Skip to main content
SpringerLink
Log in

Association of combined genetic variations in SOD3, GPX3, PON1, and GSTT1 with hypertension and severity of coronary artery disease

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Oxidative stress plays a critical role in the pathophysiology of hypertension (HT) and the progression of atherosclerotic coronary artery disease (CAD). Genetic variations in superoxide dismutase (SOD), glutathione peroxidase 3 (GPX3), paraoxonase 1 (PON1) and glutathione S-transferase theta 1 (GSTT1) may modulate their gene functions, affecting protein functions. These changes could have an impact on the pathogenesis of HT and progression of CAD. The present study investigated the associations of individual and combined antioxidant-related gene polymorphisms with the incidence of HT and severity of CAD. Two study populations were enrolled. The HT-associated study comprised 735 control and 735 hypertensive subjects (mean age 59.3 ± 9.0 years), matched for age and sex. The CAD study, hospital-based subjects (mean age 62.1 ± 9.5 years), included 279 CAD patients and 165 non-CAD subjects. Gene polymorphisms were identified in genomic DNA using polymerase chain reaction (PCR)-based technique. Genetic variations were assessed for their associations with HT and severity of CAD. Antioxidant gene variants, SOD3 rs2536512-GG, GPX3 rs3828599-GG, PON1 rs705379-TT, and GSTT1−/− and +/−, were independently associated with the incidence of HT. A combination of four HT-associated genotypes, as a genetic risk score (GRS), revealed an association of GRS 5 and GRS ≥ 6 with increased susceptibility to HT and CAD, and further with multivessel coronary atherosclerosis (multivessel CAD) compared with GRS 0–2 [respective ORs(95% CI) for GRS ≥ 6 = 2.37 (1.46–3.85), 3.26 (1.29–8.25), and 4.36 (1.36–14.0)]. Combined polymorphisms in these four antioxidant-related genes were associated with the incidences of HT and CAD, and with the severity of coronary atherosclerosis.

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. Fiebach NH, Hebert PR, Stampfer MJ, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH (1989) A prospective study of high blood pressure and cardiovascular disease in women. Am J Epidemiol 130:646–654

    Article  CAS  PubMed  Google Scholar 

  2. World Health Organization (2017) Global Health Observatory data. Blood pressure. https://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence/en/. Accessed 13 May 2018

  3. Elgendy IY, Bavry AA, Gong Y, Handberg EM, Cooper-DeHoff RM, Pepine CJ (2016) Long-term mortality in hypertensive patients with coronary artery disease: results from the US Cohort of the International Verapamil (SR)/Trandolapril Study. Hypertension 68:1110–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ning B, Chen Y, Waqar AB, Yan H, Shiomi M, Zhang J, Chen YE, Wang Y, Itabe H, Liang J, Fan J (2018) Hypertension enhances advanced atherosclerosis and induces cardiac death in watanabe heritable hyperlipidemic rabbits. Am J Pathol 188:2936–2947

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nakanishi R, Baskaran L, Gransar H, Budoff MJ, Achenbach S, Al-Mallah M, Cademartiri F, Callister TQ, Chang HJ, Chinnaiyan K, Chow BJW, DeLago A, Hadamitzky M, Hausleiter J, Cury R, Feuchtner G, Kim YJ, Leipsic J, Kaufmann PA, Maffei E, Raff G, Shaw LJ, Villines TC, Dunning A, Marques H, Pontone G, Andreini D, Rubinshtein R, Bax J, Jones E, Hindoyan N, Gomez M, Lin FY, Min JK, Berman DS (2017) Relationship of hypertension to coronary atherosclerosis and cardiac events in patients with coronary computed tomographic angiography. Hypertension 70:293–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chobanian AV (1991) Effects of hypertension on arterial gene expression and atherosclerosis. Adv Exp Med Biol 308:45–53

    Article  CAS  PubMed  Google Scholar 

  7. Saxena T, Ali AO, Saxena M (2018) Pathophysiology of essential hypertension: an update. Expert Rev Cardiovasc Ther 16:879–887

    Article  CAS  PubMed  Google Scholar 

  8. Rossi R, Chiurlia E, Nuzzo A, Cioni E, Origliani G, Modena MG (2004) Flow-mediated vasodilation and the risk of developing hypertension in healthy postmenopausal women. J Am Coll Cardiol 44:1636–1640

    Article  PubMed  Google Scholar 

  9. Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, Lehman BT, Fan S, Osypiuk E, Vita JA (2004) Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation 109:613–619

    Article  PubMed  Google Scholar 

  10. Higashi Y, Maruhashi T, Noma K, Kihara Y (2014) Oxidative stress and endothelial dysfunction: clinical evidence and therapeutic implications. Trends Cardiovasc Med 24:165–169

