Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Lipids and cardiovascular/metabolic health

Association between PON1 rs662 polymorphism and coronary artery disease

Subjects

Abstract

Background/Objectives:

Paraoxonase 1 (PON1) is a plasma enzyme that is capable of inhibiting the progression of atherosclerosis, and is associated with susceptibility of coronary artery disease (CAD). PON protein expression is present in human aortic tissue and it plays an important role in the progression of atherosclerosis. This study aimed to investigate PON1 immunohistochemistry in human coronary arteries, determine its polymorphisms and plasma status, and analyze its association with the risk of CAD.

Subjects/Methods:

PON1 expression in human coronary artery tissues was detected by immunohistochemical staining. PON1 polymorphisms were determined by polymerase chain reaction direct sequencing in 2456 unrelated Chinese Han individuals. Serum PON1 levels were indirectly reflected by PON1 activity towards paraoxon and phenylacetate by spectrophotometry, and by its concentrations using a human enzyme-linked immunosorbent assay.

Results:

Immunohistochemical analysis showed that PON1 expression was lower in atherosclerotic arteries than in normal arteries. PON1 Q192R (rs662) had a significant effect on the risk of CAD (P=0.001). In a logistic regression model, after adjusting for conventional risk factors of CAD, 192R allele carriers had a significantly higher risk of CAD than other allele carriers. Serum PON1 activity and concentrations were significantly reduced in CAD patients compared with controls (P<0.05), and highly associated with the R allele.

Conclusions:

Low PON1 expression in human atherosclerotic coronary arteries is associated with CAD. Moreover, PON1 Q192R polymorphism is significantly associated with susceptibility of CAD in the Chinese Han population, and the 192R allele might be an independent predictor for CAD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Bolognese L Changing patterns of ST elevation myocardial infarction epidemiology. Am Heart J 2010; 160 (6 Suppl): S1–S3.

    Article  Google Scholar 

  2. Abdallah M, Karrowni W, Shamseddeen W, Itani S, Kobeissi L, Ghazzal Z et al. Acute coronary syndromes: clinical characteristics, management, and outcomes at the American University of Beirut Medical Center, 2002-2005. Clin Cardiol 2010; 33 (1): E6–E13.

    Article  Google Scholar 

  3. Deakin SP, James RW Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci (Lond) 2004; 107 (5): 435–447.

    Article  CAS  Google Scholar 

  4. Nora JJ, Lortscher RH, Spangler RD, Nora AH, Kimberling WJ Genetic—epidemiologic study of early-onset ischemic heart disease. Circulation 1980; 61 (3): 503–508.

    Article  CAS  Google Scholar 

  5. Lusis AJ Atherosclerosis. Nature 2000; 407 (6801): 233–241.

    Article  CAS  Google Scholar 

  6. Schildkraut JM, Myers RH, Cupples LA, Kiely DK, Kannel WB Coronary risk associated with age and sex of parental heart disease in the Framingham Study. Am J Cardiol 1989; 64 (10): 555–559.

    Article  CAS  Google Scholar 

  7. Goldbourt U, Neufeld HN Genetic aspects of arteriosclerosis. Arteriosclerosis 1986; 6 (4): 357–377.

    Article  CAS  Google Scholar 

  8. Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 1996; 33 (3): 498–507.

    Article  CAS  Google Scholar 

  9. Deakin S, Leviev I, Gomaraschi M, Calabresi L, Franceschini G, James RW Enzymatically active paraoxonase-1 is located at the external membrane of producing cells and released by a high affinity, saturable, desorption mechanism. J Biol Chem 2002; 277 (6): 4301–4308.

    Article  CAS  Google Scholar 

  10. Mackness B, Hunt R, Durrington PN, Mackness MI Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis. Arterioscler Thromb Vasc Biol 1997; 17 (7): 1233–1238.

    Article  CAS  Google Scholar 

  11. Mackness B, Hunt R, Durrington PN, Mackness MI Immunohistochemical analysis of paraoxonases-1 and 3 in human atheromatous plaques. Eur J Clin Invest 2011; 41 (3): 308–314.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Schmidt H, Schmidt R, Niederkorn K, Gradert A, Schumacher M, Watzinger N et al. Paraoxonase PON1 polymorphism leu-Met54 is associated with carotid atherosclerosis: results of the Austrian Stroke Prevention Study. Stroke 1998; 29 (10): 2043–2048.

