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Genotype and phenotype of salt-stimulated paraoxonase 1 (PON1) is associated with atherogenic indices in type 2 diabetes

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Abstract

Background

Paraoxonase 1 (PON1) and lipid abnormalities contribute to the development of cardiovascular disease, which is the principal cause of mortality in patients with type 2 diabetes (T2D). Data are not available on the potential association between salt-stimulated activity of PON1 (PON1-salt) and the atherogenic indices in T2D, therefore, we focused on these associations and evaluated whether the functional variants PON1-Q192R and PON1-L55M influence the associations.

Methods

Paraoxonase activity (PON1-para), arylesterase activity (PON1-aryl) and salt-stimulated activity (PON1-salt) were measured by spectrophotometric assays. The atherogenic index of plasma (AIP) was calculated from the log (TG/HDL-C). The genetic analyses were made by the restricted fragment length polymorphism after PCR amplification.

Results

We observed that PON1-salt was negatively correlated with total cholesterol (TC)/HDL-C (r = −0.441,p = 0.006), LDL-C/HDL-C (r = −0.415, p = 0.011), and AIP (r = −0.422, p = 0.009). Correlations between PON1-salt and all three atherogenic indices were significantly affected by PON1-L55M and PON1-Q192R. Linear regression showed that AIP (p = 0.002), LDL-C/HDL-C (p = 0.005), and TC/HDL-C (p = 0.002) were independently associated with PON1-salt. Based on Ridge regression, the standardized coefficients −0.358, −0.297, and − 0.044 were obtained for AIP, LDL-C/HDL-C, and TC/HDL-C, respectively, and this shows that AIP could have more negative effect on PON1-salt than the others.

Conclusions

The decreased PON1-salt may be considered as a risk factor for atherosclerosis in T2D, therefore, understanding the associations between PON1-salt as an important although neglected property and atherogenic indices may be valuable in T2D. Accordingly, detection of PON1-salt status (phenotype and genotype) together with the atherogenic indices particularly AIP could be beneficial in identifying the increased atherogenicity in T2D.

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Abbreviations

ACE:

Angiotensin-converting enzyme

AIP:

Atherogenic index of plasma

ALT:

Alanine aminotransferase

CHD:

Coronary heart disease

CVD:

Cardiovascular disease

FERHDL :

Fractional esterification rate of HDL

FPG:

Fasting plasma glucose

HDL:

High density lipoprotein

LDL:

Low density lipoproteins

PON1:

Paraoxonase 1

PON1-aryl:

Arylesterase activity of PON1

PON1-para:

Paraoxonase activity of PON1

PON1-salt:

Salt-stimulated activity of PON1

PRESS:

Predicted residual error sum of squares

RFLP:

Restriction fragment length polymorphism

SNV:

Single nucleotide variant

TC:

Total cholesterol

T2D:

Type 2 diabetes

TG:

Triglyceride

VIF:

Variance inflation factors

References

  1. Précourt LP, Amre D, Denis MC, Lavoie JC, Delvin E, Seidman E, et al. The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis. 2011;214:20–36.

    Article  PubMed  CAS  Google Scholar 

  2. Mackness M, Mackness B. Human paraoxonase-1 (PON1): Gene structure and expression, promiscuous activities and multiple physiological roles. Gene. 2015;567:12–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Mahrooz A. Pharmacological interactions of paraoxonase 1 (PON1): A HDL-bound antiatherogenic enzyme. Curr Clin Pharmacol. 2016;11:259–64.

    Article  PubMed  CAS  Google Scholar 

  4. Kim DS, Marsillach J, Furlong CE, Jarvik GP. Pharmacogenetics of paraoxonase activity: elucidating the role of high-density lipoprotein in disease. Pharmacogenomics. 2013;14:1495–515.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Hegele RA, Connelly PW, Scherer SW, Hanley AJG, Harris SB, Tsui LC, et al. Paraoxonase-2 G148 variant in an aboriginal Canadian girl with non-insulin-dependent diabetes. Lancet. 1997;350:785.

    Article  PubMed  CAS  Google Scholar 

  6. Koren-Gluzer M, Aviram M, Meilin E, Hayek T. The antioxidant HDL-associated paraoxonase-1 (PON1) attenuates diabetes development and stimulates β-cell insulin release. Atherosclerosis. 2011;219:510–8.

