Skip to main content
SpringerLink
Log in

Association of PON1 and PON2 Polymorphisms with PON1 Activity and Significant Coronary Stenosis in a Tunisian Population

  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

PON1 and PON2 have attracted considerable attention as candidate genes for coronary heart disease because their enzymes function as key factors in lipoprotein catabolism pathways. We studied the distribution of PON1 and PON2 polymorphisms, including genotyping, lipid profile, and PON1 activity, and their association with PON1 activity and significant coronary stenosis (SCS) in a Tunisian population. PON1 activity was lower in patients with SCS than in controls. It increased with the R allele (QQ < QR < RR) in PON1-192 genotypes and with the L allele (MM < ML < LL) in PON1-55 genotypes. In the presence of metabolic syndrome and diabetes, PON1-192RR and PON2-311CC were associated with an increased risk of SCS and PON1-55MM seems to have lower risk. This association was evident among nonsmokers for PON1-55MM and among smokers for PON1-192RR and PON2-311CC. The GTGC haplotype seemed to increase the risk of SCS compared with the wild haplotype in a Tunisian population.

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

Similar content being viewed by others

References

  • Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553

    Article  PubMed  CAS  Google Scholar 

  • Alberti KG, Zimmet P, Shaw J (2005) The metabolic syndrome: a new worldwide definition. Lancet 366:1059–1062

    Article  PubMed  Google Scholar 

  • Aoki T, Abe T, Yamada E, Matsuto T, Okada M (2012) Increased LDL susceptibility to oxidation accelerates future carotid artery atherosclerosis. Lipids Health Dis 11:4

    Article  PubMed  CAS  Google Scholar 

  • Arca M, Ombres D, Montali A, Campagna F, Mangieri E, Tanzilli G, Campa PP, Ricci G, Verna R, Pannitteri G (2002) 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 32:9–15

    Article  PubMed  CAS  Google Scholar 

  • Aubó C, Sentí M, Marrugat J, Tomás M, Vila J, Sala J, Masiá R (2000) Risk of myocardial infarction associated with Gln/Arg 192 polymorphism in the human paraoxonase gene and diabetes mellitus The regicor investigators. Eur Heart J 21:33–38

    Article  PubMed  Google Scholar 

  • Aviram M, Rosenblat M, Billecke S, Erogul J, Sorenson R, Bisgaier CL (1999) Human serum paraoxonase (PON1) is inactivated by oxidized low-density lipoprotein and preserved by antioxidants. Free Radic Biol Med 26:892–904

    Article  PubMed  CAS  Google Scholar 

  • Azarsiza E, Kayikcioglu M, Payzinb S, Sözmen EY (2003) PON1 activities and oxidative markers of LDL in patients with angiographically proven coronary artery disease. Int J Cardiol 91:43–51

    Article  Google Scholar 

  • 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 

  • Blatter-Garin MC, James RW, Dussoix P, Blanché 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  Google Scholar 

  • Brophy VH, Jarvik GP, Richter RJ, Rozek LS, Schellenberg GD, Furlong CE (2000) Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype. Pharmacogenetics 10:453–460

    Article  PubMed  CAS  Google Scholar 

  • Camps J, Marsillach J, Joven J (2009) Measurement of serum paraoxonase-1 activity in the evaluation of liver function. World J Gastroenterol 28:1929–1933

    Article  Google Scholar 

  • Can Demirdöğen B, Türkanoğlu A, Bek S, Sanisoğlu Y, Demirkaya S, Vural O, Arinç E, Adali O (2008) Paraoxonase/arylesterase ratio, PON1 192Q/R polymorphism and PON1 status are associated with increased risk of ischemic stroke. Clin Biochem 41:1–9

    Article  PubMed  Google Scholar 

  • Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ (2003) Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. JAMA 289:2560–2572

    Article  PubMed  CAS  Google Scholar 

  • Church DF, Pryor WA (1985) The free radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect 64:111–126

    Article  PubMed  CAS  Google Scholar 

  • Durrington PN, Mackness B, Mackness MI (2001) Paraoxonase and atherosclerosis. Arterioscler Thromb Vasc Biol 21:473–480

    Article  PubMed  CAS  Google Scholar 

  • Efrat M, Aviram M (2010) Paraoxonase 1 interactions with HDL, antioxidants and macrophages regulate atherogenesis: a protective role for HDL phospholipids. Adv Exp Med Biol 660:153–166

    Article  PubMed  CAS  Google Scholar 

  • Ergun MA, Yurtcu E, Demirci H, Ilhan MN, Barkar V, Yetkin I, Menevse A (2011) PON1 55 and 192 gene polymorphisms in type 2 diabetes mellitus patients in a Turkish population. Biochem Genet 49:1–8

