Volume 7, Issue 6, December 2019, Page: 121-132
Correlation Between Serum PON1 Arylesterase Activity and Rs 854573 PON1 A < G Polymorphism with Type 2 Diabetes in an Eastern Indian Cohort
Suranjana Ray Haldar, Department of Biochemistry, University of Calcutta, Kolkata, India
Atish Haldar, Department of ENT, Calcutta National Medical College, Kolkata, India
Ipshit Mishra, Department of Surgery, Calcutta National Medical College, Kolkata, India
Arpita Chakarabarty, Institute of Postgraduate Medical Education and Research, Government of West Bengal, Kolkata, India
Sanghamitra Sengupta, Department of Biochemistry, University of Calcutta, Kolkata, India
Maitree Bhattacharyya, Department of Biochemistry, University of Calcutta, Kolkata, India
Received: Sep. 28, 2019;       Accepted: Oct. 25, 2019;       Published: Oct. 31, 2019
DOI: 10.11648/j.ajbls.20190706.11      View  275      Downloads  115
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder of glucose and lipids and characterized by defect in insulin secretion or action. Oxidative imbalance has also been implicated in the etiology of diabetes. Paraoxonase-1 (PON1) is an esterase and lactonase which is found in the circulation bound to high-density lipoproteins (HDL). Alterations and associations of circulating PON1 levels with a variety of diseases including diabetes encourages us to investigate the possible association between PON1 A/G rs854573 polymorphism and serum PON1 activity with T2DM. The study essentially follows a population based case-control format with 101 diabetic and 102 healthy controls. The findings revealed association of polymorphism with the diseased status (p value 0.0002, OR 3.49, 95% CI 1.77 to 6.9). With significantly higher range of mean serum PON1 Arylesterase (AREase) activity in control (9.99 – 0.96 kU/L) than in diabetic patients (5.25 - 0.508 kU/L) (p value,<0.001), a large difference between common diabetic AA genotype and combined diabetic heterozygous and homozygous genotypes (AG+GG) for risk allele G (assymptometic p value,<0.001), or in between two AA genotypes (Diabetic/Non diabetic, p<0.001), was explored by parametric and non parametric statistical pairwise comparison. Serum PON1 activity was found to be independent of other clinical factors such as plasma glucose levels. Western blot analysis of serum samples detected a significant difference of PON1 proteins in diabetic patients and control subjects (p value 0.008). In conclusion serum PON1 AREase activity which to an extent correlated with PON1 promoter polymorphism might be a good predictor of the disease risk.
AREase Activity, Oxidative Stress, Polymorphism, PON1, T2DM, Western Blot
To cite this article
Suranjana Ray Haldar, Atish Haldar, Ipshit Mishra, Arpita Chakarabarty, Sanghamitra Sengupta, Maitree Bhattacharyya, Correlation Between Serum PON1 Arylesterase Activity and Rs 854573 PON1 A < G Polymorphism with Type 2 Diabetes in an Eastern Indian Cohort, American Journal of Biomedical and Life Sciences. Vol. 7, No. 6, 2019, pp. 121-132. doi: 10.11648/j.ajbls.20190706.11
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Moore, D. J., Gregory, J. M., Kumah-crystal, Y. A., Simmons, J. H., 2009. Mitigating micro- and macro-vascular complications of diabetes beginning in adolescence. Vasc Health Risk Manag. 5, 1015–1031.
Wild, S., Roglic, G., Green, A., Sicree, R., King, H., 2004. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27, 1047–1053.
Adak, S., Sengupta, S., Chowdhury, S., Bhattacharyya, M., 2010. Co existence of risk and protective haplotypes of Calpain 10 gene to type 2 diabetes in the eastern Indian population. Diabet. Vasc. Dis. Res. 7, 63–68.
Ray Haldar, S., Bhattacharyya, M., 2014. Oxidative stress: Lipiperoxidation products as predictors in disease progression. Journal of Experimental and Integrative Medicine 4, 151-163.
