Paraoxonase 1 polymorphisms (L55M and Q192R) as a genetic marker of diabetic nephropathy in youth with type 1 diabetes
Abstract
Introduction: Paraoxonase 1 (PON1) polymorphisms have been largely involved in diabetes complications. The aim of the study is to evaluate the effects of PON1 polymorphisms (L55M and Q192R) on diabetic nephropathy (DN).
Material and methods: The study involved 116 children and adolescents with type 1 diabetes (T1D) and 91 healthy subjects. Albumin excretion rate (AER) was determined by immunoturbidimetry. PON1 activity was measured by a spectrophotometric method, and genotyping of PON1 gene was assessed by multiplex PCR followed by RFLP.
Results: PON1 activity was inversely correlated to AER (r = –0.245, p = 0.008). A significant decrease (p = 0.037) in PON1 activity was shown between patients with nephropathy and those without (162 [57–618] vs. 316 [37–788] IU/L, respectively). The distribution of AER was, for L55M polymorphism MM > LM > LL (p = 0.002), and for Q192R polymorphism QQ > QR > RR (p < 0.001). The opposite distribution was noted for PON 1 activity (p < 0.001). LMQQ and MMQQ haplotypes seem to increase AER (p = 0.004, p = 0.003, respectively) and to reduce PON1 activity (p = 0.011, p = 0.052, respectively) in youths with T1D. However, LLRR haplotype seems to have the opposite effect.
Conclusions: This study demonstrated that PON1 polymorphisms L55M and Q192R seem to be genetic markers involved in the development of DN in T1D. (Endokrynol Pol 2017; 68 (1): 35–41)
Keywords: paraoxonase 1 polymorphismstype 1 diabetesdiabetic nephropathyparaoxonase 1 activity
References
- Nowak M, Wielkoszyński T, Marek B, et al. Antioxidant potential, paraoxonase 1, ceruloplasmin activity and C-reactive protein concentration in diabetic retinopathy. Clin Exp Med. 2010; 10(3): 185–192.
- Tabur S, Korkmaz H, Eren MA, et al. Urotensin-II level and its association with oxidative stress in early diabetic nephropathy. J Diabetes Complications. 2015; 29(1): 115–119.
- Mackness M, Mackness B. Current Aspects of Paraoxonase-1 Research. In: Tsugikazu Komoda. The HDL Handbook: Biological functions and clinical implications. 2nd ed. Academic Press; 2014; (Chapter11) pages 273–291.
- Altuner D, Suzen SH, Ates I, et al. Are PON1 Q/R 192 and M/L 55 polymorphisms risk factors for diabetes complications in Turkish population? Clin Biochem. 2011; 44(5-6): 372–376.
- 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. 2013; 51(1-2): 76–91.
- Fekih O, Triki S, Hellara I, et al. Is paraoxonase 1 a marker of cardiovascular risk in youth with type 1 diabetes? (Study about 109 cases). Presse Med. 2015; 44(5): e185–e190.
- Shahmohamadnejad S, Vaisi-Raygani A, Shakiba Y, et al. Association between butyrylcholinesterase activity and phenotypes, paraoxonase192 rs662 gene polymorphism and their enzymatic activity with severity of rheumatoid arthritis: correlation with systemic inflammatory markers and oxidative stress, preliminary report. Clin Biochem. 2015; 48(1-2): 63–69.
- Boemi M, Leviev I, Sirolla C, et al. 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(1): 229–235.
- Tomás M, Latorre G, Sentí M, et al. The antioxidant function of high density lipoproteins: a new paradigm in atherosclerosis. Rev Esp Cardiol. 2004; 57(6): 557–569.
- Suszyńska-Zajczyk J, Sikora M, Jakubowski H. Paraoxonase 1 deficiency and hyperhomocysteinemia alter the expression of mouse kidney proteins involved in renal disease. Mol Genet Metab. 2014; 113(3): 200–206.
- Murata M, Maruyama T, Suzuki Y, et al. Paraoxonase 1 Gln/Arg polymorphism is associated with the risk of microangiopathy in Type 2 diabetes mellitus. Diabet Med. 2004; 21(8): 837–844.
- Tiwari AK, Prasad P, B K T, et al. Oxidative stress pathway genes and chronic renal insufficiency in Asian Indians with Type 2 diabetes. J Diabetes Complications. 2009; 23(2): 102–111.
- Durrington PN, Mackness B, Mackness MI. Paraoxonase and atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21:473-480.
- Hofer SE, Bennetts B, Chan AK, et al. Association between PON 1 polymorphisms, PON activity and diabetes complications. J Diabetes Complications. 2006; 20(5): 322–328.
- Leviev I, Righetti A, James RW. Paraoxonase promoter polymorphism T(-107)C and relative paraoxonase deficiency as determinants of risk of coronary artery disease. J Mol Med (Berl). 2001; 79(8): 457–463.
- Abbott CA, Mackness MI, Kumar S, et al. Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arterioscler Thromb Vasc Biol. 1995; 15(11): 1812–1818.
- Boemi M, Leviev I, Sirolla C, et al. 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(1): 229–235.
- Kao YL, Donaghue K, Chan A, et al. A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. J Clin Endocrinol Metab. 1998; 83(7): 2589–2592.
