Skip to main content
SpringerLink
Log in

Association of PON1 genotype and haplotype with susceptibility to coronary artery disease and clinical outcomes in dual antiplatelet-treated Han Chinese patients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to evaluate the association of PON1 genetic variants with the susceptibility to coronary artery disease (CAD) and with the clinical endpoints in aspirin and clopidogrel (dual antiplatelet therapy)-treated Han Chinese patients with CAD after percutaneous coronary intervention (PCI).

Methods

A total of 538 Han Chinese patients undergoing PCI and receiving dual-antiplatelet therapy were sequentially recruited to the study and followed for up to 1 year. Healthy controls (n = 539) were enrolled during the same period. All study participants were genotyped for five genetic variants in PON1 and the cytochrome P450 2C19*2 mutation (CYP2C19*2). The effect of genetic variants on disease risk and clinical outcome of major adverse cardiac events (MACE) within 1 year or bleeding within 6 months was assessed.

Results

CYP2C19*2 was associated with a higher risk of MACE (adjusted P = 0.0098), but a lower risk of bleeding events (adjusted P = 0.0016). The PON1 Q192R polymorphism was significantly associated with a lower risk of bleeding events [odds ratio (OR) 0.61, 95% confidence interval (CI) 0.43–0.87, adjusted P = 0.0066). The haplotype bearing the PON1 -126C allele was associated with a higher risk to CAD (OR 1.48, 95% CI 1.04–2.09, P = 0.029) and a higher risk of bleeding events (OR 1.68, 95% CI 1.10–2.56, P = 0.017) compared to the most frequent haplotype. The transcription activity of haplotype p-162A-126C-108C in the PON1 promoter was 2.6-fold higher than that of the most frequent haplotype (p-162G-126G-108T).

Conclusions

Based on these results, we suggest that the haplotype-bearing PON1 -126C allele contributes to the disease risk and the risk of bleeding events in dual antiplatelet-treated CAD patients after PCI.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, Fu X, Shao M, Brennan DM, Ellis SG, Brennan ML, Allayee H, Lusis AJ, Hazen SL (2008) Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 299:1265–1276

    Article  PubMed  CAS  Google Scholar 

  2. Gupta N, Binu KB, Singh S, Maturu NV, Sharma YP, Bhansali A, Gill KD (2012) Low serum PON1 activity: an independent risk factor for coronary artery disease in North-West Indian type 2 diabetics. Gene 498:13–19

    Article  PubMed  CAS  Google Scholar 

  3. Mohamed RH, Karam RA, Abd El-Aziz TA (2010) The relationship between paraoxonase1-192 polymorphism and activity with coronary artery disease. Clin Biochem 43:553–558

    Article  PubMed  CAS  Google Scholar 

  4. Dunet V, Ruiz J, Allenbach G, Izzo P, James RW, Prior JO (2011) Effects of paraoxonase activity and gene polymorphism on coronary vasomotion. EJNMMI Res 1:27

    Article  PubMed  Google Scholar 

  5. Gupta N, Singh S, Maturu VN, Sharma YP, Gill KD (2011) Paraoxonase 1 (PON1) polymorphisms, haplotypes and activity in predicting cad risk in North-West Indian Punjabis. PLoS One 6:e17805

    Article  PubMed  CAS  Google Scholar 

  6. Wang M, Lang X, Zou L, Huang S, Xu Z (2011) Four genetic polymorphisms of paraoxonase gene and risk of coronary heart disease: a meta-analysis based on 88 case–control studies. Atherosclerosis 214:377–385

    Article  PubMed  CAS  Google Scholar 

  7. Bouman HJ, Schömig E, van Werkum JW, Velder J, Hackeng CM, Hirschhäuser C, Waldmann C, Schmalz H-G, ten Berg JM, Taubert D (2010) Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 17:110–116

    Article  PubMed  Google Scholar 

  8. Tselepis AD, Tsoumani ME, Kalantzi KI, Dimitriou AA, Tellis CC, Goudevenos IA (2011) Influence of high-density lipoprotein and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy. J Thromb Haemost 9:2371–2378

    Article  PubMed  CAS  Google Scholar 

  9. Regieli JJ, Jukema JW, Doevendans PA, Zwinderman AH, Kastelein JJ, Grobbee DE, van der Graaf Y (2009) Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein-bound antioxidant in secondary prevention. J Am Coll Cardiol 54:1238–1245

    Article  PubMed  CAS  Google Scholar 

  10. Zhao LP, Li SS, Khalid N (2003) A method for the assessment of disease associations with single-nucleotide polymorphism haplotypes and environmental variables in case–control studies. Am J Hum Genet 72:1231–1250

    Article  PubMed  CAS  Google Scholar 

  11. Moura LM, Faria S, Brito M, Pinto FJ, Kristensen SD, Barros IM, Rajamannan N, Rocha-Goncalves F (2012) Relationship of PON1 192 and 55 gene polymorphisms to calcific valvular aortic stenosis. Am J Cardiovasc Dis 2:123–132

    PubMed  CAS  Google Scholar 

  12. Ahmad I, Narang R, Venkatraman A, Das N (2012) Two- and three-locus haplotypes of the paraoxonase (PON1) gene are associated with coronary artery disease in Asian Indians. Gene 506:242–247

    Article  PubMed  CAS  Google Scholar 

  13. Wang Y, Fu W, Xie F, Chu X, Wang H, Shen M, Sun W, Lei R, Yang L, Wu H, Foo J, Liu J, Jin L, Huang W (2010) Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population. J Hum Genet 55:490–494

