Serum Paraoxonase Levels and PON1(192) Polymorphism in Type 2 Diabetes Mellitus Patients
Abstract
Objective: Paraoxonase-1 (PON1) is an HDL-associated enzyme implicated in the pathogenesis of atherosclerosis by protecting lipoproteins against peroxidation. PON1 has two genetic polymorphisms both due to amino acid substitution, one involving glutamine and arginine at position 192 and the other leucineand methionine at position 55. Our study aimed to compare the effect of PON192 polymorphism and PON1 activity in patients with type 2 diabetes mellitus (T2DM) and non-diabetic controls.
Material and Methods: 50 patients with T2DM and 30 non-diabetic controls were included in this study. The PON192 polymorphism was studied by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Paraoxonase activity was measured by spectrophotometric method.
Results: The frequencies of the QQ, QR and RR genotypes were found as 36.5 and 14% in type 2 diabetes patients and 26.67, 46.66, 26.67% in control subjects, respectively. The paraoxonase activity was detected at lower levels in diabetics (102.0 ±38.9) than in control subjects (158.1±63.7). PON1192 RR homozygotes had significantly higher PON activity than QR and QQ genotypes among control and type 2 diabetes patients (p<0.005).
Conclusion: In comparing the activities of three genotypes of the control and type 2 diabetic groups; all activities were found significantly lower in diabetics. In conclusion, we suggested that paraoxonase activities are affected by PON1 genetic variability in patients with type 2 diabetes mellitus and controls.
References
Mackness MI, Durrington PN. HDL, its enzymes and its potential to influence lipid peroxidation. Atherosclerosis 1995;115:243–53.
Costa LG, Furlong CE, editors. Paraoxonase (PON1) in health and disease basic and clinical aspects. Norwell, MA: Kluwer Academic publishers; 2002; 165-168.
Mackness MI, Mackness B, Durrington PN, Connelly PW, Hegele RA. Paraoxonase biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol 1996;7: 69-76.
Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of human serum paraoxonase activity polymorphism. NatGenet 1993,3:73-6.
Li HL, Liu DP, Liang CC. Paraoxonase gene polymorphisms, oxidative stress, and diseases. J Mol Med 2003; 81: 766-9.
Costa LG, Vitalone A, Cole TB, Furlong CE. Modulation of paraoxonase (PON1) activity. BiochemPharmacol 2005; 69: 541-50.
Mackness B, Durrington PN, Mackness MI. Human serum paraoxonase.Gen Pharmacol 1998; 31: 329-36.
Boemi M, Leviev I, Sirolla C, Pieri C, Marra M, James RW. Serum paraoxonase is reduced in type 1 diabetic patients compared to non-diabetic, first degree relatives; influence on the ability of HDL to protect LDL from oxidation. Atherosclerosis 2001; 155: 229-35.
McElveen J, Mackness MI, Colley CM, Peard T, Warner S, Walker CH. Distribution of paraoxon hydrolytic activity in the serum of patients after myocardial infarction. Clin Chem 1986;32: 671-3.
Agachan B, Yilmaz H,Karaali Z, Isbir T. Paraoxonase (PON1) 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.
Mackness B, Mackness M. Paraoxonase 1: biochemistry and contribution to atherosclerosis. International Congress Series 2004;1262:91-4.
Ikeda Y, Inoue M, Suehiro T, Arii K, Kumon Y, Hashimoto K. Low human paraoxonase predicts cardiovascular events in Japanese patients with type II diabetes. Acta Diabetol 2009;46:239-42.
Gocmen AY, Ozdemir L, Gumuslu S, Semiz E. Koroner Arter Hastalığı Olan Diyabetik ve Non diyabetik Hastalarda Paraoksonaz 1 Aktivitesive Lipid Peroksidasyonu Belirteç Düzeyleri Arasındaki İlişki. Turkiye Klinikleri J Endocrin 2010; 5: 74-80.
Abbott CA, Mackness MI, Kumar S, Boulton AJ, Durrington PN. Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arterioscler Thromb Vasc Biol 1995; 15: 1808-12.
Serrato M, Marian AJ. A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease.J Clin Invest 1995 ; 96: 3005-8.
Ikeda Y, Suehiro T, Inoue M, Nakauchi Y, Morita T, Arii K, et al. Serum paraoxonase activity and its relationship to diabetic complications in patients with non-insulin-dependent diabetes mellitus.Metabolism 1998; 47: 598-602.
Ozdemirkıran F, Bozkaya G, Onman T, Gumus T, Ormen M, Çoban S, et al. Tip 2 Diyabetik Hastalarda RoziglitazonunAdiponektin, Paraoksonaz-1, İnsülin Direnci ve Lipid Parametrelerine Etkisi. Turkiye Klinikleri J Endocrin 2009; 4: 47-52.
Mackness B, Mackness MI, Arrol S, Turkie W, Julier K, Abuasha B, et al. Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. Atherosclerosis 1998;139: 341-9.