    Article  CAS  Google Scholar 

  14. Ahmad I, Narang R, Venkatraman A, Das N Frequency distribution of the single-nucleotide −108C/T polymorphism at the promoter region of the PON1 gene in Asian Indians and its relationship with coronary artery disease. J Community Genet 2011; 2 (1): 27–32.

    Article  Google Scholar 

  15. Bayrak A, Bayrak T, Tokgozoglu SL, Volkan-Salanci B, Deniz A, Yavuz B et al. Serum PON-1 activity but not Q192R polymorphism is related to the extent of atherosclerosis. J Atheroscler Thromb 2012; 19 (4): 376–384.

    Article  CAS  Google Scholar 

  16. Deshpande CS, Singhal RS, Mukherjee MS Association of Paraoxonase1 Gene Q192R Polymorphism and Apolipoprotein B in Asian Indian Women with Coronary Artery Disease Risk. Genet Test Mol Biomarkers 2013; 17 (2): 140–146.

    Article  CAS  Google Scholar 

  17. Ahmad I, Narang R, Venkatraman A, Das N Two- and three-locus haplotypes of the paraoxonase (PON1) gene are associated with coronary artery disease in Asian Indians. Gene 2012; 506 (1): 242–247.

    Article  CAS  Google Scholar 

  18. Arca M, Ombres D, Montali A, Campagna F, Mangieri E, Tanzilli G et al. PON1 L55M polymorphism is not a predictor of coronary atherosclerosis either alone or in combination with Q192R polymorphism in an Italian population. Eur J Clin Invest 2002; 32 (1): 9–15.

    Article  CAS  Google Scholar 

  19. Agrawal S, Tripathi G, Prajnya R, Sinha N, Gilmour A, Bush L et al. Paraoxonase 1 gene polymorphisms contribute to coronary artery disease risk among north Indians. Indian J Med Sci 2009; 63 (8): 335–344.

    Article  CAS  Google Scholar 

  20. Richter RJ, Furlong CE Determination of paraoxonase (PON1) status requires more than genotyping. Pharmacogenetics 1999; 9 (6): 745–753.

    Article  CAS  Google Scholar 

  21. Jarvik GP, Hatsukami TS, Carlson C, Richter RJ, Jampsa R, Brophy VH et al. Paraoxonase activity, but not haplotype utilizing the linkage disequilibrium structure, predicts vascular disease. Arterioscler Thromb Vasc Biol 2003; 23 (8): 1465–1471.

    Article  CAS  Google Scholar 

  22. Mackness B, Davies GK, Turkie W, Lee E, Roberts DH, Hill E et al. Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol 2001; 21 (9): 1451–1457.

    Article  CAS  Google Scholar 

  23. Holloway JW, Laxton RC, Rose-Zerilli MJ, Holloway JA, Andrews AL, Riaz Z et al. ADAM33 expression in atherosclerotic lesions and relationship of ADAM33 gene variation with atherosclerosis. Atherosclerosis 2010; 211 (1): 224–230.

    Article  CAS  Google Scholar 

  24. Iwai M, Nakaoka H, Senba I, Kanno H, Moritani T, Horiuchi M Possible involvement of angiotensin-converting enzyme 2 and Mas activation in inhibitory effects of angiotensin II Type 1 receptor blockade on vascular remodeling. Hypertension 2012; 60 (1): 137–144.

    Article  CAS  Google Scholar 

  25. Teo KK, Liu L, Chow CK, Wang X, Islam S, Jiang L et al. Potentially modifiable risk factors associated with myocardial infarction in China: the INTERHEART China study. Heart 2009; 95 (22): 1857–1864.

    Article  CAS  Google Scholar 

  26. Li Y, He Y, Lai J, Wang D, Zhang J, Fu P Dietary patterns are associated with stroke in Chinese adults. J Nutr 2011; 141 (10): 1834–1839.

    Article  CAS  Google Scholar 

  27. Ayub A, Mackness MI, Arrol S, Mackness B, Patel J, Durrington PN Serum paraoxonase after myocardial infarction. Arterioscler Thromb Vasc Biol 1999; 19 (2): 330–335.

    Article  CAS  Google Scholar 

  28. Bindu CM, Anand U, Anand CV Serum paraoxonase levels in patients with acute liver disease. Indian J Clin Biochem 2011; 26 (3): 230–234.

    Article  CAS  Google Scholar 

  29. Fuhrman B Regulation of hepatic paraoxonase-1 expression. J Lipids 2012; 2012: 684010.

    Article  Google Scholar 

  30. Mackness B, Beltran-Debon R, Aragones G, Joven J, Camps J, Mackness M Human tissue distribution of paraoxonases 1 and 2 mRNA. IUBMB Life 2010; 62 (6): 480–482.