    Article  PubMed  CAS  Google Scholar 

  7. Hofer SE, Bennetts B, Chan AK, Holloway B, Karschimkus C, Jenkins AJ, et al. Association between PON1 polymorphisms, PON activity and diabetes complications. J Diabetes Complicat. 2006;20:322–8.

    Article  PubMed  Google Scholar 

  8. Aubo C, Senti M, Marrugat J, et al. Risk of myocardial infarction associated with Gln/Arg 192 polymorphism in the human paraoxonase gene and diabetes mellitus. Eur Heart J. 2000;21:33–8.

    Article  PubMed  CAS  Google Scholar 

  9. Li J, Wang X, Huo Y, Niu T, Chen C, Zhu G, et al. PON1 polymorphism, diabetes mellitus, obesity, and risk of myocardial infarction: Modifying effect of diabetes mellitus and obesity on the association between PON1 polymorphism and myocardial infarction. Genet Med. 2005;7:58–63.

    Article  PubMed  CAS  Google Scholar 

  10. Mahrooz A, Alizadeh A, Gohari G. The salt stimulation property of serum paraoxonase (PON1) could be a valuable factor in evaluating the enzyme status in ischemic stroke: The role of activity-determined PON1 192Q/R phenotypes. J Neurol Sci. 2014;338:197–202.

    Article  PubMed  CAS  Google Scholar 

  11. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129–34.

    Article  PubMed  Google Scholar 

  12. Irie Y, Katakami N, Kaneto H, Nishio M, Kasami R, Sakamoto K, et al. The utility of carotid ultrasonography in identifying severe coronary artery disease in asymptomatic type 2 diabetic patients without history of coronary artery disease. Diabetes Care. 2013;36:1327–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Verges B. New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. Diabetes Metab. 2005;31:429–39.

    Article  PubMed  CAS  Google Scholar 

  14. Brown WV, Clark L, Falko JM, Guyton JR, Rees TJ, Schonfeld G, et al. Optimal management of lipids in diabetes and metabolic syndrome. J Clin Lipidol. 2008;2:335–42.

    Article  PubMed  Google Scholar 

  15. Brehm A, Pfeiler G, Pacini G, Vierhapper H, Roden M. Relationship between serum lipoprotein ratios and insulin resistance in obesity. Clin Chem. 2004;50:2316–22.

    Article  PubMed  CAS  Google Scholar 

  16. Dobiás̆ová M, Frohlich J. The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate inapoB-lipoprotein-depleted plasma (FERHDL). Clin Biochem. 2001;34:583–8.

    Article  PubMed  Google Scholar 

  17. Tan MH, Johns D, Glazer NB. Pioglitazone reduces atherogenic index of plasma in patients with type 2 diabetes. Clin Chem. 2004;50:1184–8.

    Article  PubMed  CAS  Google Scholar 

  18. Mahrooz A, Gohari G, Hashemi MB, Zargari M, Musavi H, Abedini M, et al. R-carrying genotypes of serum paraoxonase (PON1) 192 polymorphism and higher activity ratio are related to susceptibility against ischemic stroke. Mol Biol Rep. 2012;39:11177–85.

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  20. Garin MC, James RW, Dussoix P, Blanché H, Passa P, Froguel P, et al. 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. 1997;99:62–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Viktorinova A, Svitekova K, Stecova A, Krizko M. Relationship between selected oxidative stress markers and lipid risk factors for cardiovascular disease in middle-aged adults and its possible clinical relevance. Clin Biochem. 2016;49:868–72.

    Article  PubMed  CAS  Google Scholar 

  22. Rizzi F, Conti C, Dogliotti E, Terranegra A, Salvi E, Braga D, et al. Interaction between polyphenols intake and PON1 gene variants on markers of cardiovascular disease: a nutrigenetic observational study. J Transl Med. 2016;14:186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Sarkar PD, Shivaprakash TM, Madhusudhan B. Association between paraoxonase activity and lipid levels in patients with premature coronary artery disease. Clin Chim Acta. 2006;373:77–81.

    Article  PubMed  CAS  Google Scholar 

  24. Zargari M, Sharafeddin F, Mahrooz A, Alizadeh A, Masoumi P. The common variant Q192R at the paraoxonase 1 (PON1) gene and its activity are responsible for a portion of the altered antioxidant status in type 2 diabetes. Exp Biol Med. 2016;241:1489–96.

    Article  CAS  Google Scholar 

  25. Van den Berg SW, Jansen EH, Kruijshoop M, et al. Paraoxonase 1 phenotype distribution and activity differs in subjects with newly diagnosed Type 2 diabetes (the CODAM Study). Diabet Med. 2008;25:186–93.