Mackness MI, Arrol S, AbbottCA, Durrington PN. Is paraoxonase related to atherosclerosis. Chem Biol Interact 1993; 87: 161-71.
Pfohl M, Koch M, Enderle MD, Kuhn R, Fullhase J, Karsch KR, et al. Paraoxonase 192 Gln/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes. Diabetes 1999; 48: 623-7.
Heinecke JW, Lusis AJ. Paraoxonase-gene polymorphisms associated with coronary heart disease: support for the oxidative damage hypothesis ? Am J Hum Genet 1998; 62: 20-4.
Mackness MI, Harty D, Bhatnagar D, Winocour PH, Arrol S, Ishola M, et al. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis 1991; 86: 193-9.
Allebrandt KV, Souza RL, Chautard-Freire-Maia EA. Variability of the paraoxonase gene (PON1) in Euro- and Afro-Brazilians. Toxicol Appl Pharmacol 2002; 180: 151-6.
Cherry N, Mackness M, Durrington P, Povey A, Dippnall M, Smith T, et al. Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip. Lancet 2002; 359: 763-4.
Ito T, Yasue H, Yoshimura M, Nakamura S, Nakayama M, Shimasaki Y, et al. Paraoxonase gene Gln192Arg (Q192R) polymorphism is associated with coronary artery spasm. Hum Genet 2002;110:89-94.
Osei-Hyiaman D, Hou L, Mengbai F, Zhiyin R, Zhiming Z, Kano K. Coronary artery disease risk in Chinese type 2 diabetics: is there a role for paraxonase 1 gene (Q192R) polymorphism? Eur J Endocrinol 2001; 144: 639-44.
Worth J. Paraoxonase polymorphisms and organophosphates. Lancet 2002;360: 802-3.
Malin R, Knuuti J, Janatuinen T, Laaksonen R, Vesalainen R, Nuutila P, et al. Paraoxonase gene polymorphisms and coronary reactivity in young healthy men. J Mol Med 2001;79: 449-58.
Sangvanich P, Mackness B, Gaskell SJ, Durrington P, Mackness M. The effect of high-density lipoproteins on the formation of lipid/protein conjugates during in vitro oxidation of low-density lipoprotein. Biochem Biophys Res Commun 2003; 300: 501-6.
Voetsch B, Benke KS, Damasceno BP, Siqueira LH, Loscalzo J. Paraoxonase 192 Gln-->Arg polymorphism: an independent risk factor for nonfatal arterial ischemic stroke among young adults. Stroke 2002; 33: 1459-64.
Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN. Effect of the molecular polymorphisms of human paraoxonase (PON1) on the rate of hydrolysis of paraoxon. Br J Pharmacol 1997;122: 265-8.
Agachan B, Yilmaz H, Ergen HA, Karaali ZE, Isbir T.Paraoxonase (PON1) 55 and 192 polymorphism and its effects to oxidant-antioxidant system in Turkish patients with type 2 diabetes mellitus. Physiol Res 2005; 54: 287-93.
Mackness MI, Arrol S, Mackness B, Durrington PN. Alloenzymes of paraoxonase and effectiveness of high-density lipoproteins in protecting low-density lipoprotein against lipid peroxidation. Lancet 1997; 349: 851-2.
Hu Y, Tian H, Liu R. Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese. Diabetes Res ClinPract 2003; 61: 21-7.
Antikainen M, Murtomaki S, Syvanne M, Pahlman R, Tahvanainen E, Jauhiainen M, et al. The Gln-Arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns J Clin Invest 1996; 98: 883-5.
Aubo C, Senti M, Marrugat J, Tomas M, Vila J, Sala J, et al. Risk of myocardial infarction associated with Gln/Arg 192 polymorphism in the human paraoxonase gene and diabetes mellitus. The REGICOR Investigators. Eur Heart J 2000; 21: 33-8.
Helbecque N, Cottel D, Meirhaeghe A, Dallongeville J, Amouyel P. Paraoxonase (Gln192-Arg) polymorphism in French type 2 diabetics. Atherosclerosis 1999;147: 415-6.
Pati N, Pati U. Paraoxonase gene polymorphism and coronary artery disease in Indian subjects. Int J Cardiol 1998; 66: 165-8.
Altuner D, Suzen SH, Ates I, Koc GV, Aral Y, Karakaya A. Are PON1 Q/R 192 and M/L 55 polymorphisms risk factors for diabetes complications in Turkish population? Clin Biochem 2011; 44:372-6.
Ergun MA, Yurtcu E, Demirci H, Ilhan MN, Barkar V, Yetkin I, et al. Biochem Genet. PON1 55 and 192 gene polymorphisms in type 2 diabetes mellitus patients in a Turkish population. Biochem Genet 2011; 49:1-8.
Altuner D, Ates I, Suzen SH, Koc GV, Aral Y, Karakaya A. The relationship of PON1 QR 192 and LM 55 polymorphisms with serum paraoxonase activities of Turkish diabetic patients. Toxicol Ind Health. 2011;27:873-8.