    Article  PubMed  CAS  Google Scholar 

  • Farmer JA, Liao J (2011) Evolving concepts of the role of high-density lipoprotein in protection from atherosclerosis. Curr Atheroscler Rep 13:107–114

    Article  PubMed  CAS  Google Scholar 

  • Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502

    PubMed  CAS  Google Scholar 

  • Gluba A, Pietrucha T, Banach M, Piotrowski G, Rysz J (2010) The role of polymorphisms within paraoxonases (192 Gln/Arg in PON1 and 311Ser/Cys in PON2) in the modulation of cardiovascular risk: a pilot study. Angiology 61:157–165

    Article  PubMed  CAS  Google Scholar 

  • Gupta N, Gill K, Singh S (2009) Paraoxonases: structure, gene polymorphism and role in coronary artery disease. Indian J Med Res 130:361–368

    PubMed  CAS  Google Scholar 

  • Guxens M, Tomás M, Elosua R, Aldasoro E, Segura A, Fiol M, Sala J, Vila J, Fullana M, Sentí M, Vega G, de la Rica M, Marrugat J (2008) Association between paraoxonase-1 and paraoxonase-2 polymorphisms and the risk of acute myocardial infarction. Investigadores del estudio Iberica. Rev Esp Cardiol 61:269–275

    Article  PubMed  Google Scholar 

  • Humbert R, Adler DA, Disteche CK, Hassett C, Omiecinski CJ, Furlong CE (1993) The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet 3:73–76

    Article  PubMed  CAS  Google Scholar 

  • Jalilian A, Javadi E, Akrami M, Fakhrzadeh H, Heshmat R, Rahmani M, Bandarian F (2008) Association of cys 311 ser polymorphism of paraoxonase-2 gene with the risk of coronary artery disease. Arch Iran Med 11:544–549

    PubMed  CAS  Google Scholar 

  • Kallel A, Sediri Y, Sbaï MH, Mourali MS, Feki M, Elasmi M, Taieb SH, Sanhaji H, Souheil O, Mechmeche R, Jemaa R, Kaabachi N (2010) The paraoxonase L55M and Q192R gene polymorphisms and myocardial infarction in a Tunisian population. Clin Biochem 43:1461–1463

    Article  PubMed  CAS  Google Scholar 

  • Kaman D, Ilhan N, Metin K, Akbulut M, Ustündağ B (2009) A preliminary study of human paraoxonase and PON 1 L/M 55–PON 1 Q/R 192 polymorphisms in Turkish patients with coronary artery disease. Cell Biochem Funct 27:88–92

    Article  PubMed  CAS  Google Scholar 

  • Kuo CL, La Du BN (1995) Comparison of purified human and rabbit serum paraoxonases. Drug Metab Dispos 23:935–944

    PubMed  CAS  Google Scholar 

  • Mackness MI, Arrol S, Mackness B, Durrington PN (1997) Alloenzymes of paraoxonase and effectiveness of high-density lipoproteins in protecting low-density lipoprotein against lipid peroxidation. Lancet 349:851–852

    Article  PubMed  CAS  Google Scholar 

  • Mackness B, Durrington PN, Abuashia B, Boulton AJM, Mackness MI (2000) Low paraoxonase activity in type II diabetes mellitus complicated by retinopathy. Clin Sci 98:355–363

    Article  PubMed  CAS  Google Scholar 

  • Mackness B, Davies GK, Turkie W, Lee E, Roberts DH, Hill E, Roberts C, Durrington PN, Mackness MI (2001) Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol 21:1451–1457

    Article  PubMed  CAS  Google Scholar 

  • Mackness B, Durrington PN, Mackness MI (2002) The paraoxonase gene family and coronary heart disease. Curr Opin Lipidol 13:357–362

    Article  PubMed  CAS  Google Scholar 

  • Mackness B, Durrington P, McElduff P, Yarnell J, Azam N, Watt M, Mackness M (2003) Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study. Circulation 107:2775–2779

    Article  PubMed  CAS  Google Scholar 

  • Mackness B, McElduff P, Mackness MI (2005) The paraoxonase-2-310 polymorphism is associated with the presence of microvascular complications in diabetes mellitus. J Intern Med 258:363–368

    Article  PubMed  CAS  Google Scholar 

  • Martinelli N, Girelli D, Olivieri O, Stranieri C, Trabetti E, Pizzolo F, Friso S, Tenuti I, Cheng S, Grow MA, Pignatti PF, Corrocher R (2004) Interaction between smoking and PON2 Ser311Cys polymorphism as a determinant of the risk of myocardial infarction. Eur J Clin Invest 34:14–20