Furlong, C. E., Suzuki, S. M., Stevens, R. C., Marsillach, J., Richter, R. J., Jarvik, G. P., Checkoway, H., Samii, A., Costa L. G., Griffith, A., Roberts J. W., Yearout, D., Zabetian, C. P., 2010. Human PON1, a biomarker of risk of disease and exposure. Chem. Biol. Interact. 187, 355–361.
Draganov, D. I., Teiber, J. F., Speelman, A., Osawa, Y., Sunahara, R., La Du, B. N., 2005. Human paraoxonase (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J. Lip. Res. 46, 1239-1247.
Mackness, M. I., Arrol, P., Durrington, P. N., 1993. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis 104, 129-135.
Mackness, B., Quack, R., Verreth, W., Mackness, M., Holvoet, P., 2006. Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome. Arterioscler Thromb Vasc. Biol. 26, 1545-1550.
Camps, J., Marsillach, J., Rull, A., Alonso-Villaverde, C., Joven, J., 2010. Interrelationships between paraoxonase-1 and monocytes chemoattractant protein-1 in the regulation of hepatic inflammation. Adv. Exp. Med. Biol. 660, 5-18.
Parthasarathy, S., Barnett, J., Fong, L. G., 1990. High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim. Biophys. Acta. 1044, 275–83.
Aviram, M., Rosenblat, M., Bisgaier, C. L., Newton, R. S., Primo-Parmo, S. L., La Du, B. N., 1998. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative 15, 1581-90.
Mackness, M. I., Arrol, S., Durrington, P. N., 1991. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. 286, 152–4.
Deakin, S., Leviev, I., Gomaraschi, M., Calabresi, L., Franceschini, G., James, R. W., 2002. Enzymatically active paraoxonase-1 is located at the external membrane of producing cells and released by a high affinity, saturable, desorption mechanism. J. Biol. Chem. 277, 4301–8.
Deakin, S., Moren, X., James, R. W., 2005. Very low density lipoproteins provide a vector for secretion of paraoxonase-1 from cells. Atherosclerosis 179, 17–25.
Ceron, J. J., Tecles, F., and Tvarijonaviciute, A., 2014. Serum paraoxonase 1 (PON1) measurement: an update. BMC Veterinary Research 10, 74.
Dantoine, T., Debord, J., Charmes, J. P., Merle L., Marquet, P., Lachatre, G., Leroux- Robert, C., 1998. Decrease of serum paraoxonase activity in chronic renal failure. J. Am. Soc. Nephrol. 9, 2082–2088.
Keskin, M., Dolar, E., Dirican, M., Kiyici, M., Ylmaz, Y., Gurel, S., Nak, S. G., Erdinc, S., Gulten, M., 2009. Baseline and salt-stimulated paraoxonase and arylesterase activities in patients with chronic liver disease: relation to disease activity. Inter. Med. J. 39, 243–248.
Ferré, N., Feliu, A., García-Heredia, A., Marsillach, J., París, N., Zaragoza-Jordana, M., Mackness, B., Mackness, M., Escribano, J., Closa-Monasterolo, R., Joven, J., Camps, J., 2013. Impaired paraoxonase-1 status in obese children. Relationships with insulin resistance and metabolic syndrome. Clin. Biochem. 46, 1830-6.
Gupta, N., Binu, K. B. K., Singh, S., et al., 2011. Low Serum PON1 activity: An independent risk factor for coronary artery disease in North-West Indian type 2 diabetics. Gene 487, 13-19.
Wheeler, J. G., Keavney, B. D., Watkins, H., Collins, R., Danesh, J., 2004. Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies. Lancet 363, 689–695.
Boemi, M., Leviev, I., Sirolla, C., Pieri, C., Marra, M., James, R. W., 2001. 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 155, 229–235.
MacKness, B., Mackness, M. I., Durrington, P. N., Arrol, S., Evans, A. E., et al., 2000. Paraoxonase activity in two healthy populations with differing rates of coronary heart disease. Euro. J. Clin. Invest. 30, 4–10.