    Article  PubMed  CAS  Google Scholar 

  14. Birjmohun RS, Vergeer M, Stroes ES, Sandhu MS, Ricketts SL, Tanck MW, Wareham NJ, Jukema JW, Kastelein JJ, Khaw KT, Boekholdt SM (2009) Both paraoxonase-1 genotype and activity do not predict the risk of future coronary artery disease; the EPIC-Norfolk Prospective Population Study. PLoS One 4:e6809

    Article  PubMed  Google Scholar 

  15. Brophy VH, Jampsa RL, Clendenning JB, McKinstry LA, Jarvik GP, Furlong CE (2001) Effects of 5′ regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. Am J Hum Genet 68:1428–1436

    Article  PubMed  CAS  Google Scholar 

  16. Arii K, Suehiro T, Ota K, Ikeda Y, Kumon Y, Osaki F, Inoue M, Inada S, Ogami N, Takata H, Hashimoto K, Terada Y (2009) Pitavastatin induces PON1 expression through p44/42 mitogen-activated protein kinase signaling cascade in Huh7 cells. Atherosclerosis 202:439–445

    Article  PubMed  CAS  Google Scholar 

  17. Arii K, Suehiro T, Ikeda Y, Kumon Y, Inoue M, Inada S, Takata H, Ishibashi A, Hashimoto K, Terada Y (2010) Role of protein kinase C in pitavastatin-induced human paraoxonase I expression in Huh7 cells. Metabolism 59:1287–1293

    Article  PubMed  CAS  Google Scholar 

  18. Osaki F, Ikeda Y, Suehiro T, Ota K, Tsuzura S, Arii K, Kumon Y, Hashimoto K (2004) Roles of Sp1 and protein kinase C in regulation of human serum paraoxonase 1 (PON1) gene transcription in HepG2 cells. Atherosclerosis 176:279–287

    Article  PubMed  CAS  Google Scholar 

  19. Ancrenaz V, Desmeules J, James R, Fontana P, Reny JL, Dayer P, Daali Y (2012) The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro. Br J Pharmacol 166:2362–2370

    Article  PubMed  CAS  Google Scholar 

  20. Reny JL, Combescure C, Daali Y, Fontana P (2012) Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 10:1242–1251

    Article  PubMed  CAS  Google Scholar 

  21. Simon T, Steg PG, Becquemont L, Verstuyft C, Kotti S, Schiele F, Ferrari E, Drouet E, Grollier G, Danchin N (2011) Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction. Clin Pharmacol Ther 90:561–567

    Article  PubMed  CAS  Google Scholar 

  22. Gong IY, Crown N, Suen CM, Schwarz UI, Dresser GK, Knauer MJ, Sugiyama D, Degorter MK, Woolsey S, Tirona RG, Kim RB (2012) Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response. Eur Heart J 3(22):2856–2464a

    Google Scholar 

  23. Shuldiner AR, Vesely MR, Fisch A (2012) CYP2C19 genotype and cardiovascular events. JAMA 307:1482, author reply 1484–1485

    PubMed  CAS  Google Scholar 

  24. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304:1821–1830

    Article  PubMed  CAS  Google Scholar 

  25. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL, Schork NJ, Teirstein PS, Topol EJ (2012) Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol 59:1928–1937

    Article  PubMed  CAS  Google Scholar 

  26. Steg PG, Huber K, Andreotti F, Arnesen H, Atar D, Badimon L, Bassand JP, De Caterina R, Eikelboom JA, Gulba D, Hamon M, Helft G, Fox KA, Kristensen SD, Rao SV, Verheugt FW, Widimsky P, Zeymer U, Collet JP (2011) Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 32:1854–1864

    Article  PubMed  Google Scholar 

  27. Santanam N, Parthasarathy S (2007) Aspirin is a substrate for paraoxonase-like activity: implications in atherosclerosis. Atherosclerosis 191:272–275

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Science Foundation of China (81072701), Natural Science Foundation of Guangdong Province, China (S2011010005830), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Medical Research Center, Guangdong General Hospital, Guangzhou, Guangdong, 510080, China

    Yan-Hong Kang, Xin-Xin Li, Xi-Yong Yu & Shi-Long Zhong

  2. Department of Pharmacy, Guangdong General Hospital, Guangzhou, Guangdong, 510080, China

    Hai-Yan Lao & Wei-Hua Lai

  3. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510020, China

    Hong Wu

  4. Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, China

    Xi-Yong Yu, Ji-Yan Chen & Shi-Long Zhong

  5. Medical Research Center, Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 96 Dongchuan Road, Weilun Bldg., Guangzhou, 510080, People’s Republic of China

    Shi-Long Zhong

Authors
  1. Yan-Hong Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hai-Yan Lao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei-Hua Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin-Xin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xi-Yong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ji-Yan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shi-Long Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shi-Long Zhong.

Additional information

Yan-Hong Kang, Hai-Yan Lao and Hong Wu contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 52 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kang, YH., Lao, HY., Wu, H. et al. Association of PON1 genotype and haplotype with susceptibility to coronary artery disease and clinical outcomes in dual antiplatelet-treated Han Chinese patients. Eur J Clin Pharmacol 69, 1511–1519 (2013). https://doi.org/10.1007/s00228-013-1516-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-013-1516-6

Keywords

Search

Navigation