    Article  PubMed  CAS  Google Scholar 

  • Martinelli N, Girelli D, Olivieri O, Cavallari U, Biscuola M, Trabetti E, Friso S, Pizzolo F, Tenuti I, Bozzini C, Villa G, Ceradini B, Sandri M, Cheng S, Grow MA, Pignatti PF, Corrocher R (2005) Interaction between metabolic syndrome and PON1 polymorphisms as a determinant of the risk of coronary artery disease. Clin Exp Med 5:20–30

    Article  PubMed  CAS  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  PubMed  CAS  Google Scholar 

  • Motti C, Dessì M, Gnasso A, Irace C, Indigeno P, Angelucci CB, Bernardini S, Fucci G, Federici G, Cortese C (2001) A multiplex PCR-based DNA assay for the detection of paraoxonase gene cluster polymorphisms. Atherosclerosis 158:35–40

    Article  PubMed  CAS  Google Scholar 

  • Ng CJ, Bourquard N, Grijalva V, Hama S, Shih DM, Navab M, Fogelman AM, Lusis AJ, Young S, Reddy ST (2006) Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2. J Biol Chem 281:29491–29500

    Article  PubMed  CAS  Google Scholar 

  • Nishio E, Watanabe Y (1997) Cigarette smoke extract inhibits plasma paraoxonase activity by modification of the enzyme’s free thiols. Biochem Biophys Res Commun 236:289–293

    Article  PubMed  CAS  Google Scholar 

  • Oliveira SA, Mansur AP, Ribeiro CC, José Ramires AF, Annichino-Bizzacchi JM (2004) PON1M/L55 mutation protects high-risk patients against coronary artery disease. Int J Cardiol 94:73–77

    Article  PubMed  Google Scholar 

  • Osei-Hyiaman D, Hou L, Mengbai F, Zhiyin R, Zhiming Z, Kano K (2001) Coronary artery disease risk in Chinese type 2 diabetics: is there a role for paraxonase 1 gene (Q192R) polymorphism? Eur J Endocrinol 144:639–644

    Article  PubMed  CAS  Google Scholar 

  • Pasdar A, Ross-Adams H, Cumming A, Cheung J, Whalley L, St Clair D, MacLeod MJ (2006) Paraoxonase gene polymorphisms and haplotype analysis in a stroke population. BMC Med Genet 7:28

    Article  PubMed  Google Scholar 

  • Précourt LP, Amre D, Denis MC, Lavoie JC, Delvin E, Seidman E, Levy E (2011) The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis 214:20–36

    Article  PubMed  Google Scholar 

  • Princen HMG, van Poppel G, Vogelezang C, Buytenhek R, Kok FJ (1992) Supplementation with vitamin E but not b-carotene in vivo protects low density lipoprotein from lipid peroxidation in vitro: effect of cigarette smoking. Arterioscler Thromb 12:554–562

    Article  PubMed  CAS  Google Scholar 

  • Qu Y, Yang Z, Jin F, Sun L, Zhang C, Ji L, Sun H, Wang B, Wang L (2008) The Ser311Cys variation in the paraoxonase 2 gene increases the risk of type 2 diabetes in northern Chinese. J Genet 87:165–169

    Article  PubMed  CAS  Google Scholar 

  • Ranade K, Kirchgessner TG, Iakoubova OA, Devlin JJ, DelMonte T, Vishnupad P, Hui L, Tsuchihashi Z, Sacks FM, Sabatine MS, Braunwald E, White TJ, Shaw PM, Dracopoli NC (2005) Evaluation of the paraoxonases as candidate genes for stroke: Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke. Stroke 36:2346–2350

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Rejeb J, Omezzine A, Rebhi L, Naffeti I, Kchok K, Belkahla R, Bel Hadjmbarek I, Ben Rejeb N, Nabli N, Boujelbene A, Ben Abdelaziz A, Boughzala E, Bouslama A (2008) Association of the cholesteryl ester transfer protein Taq1 B2B2 genotype with higher high-density lipoprotein cholesterol concentrations and lower risk of coronary artery disease in a Tunisian population. Arch Cardiovasc Dis 101:629–636

    Article  PubMed  Google Scholar 

  • Rejeb J, Omezzine A, Boumaiza I, Rebhi L, Kalboussi N, Laouini A, Rejeb NB, Nabli N, Abdelaziz AB, Boughzala E, Bouslama A (2010) Metabolic syndrome is a risk factor for coronary artery disease in a Tunisian population. Metab Syndr Relat Disord 8:105–112

