Abstract

Introduction: The activity of human Paraoxonase 1 (PON1), an HDL-associated enzyme with anti-atherogenic properties, has been observed to be reduced in a number of diseases, including diabetes. This has partly been attributed to a PON1 Glutamine (Q)/Arginine (R) polymorphism at codon 192 of the PON1 gene. Aim: To determine the prevalence of PON1 Q192R polymorphism in Ghanaian patients with type 2 diabetes (T2DM), and it impact on lipid profiles of T2DM subjects. Methods: PON1 Q192R was genotyped in 112 individuals with type 2 diabetes mellitus (T2DM) and 97 nondiabetic control individuals, using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. Other investigations determined using standard methods included fasting blood glucose (FPG), body mass index (BMI), lipid profile, atherogenic indices and hip-waist ratios. Results: The PON1 RR genotype found to be was the most common in both T2DM patients (74.6 %) and controls (57.1 %), whilst the QR genotype was the least frequent in both groups (7.3 % and 9.5% for T2DM and controls respectively). These genotype distributions were however not significantly different between the study groups. Allele frequencies in T2DM and the control groups were significantly different, with R allele being the most common in both T2DM patients and controls. The R allele was found to be increased in T2DM. The Q192R genotype does not consistently affect the lipid and lipoprotein concentrations of T2DM and healthy populations. Conclusion: The RR genotype was the most predominant in T2DM patients and healthy individuals within a Ghanaian population. The prevalence of the R allele in T2DM may have implications for the metabolism of oxidized lipoproteins as these oxidative modifications are central to the development of cardiovascular disease in T2DM.

References

1. Mackness MI, Mackness B, Durrington PN, et al.: Paraoxonase: Biochemistry, genetics, and relationship to plasma lipoproteins. Cur. Opin. Lipidol. 1996, 7:69-76. 10.1097/00041433-199604000-00004
2. Montella IR, Schama R, Valle D: The classification of esterases: An important gene family involved in insecticide resistance. A review. Mem Inst Oswaldo Cruz. 2012, 107:437-49. 10.1590/s0074-02762012000400001
3. Costa C, Gangemi S, Giambò F, et al.: Oxidative stress biomarkers and paraoxonase 1 polymorphism frequency in farmers occupationally exposed to pesticides. Mol Med Rep. 2015, 12:6353-6357. 10.3892/mmr.2015.4196
4. Sharma GS, Kumar T, Singh LR: N-homocysteinylation induces different structural and functional consequences on acidic and basic proteins. PLoS One. 2014, 9:1163. 10.1371/journal.pone.0116386
5. Costa LG, Vitalone A, Cole TB, and Furlong CE: Modulation of paraoxonase (PON1) activity. Biochem. Pharmacol. 2005, 69:541-550.
6. Durrington PN, Mackness B, Mackness MI: The hunt for nutritional and pharmacological modulators of paraoxonase. Arterioscler. Thromb. Vasc. Biol. 2002, 22:1248-1250.
7. Wysocka A Zwolak A: The Relevance of non-coding DNA variations of Paraoxonase gene cluster in 5 of 6: Atherosclerosis-related diseases. Int. J. Mol. Sci. 2021, 22:2137.
8. Levy D, Reichert CO, Bydlowski SP: Paraoxonases Activities and Polymorphisms in Elderly and Old-Age Diseases: An Overview. Antioxidants. 2019, 8:118.
9. Leviev I, James RW: Promoter polymorphisms of human paraoxonase PON 1 gene and serum paraoxonase activities and concentrations. Arterioscler. Thromb. Vasc. Biol. 2000, 20:516-521. 10.1161/01.ATV.20.2.516
10. Mahsa A, Sedigheh EB, Amir A, et al.: Paraoxonase-1 Q192R polymorphism and its association with hs-CRP and fasting blood glucose levels and risk of coronary artery disease. Diabetes Metab. Syndr. 2019, 13:1053-1057.
11. Flekac M, Skrha J, Zidkova K, Lacinova Z, Hilgertova J: Paraoxonase1 gene polymorphisms and enzyme activities in diabetes mellitus. Physiol. Res. 2008, 57:717-726. 10.33549/physiolres.931285
12. Abbot CA, Mackness, MI, Kumar S: Serum Paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus in relation to serum lipids and lipoproteins. Thromb. Vasc. Biol. 1995, 15:1812. 10.1161/01.atv.15.11.1812
13. Wild S, Roglic G, Sicree R, King H: Global prevalence of Diabetes estimates for the year 2000 and projections. for. 20302004, 27:1047-1053. 10.2337/diacare.27.5.1047
14. Tuomilehto J, Lindstrom J, Eriksson JG, et al.: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 2001, 344:1343-1350. 10.1056/NEJM200105033441801
15. Karakaya P. Ozdemir B. Mert M. Okuturlar Y: Relation of Paraoxonase 1 Activity with Biochemical Variables, Brachial Artery Intima-Media Thickness in Patients with Diabetes with or without Obesity. Obes Facts. 2018, 11:56-66.
16. Tward A, Xia YR, Wang XP, et al.: Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation. 2002, 23:484-90. 10.1161/01.ATV.0000222924.62641.aa
17. Mackness B, Quarck R, Verreth W, et al.: Human paraoxonase 1 over-expression inhibits atherosclerosis in a mouse model of metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 2006, 26:1545-1550. 10.1161/01.ATV.0000222924. 62641.aa
18. WHO: Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus. World Health Organization. 1999
19. Friedewald 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.
20. Mackness MI, Mackness B, Durrington PN, et al.: Paraoxonase and coronary heart disease. Curr Opin Lipidol. 1998, 9:319-24. 10.1097/00041433-199808000-00006
21. Bounafaa A, Berrougui H, Ghalim N, et al.: Association between Paraoxonase 1 (PON1) Polymorphisms and the Risk of Acute Coronary Syndrome in a North African Population. PLoS ONE. 2015, 10:0133719.
22. Draganov DI, La Du BN: Pharmacogenetics of paraoxonases: a brief review. Naunyn Schmiedebergs Arch Pharmacol. 2004, 69:78-88.
23. Khodier SA, Abd El Raouf YM, Amer AE, et al.: Paraoxonase gene polymorphism and activity in type 2 diabetes mellitus with microvascular complications. J. Amer. Sci. 2012, 8:303-309. 10.1007/s00210-003-0833-1
24. El Fasakhany FM, El-Segay O, Alahwal L, et al.: Paraoxonse 1 activity and paraoxonase 192 gene polymorphism in non-insulin dependent diabetes mellitus patients among Egyptian population. Tanta Med Sci J. 2007, 2:68-77.
25. Agachan B, Yilmaz H, Karaali Z, et al.: Paraoxonase 55 and 192 polymorphism and its relationship to serum paraoxonase activity and serum lipids in Turkish patients with non-insulin dependent diabetes mellitus. Cell Biochem Funct. 2004, 22:163-8. 10.1002/cbf.1070.