRACM1 gene polymorphisms and Kawasaki disease in the Taiwanese children. J Clin Immunol 31:650–655

    Article  CAS  Google Scholar 

  25. 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 American Heart Association. Circulation 110:2747–2771

    Article  Google Scholar 

  26. Dallaire F, Dahdah N (2011) New equations and a critical appraisal of coronary artery Z scores in healthy children. J Am Soc Echocardiogr 24:60–74

    Article  Google Scholar 

  27. Kushner HI, Macnee R, Burns JC (2006) Impressions of Kawasaki syndrome in India. Indian Pediatr 43:939–942

    PubMed  Google Scholar 

  28. Singh S, Bansal A, Gupta A, Kumar RM, Mittal BR (2005) Kawasaki disease: a decade of experience from North India. Int Heart J 46(4):679–689. https://doi.org/10.1536/ihj.46.679

    Article  PubMed  Google Scholar 

  29. Singh S, Aulakh R (2010) Kawasaki disease and Henoch Schonlein purpura: changing trends at a tertiary care hospital in north India (1993–2008). Rheumatol Int 30(6):771–774. https://doi.org/10.1007/s00296-009-1065-6

    Article  PubMed  Google Scholar 

  30. Singh S, Bhattad S (2016) Kawasaki disease incidence at Chandigarh, North India, during 2009–2014. Rheumatol Int 36(10):1391–1397. https://doi.org/10.1007/s00296-016-3543-y

    Article  PubMed  Google Scholar 

  31. Jindal AK, Pilania RK, Guleria S, Vignesh P, Suri D, Gupta A, Singhal M, Rawat A, Singh S (2020) Kawasaki disease in children older than 10 years: a clinical experience from Northwest India. Front Pediatr 8:24. https://doi.org/10.3389/fped.2020.00024

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kumrah R, Vignesh P, Rawat A, Singh S (2020) Immunogenetics of Kawasaki disease. Clin Rev Allergy Immunol 59(1):122–139. https://doi.org/10.1007/s12016-020-08783-9

    Article  PubMed  Google Scholar 

  33. Loghmani H, Conway EM (2018) Exploring traditional and nontraditional roles for thrombomodulin. Blood 132(2):148–158. https://doi.org/10.1182/blood-2017-12-768994

    Article  CAS  PubMed  Google Scholar 

  34. Taylor FB, Stearns-Kurosawa DJ, Kurosawa S et al (2000) The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 95:1680–1686

    Article  CAS  Google Scholar 

  35. Ishii H, Majerus PW (1985) Thrombomodulin is present in human plasma and urine. J Clin Invest 76(6):2178–2181

    Article  CAS  Google Scholar 

  36. Nakagawa I, Matsubara T, Hori T et al (2001) Significance of soluble thrombomodulin in the coronary circulation of patients with coronary artery disease. J Cardiol 38:145–152

    CAS  PubMed  Google Scholar 

  37. Alkhiary W, Abdalaal M, Mohamed E-S (2018) The relation of thrombomodulin G33A and C1418T gene polymorphisms to the risk of acute myocardial infarction in Egyptians. Egypt J Med Hum Genet 19(1):19–22

    Article  Google Scholar 

  38. Wu KK, Aleksic N, Ahn C et al (2001) Thrombomodulin Ala455Val polymorphism and risk of coronary heart disease. Circulation 103:1386–1389

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Indian Council of Medical Research (ICMR) thesis grant for partially funding the study vide letter no. 3/2/March-2019/PG-Thesis-HRD.

Funding

This study was partially funded by Indian Council of Medical Research (ICMR) thesis grant vide letter no. 3/2/March-2019/PG-Thesis-HRD.

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Authors and Affiliations

  1. Allergy Immunology Unit, Post Graduate Institute of Medical Education & Research, PGIMER, Chandigarh, 160012, India

    Ankita Singh, Amit Rawat, Anit Kaur, Rajni Kumrah, Nameirakpam Johnson, Himanshi Chaudhary, Rakesh Kumar Pilania & Surjit Singh

  2. Genetic Metabolic Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education & Research, PGIMER, Chandigarh, 160012, India

    Anupriya Kaur & Priyanka Srivastava

Authors
  1. Ankita Singh
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  2. Amit Rawat
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  4. Anupriya Kaur
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  10. Surjit Singh
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by AS, AR, AK and SS. The first draft of the manuscript was written by AS, PS, SS and all authors were involved in editing and revising the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Priyanka Srivastava.

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Conflict of interest

Authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The study protocol was approved by Thesis Committee and Ethics Committee of Postgraduate Institute of Medical Education and Research, Chandigarh, India (Approval no. INT/IEC/2018/001941). The manuscript has been approved by Departmental Review Board (DRB-27-21).

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Written informed consent was obtained from the parents.

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Singh, A., Rawat, A., Kaur, A. et al. Association of SNP (rs1042579) in thrombomodulin gene and plasma thrombomodulin level in North Indian children with Kawasaki disease. Mol Biol Rep 49, 7399–7407 (2022). https://doi.org/10.1007/s11033-022-07533-8

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  • DOI: https://doi.org/10.1007/s11033-022-07533-8

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