- Mackness MI, Harty D, Bhatnagar D, et al. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis. 1991; 86(2-3): 193–199.
- Araoud M. Development of an automated method for the determination of human paraoxonase1 activity. Asian Biomedicine. 2011; 5(2).
- Motti C, Dessì M, Gnasso A, et al. A multiplex PCR-based DNA assay for the detection of paraoxonase gene cluster polymorphisms. Atherosclerosis. 2001; 158(1): 35–40.
- Krolewski AS. Genetics of diabetic nephropathy: evidence for major and minor gene effects. Kidney Int. 1999; 55(4): 1582–1596.
- Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999; 48(1): 1–9.
- Connelly PW, Zinman B, Maguire GF, et al. Association of the novel cardiovascular risk factors paraoxonase 1 and cystatin C in type 2 diabetes. J Lipid Res. 2009; 50(6): 1216–1222.
- Bhattacharyya T, Nicholls SJ, Topol EJ, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008; 299(11): 1265–1276.
- Gugliucci A, Menini T. Paraoxonase 1 and HDL maturation. Clin Chim Acta. 2015; 439: 5–13.
- Tannus LR, Drummond KR, Clemente EL, et al. Brazilian Type 1 Diabetes Study Group (BrazDiab1SG). Predictors of cardiovascular autonomic neuropathy in patients with type 1 diabetes. Front Endocrinol (Lausanne). 2014; 5: 191.
- Mackness B, Durrington PN, Boulton AJM, et al. Serum paraoxonase activity in patients with type 1 diabetes compared to healthy controls. Eur J Clin Invest. 2002; 32(4): 259–264.
- Deakin SP, James RW. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci (Lond). 2004; 107(5): 435–447.
- Gugliucci A, Kinugasa E, Ogata H, et al. Activation of paraoxonase 1 after hemodialysis is associated with HDL remodeling and its increase in the HDL2 fraction and VLDL. Clin Chim Acta. 2014; 430: 9–14.
- Sun Ym. [Study of SOD and PON-1 expression in type 2 diabetes mellitus nephropathy and its clinical significance]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2010; 26(11): 1120–1121.
- Ikeda Y, Suehiro T, Inoue M, et al. Serum paraoxonase activity and its relationship to diabetic complications in patients with non-insulin-dependent diabetes mellitus. Metabolism. 1998; 47(5): 598–602.
- Wang H, Deng H, Liu W. [The effects of paraoxonase-1 and oxidized low density lipoprotein on nephropathy in type-2 diabetes mellitus]. Zhonghua Nei Ke Za Zhi. 2002; 41(3): 179–182.
- Flekac M, Skrha J, Zídková K, et al. Paraoxonase 1 gene polymorphisms and enzyme activities in diabetes mellitus. Physiol Res. 2008; 57(5): 717–726.
- Sepahvand F, Rahimi-Moghaddam P, Shafiei M, et al. Frequency of paraoxonase 192/55 polymorphism in an Iranian population. J Toxicol Environ Health A. 2007; 70(13): 1125–1129.
- Haj Mouhamed D, Ezzaher A, Mechri A, et al. Effect of cigarette smoking on paraoxonase 1 activity according to PON1 L55M and PON1 Q192R gene polymorphisms. Environ Health Prev Med. 2012; 17(4): 316–321.
- Ergun MA, Yurtcu E, Demirci H, et al. PON1 55 and 192 gene polymorphisms in type 2 diabetes mellitus patients in a Turkish population. Biochem Genet. 2011; 49(1-2): 1–8.
- Jenkins AJ, Klein RI, Zheng D, Hunter S, Smith K, Lyons TJ. Paraoxonase genotype (192 Gln-Arg) and serum paraoxonase-arylesterase activity: Relationship with Type 1 diabetes and nephropathy. Diabetes 2000; 49(1): A157.
- Kao Y, Donaghue KC, Chan A, et al. Paraoxonase gene cluster is a genetic marker for early microvascular complications in type 1 diabetes. Diabet Med. 2002; 19(3): 212–215.
- Wang J, Yang MM, Rong SS, et al. Association of paraoxonase gene polymorphisms with diabetic nephropathy and retinopathy. Mol Med Rep. 2013; 8(6): 1845–1851.
- Altuner D, Ates I, Suzen SH, et al. The relationship of PON1 QR 192 and LM 55 polymorphisms with serum paraoxonase activities of Turkish diabetic patients. Toxicol Ind Health. 2011; 27(10): 873–878.
- Kaman D, Ilhan N, Metin K, et al. A preliminary study of human paraoxonase and PON 1 L/M55-PON 1 Q/R 192 polymorphisms in Turkish patients with coronary artery disease. Cell Biochem Funct. 2009; 27(2): 88–92.
- Ozkök E, Aydin M, Babalik E, et al. Combined impact of matrix metalloproteinase-3 and paraoxonase 1 55/192 gene variants on coronary artery disease in Turkish patients. Med Sci Monit. 2008; 14(10): CR536–CR542.
- Arca M, Ombres D, Montali A, et al. 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. 2002; 32(1): 9–15.
- Shemesh T, Whybra C, Delgado-Sanchez S, et al. Paraoxonase (PON1) gene polymorphisms in Fabry disease: correlation with renal disease. Nephron Clin Pract. 2010; 116(4): c289–c293.
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)