    Article  PubMed  Google Scholar 

  • Rios DL, D’Onofrio LO, Cerqueira CC, Bonfim-Silva R, Carvalho HG, Santos-Filho A, Galvão-Castro B (2007) Paraoxonase 1 gene polymorphisms in angiographically assessed coronary artery disease: evidence for gender interaction among Brazilians. Clin Chem Lab Med 45:874–878

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Scheffler E, Wiest E, Woehrle J, Otto I, Schulz I, Huber L, Ziegler R, Dresel HA (1992) Smoking influences the atherogenic potential of low-density lipoprotein. Clin Invest Med 70:263–268

    CAS  Google Scholar 

  • Sen-Banerjee S, Siles X, Campos H (2000) Tobacco smoking modifies association between Gln-Arg192 polymorphism of human paraoxonase gene and risk of myocardial infarction. Arterioscler Thromb Vasc Biol 20:2120–2126

    Article  PubMed  CAS  Google Scholar 

  • Sentí M, Tomás M, Fitó M, Weinbrenner T, Covas MI, Sala J, Masiá R, Marrugat J (2003) Antioxidant paraoxonase 1 activity in the metabolic syndrome. J Clin Endocrinol Metab 88:5422–5426

    Article  PubMed  Google Scholar 

  • Shin BS (2009) Paraoxonase gene polymorphism in southwestern Korean population. J Korean Med Sci 24:561–566

    Article  PubMed  CAS  Google Scholar 

  • Shin BS, Oh SY, Kim YS, Kim KW (2008) The paraoxonase gene polymorphism in stroke patients and lipid profile. Acta Neurol Scand 117:237–243

    Article  PubMed  CAS  Google Scholar 

  • Tsompanidi EM, Brinkmeier MS, Fotiadou EH, Giakoumi SM, Kypreos KE (2010) HDL biogenesis and functions: role of HDL quality and quantity in atherosclerosis. Atherosclerosis 208:3–9

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Watzinger N, Schmidt H, Schumacher M, Schmidt R, Eber B, Fruhwald FM, Zweiker R, Kostner GM, Klein W (2002) Human paraoxonase 1 gene polymorphisms and the risk of coronary heart disease: a community-based study. Cardiology 98:116–122

    Article  PubMed  CAS  Google Scholar 

  • Yang X, Gao Y, Zhou J, Zhen Y, Yang Y, Wang J, Song L, Liu Y, Xu H, Chen Z, Hui R (2006) Plasma homocysteine thiolactone adducts associated with risk of coronary heart disease. Clin Chim Acta 364:230–234

    Article  PubMed  CAS  Google Scholar 

  • Yoo J, Seo B, Kim Y (2005) SNPAnalyzer: a web-based integrated work-bench for single-nucleotide polymorphism analysis. Nucleic Acids Res 33:483–488

    Article  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Tunisian Ministry of Higher Education, Scientific Research, and Technology and the Tunisian Ministry of Health (UR 28/04); without their extremely generous and strong support, this study could not have been undertaken. We are especially grateful to the study participants. We acknowledge the excellent technical assistance of members of the Biochemistry and Cardiology Departments of Sahloul University Hospital.

Author information

Authors and Affiliations

  1. Department of Biochemistry, UR MSP 28/04, Sahloul University Hospital, 4054, Sousse, Tunisia

    Jihène Rejeb, Asma Omezzine, Lamia Rebhi, Imen Boumaiza, Hamida Rhif, Nabila Ben Rejeb, Naoufel Nabli & Ali Bouslama

  2. Laboratory of Biochemistry-Toxicology, University Hospital Fattouma Bourguiba, Monastir, Tunisia

    Hajer Mabrouk & Wahiba Douki

  3. Information System Direction, Sahloul University Hospital, Sousse, Tunisia

    Ahmed Ben Abdelaziz

  4. Department of Cardiology, Sahloul University Hospital, Sousse, Tunisia

    Essia Boughzala

Authors
  1. Jihène Rejeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asma Omezzine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lamia Rebhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Imen Boumaiza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hajer Mabrouk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hamida Rhif
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nabila Ben Rejeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naoufel Nabli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wahiba Douki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ahmed Ben Abdelaziz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Essia Boughzala
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ali Bouslama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Bouslama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rejeb, J., Omezzine, A., Rebhi, L. et al. Association of PON1 and PON2 Polymorphisms with PON1 Activity and Significant Coronary Stenosis in a Tunisian Population. Biochem Genet 51, 76–91 (2013). https://doi.org/10.1007/s10528-012-9544-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-012-9544-y

Keywords

Search

Navigation