    Article  CAS  PubMed  Google Scholar 

  11. Sousa T, Pinho D, Morato M, Marques-Lopes J, Fernandes E, Afonso J, Oliveira S, Carvalho F, Albino-Teixeira A (2008) Role of superoxide and hydrogen peroxide in hypertension induced by an antagonist of adenosine receptors. Eur J Pharmacol 588:267–276

    Article  CAS  PubMed  Google Scholar 

  12. Cracowski JL, Devillier P, Durand T, Stanke-Labesque F, Bessard G (2001) Vascular biology of the isoprostanes. J Vasc Res 38:93–103

    Article  CAS  PubMed  Google Scholar 

  13. Bir SC, Kolluru GK, Fang K, Kevil CG (2012) Redox balance dynamically regulates vascular growth and remodeling. Semin Cell Dev Biol 23:745–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stephens JW, Gable DR, Hurel SJ, Miller GJ, Cooper JA, Humphries SE (2006) Increased plasma markers of oxidative stress are associated with coronary heart disease in males with diabetes mellitus and with 10-year risk in a prospective sample of males. Clin Chem 52:446–452

    Article  CAS  PubMed  Google Scholar 

  15. Xuan Y, Bobak M, Anusruti A, Jansen E, Pajak A, Tamosiunas A, Saum KU, Holleczek B, Gao X, Brenner H, Schottker B (2019) Association of serum markers of oxidative stress with myocardial infarction and stroke: pooled results from four large European cohort studies. Eur J Epidemiol 34:471–481

    Article  CAS  PubMed  Google Scholar 

  16. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN (1998) Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest 101:1581–1590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Faraci FM, Didion SP (2004) Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol 24:1367–1373

    Article  CAS  PubMed  Google Scholar 

  18. Chen N, Liu Y, Greiner CD, Holtzman JL (2000) Physiologic concentrations of homocysteine inhibit the human plasma GSH peroxidase that reduces organic hydroperoxides. J Lab Clin Med 136:58–65

    Article  CAS  PubMed  Google Scholar 

  19. Miller JD, Peotta VA, Chu Y, Weiss RM, Zimmerman K, Brooks RM, Heistad DD (2010) MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure. Am J Physiol Heart Circ Physiol 298:H1600–1607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jin RC, Mahoney CE, Coleman Anderson L, Ottaviano F, Croce K, Leopold JA, Zhang YY, Tang SS, Handy DE, Loscalzo J (2011) Glutathione peroxidase-3 deficiency promotes platelet-dependent thrombosis in vivo. Circulation 123:1963–1973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Foresman EL, Miller FJ Jr (2013) Extracellular but not cytosolic superoxide dismutase protects against oxidant-mediated endothelial dysfunction. Redox Biol 1:292–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jung O, Marklund SL, Xia N, Busse R, Brandes RP (2007) Inactivation of extracellular superoxide dismutase contributes to the development of high-volume hypertension. Arterioscler Thromb Vasc Biol 27:470–477

    Article  CAS  PubMed  Google Scholar 

  23. Chistiakov DA, Melnichenko AA, Orekhov AN, Bobryshev YV (2017) Paraoxonase and atherosclerosis-related cardiovascular diseases. Biochimie 132:19–27

    Article  CAS  PubMed  Google Scholar 

  24. Guns PJ, Van Assche T, Verreth W, Fransen P, Mackness B, Mackness M, Holvoet P, Bult H (2008) Paraoxonase 1 gene transfer lowers vascular oxidative stress and improves vasomotor function in apolipoprotein E-deficient mice with pre-existing atherosclerosis. Br J Pharmacol 153:508–516

    Article  CAS  PubMed  Google Scholar 

  25. Hurst R, Bao Y, Jemth P, Mannervik B, Williamson G (1998) Phospholipid hydroperoxide glutathione peroxidase activity of human glutathione transferases. Biochem J 332:97–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Souiden Y, Mallouli H, Meskhi S, Chaabouni Y, Rebai A, Cheour F, Mahdouani K (2016) MnSOD and GPx1 polymorphism relationship with coronary heart disease risk and severity. Biol Res 49:22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Pourvali K, Abbasi M, Mottaghi A (2016) Role of superoxide dismutase 2 gene Ala16Val polymorphism and total antioxidant capacity in diabetes and its complications. Avicenna J Med Biotechnol 8:48–56

    PubMed  PubMed Central  Google Scholar 

  28. Petrovic D, Peterlin B (2014) GSTM1-null and GSTT1-null genotypes are associated with essential arterial hypertension in patients with type 2 diabetes. Clin Biochem 47:574–577