    CAS  PubMed  Google Scholar 

  31. Enas EA, Garg A, Davidson MA, Nair VM, Huet BA, Yusuf S Coronary heart disease and its risk factors in first-generation immigrant Asian Indians to the United States of America. Indian Heart J 1996; 48 (4): 343–353.

    CAS  Google Scholar 

  32. McKeigue PM, Ferrie JE, Pierpoint T, Marmot MG Association of early-onset coronary heart disease in South Asian men with glucose intolerance and hyperinsulinemia. Circulation 1993; 87 (1): 152–161.

    Article  CAS  Google Scholar 

  33. Janus ED, Postiglione A, Singh RB, Lewis B The modernization of Asia. Implications for coronary heart disease. Council on Arteriosclerosis of the International Society and Federation of Cardiology. Circulation 1996; 94 (11): 2671–2673.

    Article  CAS  Google Scholar 

  34. Kotur-Stevuljevic J, Spasic S, Stefanovic A, Zeljkovic A, Bogavac-Stanojevic N, Kalimanovska-Ostric D et al. Paraoxonase-1 (PON1) activity, but not PON1(Q192R) phenotype, is a predictor of coronary artery disease in a middle-aged Serbian population. Clin Chem Lab Med 2006; 44 (10): 1206–1213.

    Article  CAS  Google Scholar 

  35. Su SY, Chen JH, Huang JF, Wang XL, Zhao JG, Shen Y et al. Paraoxonase gene cluster variations associated with coronary heart disease in Chinese Han women. Chin Med J (Engl) 2005; 118 (14): 1167–1174.

    CAS  Google Scholar 

  36. Qin Q, Li YL, Zhao FM, Wang H, Li Y, Cui RZ et al. Association of paraoxonase polymorphisms and serum homocysteine thiolactone complex with coronary heart disease. Zhonghua Xin Xue Guan Bing Za Zhi 2006; 34 (9): 803–807.

    CAS  PubMed  Google Scholar 

  37. Jarvik GP, Rozek LS, Brophy VH, Hatsukami TS, Richter RJ, Schellenberg GD et al. Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype. Arterioscler Thromb Vasc Biol 2000; 20 (11): 2441–2447.

    Article  CAS  Google Scholar 

  38. Tomas M, Senti M, Elosua R, Vila J, Sala J, Masia R et al. Paraoxonase1-192 polymorphism modulates the effects of regular and acute exercise on paraoxonase1 activity. J Lipid Res 2002; 43 (5): 713–720.

    CAS  PubMed  Google Scholar 

  39. Tomas M, Elosua R, Senti M, Molina L, Vila J, Anglada R et al. Interaction between the Gln-Arg 192 variants of the paraoxonase gene and oleic acid intake as a determinant of high-density lipoprotein cholesterol and paraoxonase activity. Eur J Pharmacol 2001; 432 (2–3): 121–128.

    Article  CAS  Google Scholar 

  40. Lee YC, Lai CQ, Ordovas JM, Parnell LD A Database of Gene-Environment Interactions Pertaining to Blood Lipid Traits, Cardiovascular Disease and Type 2 Diabetes. J Data Mining Genomics Proteomics 2011; 2 (1): 106.

    Article  Google Scholar 

  41. Balcerzyk A, Zak I, Krauze J Synergistic effects between Q192R polymorphism of paraoxonase 1 gene and some conventional risk factors in premature coronary artery disease. Arch Med Res 2007; 38 (5): 545–550.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by grants from the National Basic Research Program of China (973 Program (2012CB517804), the National Research Key Project of the Twelfth Five-Year Plan of the Republic of China (2011BAI11B07 and 2012ZX09303016-002), Major High-tech Clinical Army Project (2010GXJS001), and the National Youth Science Foundation of China (81100135). This work was supported by grants from the the National Research Key Project of The Twelfth Five-Year Plan of Republic of China (2011BAI11B07), National Basic Research Program of China (973 Program 2012CB517804), Major High-tech Clinical Army Projects (2010GXJS001) and National Youth Science Foundation of China (81100135).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Z Zhu or Y Han.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, T., Zhang, X., Zhang, J. et al. Association between PON1 rs662 polymorphism and coronary artery disease. Eur J Clin Nutr 68, 1029–1035 (2014). https://doi.org/10.1038/ejcn.2014.105

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2014.105

This article is cited by

Search

Quick links