    Article  PubMed  CAS  Google Scholar 

  26. Mirdamadi HZ, Sztanek F, Derdak Z, Seres I, Harangi M, Paragh G. The human paraoxonase-1 phenotype modifies the effect of statins on paraoxonase activity and lipid parameters. Brit J Clin Pharmacol. 2008;66:366–74.

    Article  CAS  Google Scholar 

  27. Eckerson HW, Romson J, Wyte CM, la du BN. The human serum paraoxonase polymorphism: Identification of phenotypes by their response to salts. Am J Hum Genet. 1983;35:214–27.

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Patra SK, Singh K, Singh R. Paraoxonase 1: a better atherosclerotic risk predictor than HDL in type 2 diabetes mellitus. Diabetes Metab Syndr. 2013;7:108–11.

    Article  PubMed  Google Scholar 

  29. Stefanović A, Kotur-Stevuljević J, Vujović A, Spasić S, Spasojević-Kalimanovska V, Jelic-Ivanović Z, et al. Association of the atherogenic index of plasma and oxidative stress status with weight gain during non-complicated pregnancy. Clin Chem Lab Med. 2012;50:2019–25.

    Article  PubMed  Google Scholar 

  30. Aydin M, Gencer M, Cetinkaya Y, Ozkok E, Ozbek Z, Kilic G, et al. PON1 55/192 polymorphism, oxidative stress, type, prognosis and severity of stroke. IUBMB Life. 2006;58:165–72.

    Article  PubMed  CAS  Google Scholar 

  31. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008;299:1265–76.

    Article  PubMed  CAS  Google Scholar 

  32. Aviram M, Billeke S, Sorenson R, et al. Paraoxonase active site required for protection against LDL oxidation involves its free sulfhydryl group and is different from that required for its arylesterase/paraoxonase activities: selective action of human paraoxonase allozymes Q and R. Arterioscler Thromb Vasc Biol. 1998;18:1617–24.

    Article  PubMed  CAS  Google Scholar 

  33. Barbieri M, Bonafè M, Marfella R, Ragno E, Giugliano D, Franceschi C, et al. LL-paraoxonase genotype is associated with a more severe degree of homeostasis model assessment IR in healthy subjects. J Clin Endocrinol Metab. 2002;87:222–5.

    Article  PubMed  CAS  Google Scholar 

  34. Rios DL, D'Onofrio LO, Cerqueira C, Bonfim-Silva R, Carvalho HG, Santos-Filho A, et al. Paraoxonase 1 gene polymorphisms in angiographically assessed coronary artery disease: evidence for gender interaction among Brazilians. Clin Chem Lab Med. 2007;45:874–8.

    Article  PubMed  CAS  Google Scholar 

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Funding

This study was funded by Mazandaran University of Medical Sciences (Grant number: 1394–3).

Author information

Authors and Affiliations

  1. Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran

    Durdi Qujeq

  2. Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Abdolkarim Mahrooz

  3. Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Abdolkarim Mahrooz

  4. Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Km 17 Khazarabad Road, Sari, Iran

    Abdolkarim Mahrooz, Parisa Masoumi, Saleh Annemohammadzadeh & Ruzbeh Boorank

  5. Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Ahad Alizadeh

Authors
  1. Durdi Qujeq
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  4. Parisa Masoumi
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  5. Saleh Annemohammadzadeh
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Contributions

A.M. obtained the funding, contributed to the design and conduct of the study, interpretation of data and writing of the manuscript. D.Q. contributed to study design, clinical interpretation, reviewed the manuscript, and contributed to the discussion. A.A. contributed to the statistical analysis, and reviewed and edited the manuscript. P.M., S.A., and R.B. contributed to study design, researched and analyzed data, and performed the experiments. All authors drafted the manuscript and gave final approval.

Corresponding author

Correspondence to Abdolkarim Mahrooz.

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Ethics approval

The study protocol was approved by the review committee and the Ethical committee at Mazandaran University of Medical Sciences.

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Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Qujeq, D., Mahrooz, A., Alizadeh, A. et al. Genotype and phenotype of salt-stimulated paraoxonase 1 (PON1) is associated with atherogenic indices in type 2 diabetes. J Diabetes Metab Disord 17, 1–10 (2018). https://doi.org/10.1007/s40200-018-0332-z

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  • DOI: https://doi.org/10.1007/s40200-018-0332-z

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