    Article  CAS  PubMed  Google Scholar 

  29. Yang YM, Xie XR, Jin AL (2016) Genetic polymorphisms in extracellular superoxide dismutase Leu53Leu, Arg213Gly, and Ala40Thr and susceptibility to type 2 diabetes mellitus. Genet Mol Res. https://doi.org/10.4238/gmr15048418

    Article  PubMed  Google Scholar 

  30. Samoila OC, Carter AM, Futers ST, Otiman G, Anghel A, Tamas L, Seclaman E (2008) Polymorphic variants of extracellular superoxide dismutase gene in a Romanian population with atheroma. Biochem Genet 46:634–643

    Article  CAS  PubMed  Google Scholar 

  31. Mansego ML, Solar Gde M, Alonso MP, Martinez F, Saez GT, Escudero JC, Redon J, Chaves FJ (2011) Polymorphisms of antioxidant enzymes, blood pressure and risk of hypertension. J Hypertens 29:492–500

    Article  CAS  PubMed  Google Scholar 

  32. Arcaroli JJ, Hokanson JE, Abraham E, Geraci M, Murphy JR, Bowler RP, Dinarello CA, Silveira L, Sankoff J, Heyland D, Wischmeyer P, Crapo JD (2009) Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality. Am J Respir Crit Care Med 179:105–112

    Article  CAS  PubMed  Google Scholar 

  33. Voetsch B, Jin RC, Bierl C, Deus-Silva L, Camargo EC, Annichino-Bizacchi JM, Handy DE, Loscalzo J (2008) Role of promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene as a risk factor for cerebral venous thrombosis. Stroke 39:303–307

    Article  CAS  PubMed  Google Scholar 

  34. Voetsch B, Jin RC, Bierl C, Benke KS, Kenet G, Simioni P, Ottaviano F, Damasceno BP, Annichino-Bizacchi JM, Handy DE, Loscalzo J (2007) Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke 38:41–49

    Article  CAS  PubMed  Google Scholar 

  35. Hao Y, Wu BG, Shi J, Chen YL, Sun ZQ, Zheng LQ, Zhang XG, Geng N, Li TJ, Li H, Sun YX (2011) Association of tag SNPs of GPx-3 with essential hypertension in rural Han Chinese in Fuxin, Liaoning, China. Chin Med J (Engl ) 124:2113–2116

    CAS  Google Scholar 

  36. James RW, Leviev I, Ruiz J, Passa P, Froguel P, Garin MC (2000) Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients. Diabetes 49:1390–1393

    Article  CAS  PubMed  Google Scholar 

  37. Song Y, Shan Z, Luo C, Kang C, Yang Y, He P, Li S, Chen L, Jiang X, Liu L (2017) Glutathione S-transferase T1 (GSTT1) null polymorphism, smoking, and their interaction in coronary heart disease: a comprehensive meta-analysis. Heart Lung Circ 26:362–370

    Article  PubMed  Google Scholar 

  38. Turgut Cosan D, Colak E, Saydam F, Yazici HU, Degirmenci I, Birdane A, Gunes HV (2016) Association of paraoxonase 1 (PON1) gene polymorphisms and concentration with essential hypertension. Clin Exp Hypertens 38:602–607

    Article  CAS  PubMed  Google Scholar 

  39. Ioannidis JP (2003) Genetic associations: false or true? Trends Mol Med 9:135–138

    Article  PubMed  Google Scholar 

  40. DePalma SM, Himmelfarb CD, MacLaughlin EJ, Taler SJ (2018) Hypertension guideline update: a new guideline for a new era. JAAPA 31:16–22

    Article  PubMed  Google Scholar 

  41. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, Maccarthy PA, Van't Veer M, Pijls NH (2010) Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 55:2816–2821

    Article  PubMed  Google Scholar 

  42. World Health Organization. Regional Office for the Western Pacific, International Diabetes Institute, International Association for the Study of Obesity, Force IOT (2000) The Asia-Pacific perspective: redelfining obesity and its treatment. Health Communications Australia, Sydney

    Google Scholar 

  43. American Diabetes Association (2013) Standards of medical care in diabetes–2013. Diabetes Care 36:S11–66

    Article  CAS  Google Scholar 

  44. Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P (1997) Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clin Chem 43:1209–1214

    Article  CAS  PubMed  Google Scholar 

  45. Wong SH, Knight JA, Hopfer SM, Zaharia O, Leach CN Jr, Sunderman FW Jr (1987) Lipoperoxides in plasma as measured by liquid-chromatographic separation of malondialdehyde-thiobarbituric acid adduct. Clin Chem 33:214–220

    Article  CAS  PubMed  Google Scholar 

  46. Sprenger R, Schlagenhaufer R, Kerb R, Bruhn C, Brockmoller J, Roots I, Brinkmann U (2000) Characterization of the glutathione S-transferase GSTT1 deletion: discrimination of all genotypes by polymerase chain reaction indicates a trimodular genotype-phenotype correlation. Pharmacogenetics 10:557–565

    Article  CAS  PubMed  Google Scholar 

  47. Giegerich R, Meyer F, Schleiermacher C (1996) GeneFisher-software support for the detection of postulated genes. Proc Int Conf Intell Syst Mol Biol 4:68–77

    CAS  PubMed  Google Scholar 

  48. Dong X, Li D, Liu H, Zhao Y (2014) SOD3 and eNOS genotypes are associated with SOD activity and NOx. Exp Ther Med 8:328–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang JY, Yang IP, Wu DC, Huang SW, Wu JY, Juo SH (2010) Functional glutathione peroxidase 3 polymorphisms associated with increased risk of Taiwanese patients with gastric cancer. Clin Chim Acta 411:1432–1436

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  51. Deakin S, Leviev I, Brulhart-Meynet MC, James RW (2003) Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position—107, implicating the Sp1 transcription factor. Biochem J 372:643–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Leviev I, James RW (2000) Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations. Arterioscler Thromb Vasc Biol 20:516–521

    Article  CAS  PubMed  Google Scholar 

  53. Brophy VH, Hastings MD, Clendenning JB, Richter RJ, Jarvik GP, Furlong CE (2001) Polymorphisms in the human paraoxonase (PON1) promoter. Pharmacogenetics 11:77–84

    Article  CAS  PubMed  Google Scholar 

  54. Garin MC, James RW, Dussoix P, Blanche H, Passa P, Froguel P, Ruiz J (1997) Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest 99:62–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shakeri R, Khajeniazi S, Marjani A (2017) Association between promoter polymorphism (− 108C%3eT) of paraoxonase1 gene and it's paraoxonase activity in patients with Type2 diabetes in northern Iran. Clin Chim Acta 474:34–37

    Article  CAS  PubMed  Google Scholar 

  56. Du Y, Wang H, Fu X, Sun R, Liu Y (2012) GSTT1 null genotype contributes to coronary heart disease risk: a meta-analysis. Mol Biol Rep 39:8571–8579

    Article  CAS  PubMed  Google Scholar 

  57. Kelley R, Ideker T (2005) Systematic interpretation of genetic interactions using protein networks. Nat Biotechnol 23:561–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ottaviano FG, Handy DE, Loscalzo J (2008) Redox regulation in the extracellular environment. Circ J 72:1–16

    Article  CAS  PubMed  Google Scholar 

  59. Frijhoff J, Winyard PG, Zarkovic N, Davies SS, Stocker R, Cheng D, Knight AR, Taylor EL, Oettrich J, Ruskovska T, Gasparovic AC, Cuadrado A, Weber D, Poulsen HE, Grune T, Schmidt HH, Ghezzi P (2015) Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal 23:1144–1170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The funding for this study was supported by the National Research Council of Thailand (NRCT, Grant no. 555854). Nisa Decharatchakul was supported by a Research Grant from Graduate School, Khon Kaen University (Grant no. 57212108); Postgraduate Program in Biomedical Sciences, Graduate School; and Cardiovascular Research Group (CVRG), Khon Kaen University, Thailand. The Faculty of Associated Medical Sciences, Khon Kaen University, provided all necessary facilities throughout the study.

Author information

Authors and Affiliations

  1. Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, 40002, Thailand

    Nisa Decharatchakul

  2. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Chatri Settasatian

  3. School of Medical Technology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand

    Nongnuch Settasatian & Nantarat Komanasin

  4. Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Upa Kukongviriyapan

  5. Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Vichai Senthong & Kittisak Sawanyawisuth

  6. Queen Sirikit Heart Center of the Northeast, Khon Kaen University, Khon Kaen, 40002, Thailand

    Pongsak Intharapetch & Vichai Senthong

  7. Cardiovascular Research Group, Khon Kaen University, Khon Kaen, 40002, Thailand

    Nisa Decharatchakul, Chatri Settasatian, Nongnuch Settasatian, Nantarat Komanasin, Upa Kukongviriyapan, Pongsak Intharapetch & Vichai Senthong

Authors
  1. Nisa Decharatchakul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chatri Settasatian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nongnuch Settasatian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nantarat Komanasin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Upa Kukongviriyapan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pongsak Intharapetch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vichai Senthong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kittisak Sawanyawisuth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chatri Settasatian.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 406 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Decharatchakul, N., Settasatian, C., Settasatian, N. et al. Association of combined genetic variations in SOD3, GPX3, PON1, and GSTT1 with hypertension and severity of coronary artery disease. Heart Vessels 35, 918–929 (2020). https://doi.org/10.1007/s00380-020-01564-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-020-01564-6

Keywords

Search

Navigation