Sonoki, K., Iwase, M., Sasaki, N., Ohdo, S., Higuchi, S., Matsuyama, N., Iida, M., 2009. Relations of lyso phosphatidylcholine in low-density lipoprotein with serum lipoprotein- associated phospholipase A2, paraoxonase and homocysteine thiolactonase activities in patients with type 2 diabetes mellitus. Diabetes Res. Clin. Pract. 86, 117–123.
Ueno, et al., Ueno, T., Shimazaki, E., Matsumoto, T., Watanabe, H., Tsunemi, A., Takahashi, Y., Mori, M., Hamano, R., Fujioka, T., Soma, M., Matsumoto, K., Kanmatsuse, K., 2003. Paraoxonase1 polymorphism Leu-Met55 is associated with cerebral infarction in Japanese population. Med. Sci. Monit. 9, CR208–CR212.
Aynacioglu, A. S., Kepekci, Y., 2000. The human paraoxonase Gln-Argl92 (Q/R) polymorphism in Turkish patients with coronary artery disease. Int. J. Cardiol. 74, 33–37.
Ozko¨k. et al., Ozko.¨k. E., Aydin, M., Babalik, E., Ozbek, Z., Ince, N., Kara, I., 2008. Combined impact of matrix metalloproteinase-3 and paraoxonase 1 55/192 gene variants on coronary artery disease in Turkish patients. Med. Sci. Monit. 14, CR536–CR542.
Gluba, A., Pietrucha, T., Banach, M., Piotrowski, G., Rysz, J., 2010. The role of polymorphisms within paraoxonases (192 Gln/Arg in PON1 and 311 Ser/Cys in PON2) in the modulation of cardiovascular risk: a pilot study. Angiology 61, 157–165.
Agrawal, S., Tripathi, G., Prajnya, R., Sinha, N., Gilmour, A., Bush, L., Mastana, S., 2009. Paraxonase 1 gene polymorphisms contribute to coronary artery disease risk among north Indians. Ind. J. Med. Sci. 63, 335–344.
Miller, S. A., Dykes, D. D., Polesky, H. F., 1988. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215.
Haagen, L., and Brock, A. A., 1992. New automated method for phenotyping arylesterase based upon inhibition of enzymatic hydrolysis of 4-nitrophenlyacetate by phenylacetate. Eur. J. Clin. Chem. 30, 391-395.
Eckerson, H. W., Wyte, C. M., La Du, B. N., 1983. The human serum paraoxonase/ arylesterase polymorphism. Am. J. Hum. Genet. 35, 1126–38.
Lewis, C., 2002. Genetic association studies: Design, analysis and Interpretation. Briefs in Bioinformatics 3, 146-153.
Deakin, S. P., and James, R. W., 2004. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin. Sci. (Lond.). 107, 435–447.
Hofer, S. E., Bennetts, B., Chan, A. K., Holloway, B., Karschimkus, C., Jenkins, A. J., Silink, M., and Donaghue, K. C., 2006. Association between PON1 polymorphisms, PON1 activity and diabetes complications. J. Diabetes Complications 20, 322–328.
Hampe, M. H., Mogarekar, M. R., 2014. Paraoxonase1 activity, its Q192R polymorphism and diabetic retinopathy in type 2 diabetes mellitus. Int. J. Biomed. Adv. Res. 5, 35-40.
Ergun, M. A., Yurtcu, E., Demirci, H., Ilhan, M. N., 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.
Pappa, K. I, Gazouli, M., Anastasiou, E., Loutradis D., & Anagnou, N. P., 2017. The Q192 Rpolymorphism of the paraoxonase-1 (PON1) gene is associated with susceptibility to gestational diabetesmellitus in the Greek population. Gynecol Endocrinol. 33( 8): 617-620.
Kao, Y. L., Donaghue, K., Chan, A., Knight, J., Silink, M., 1998. A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. J. Clin. Endocrinol. Metab. 83, 2589–2592.
Zama, T., Murata, M., Matsubara, Y., Kawano, K., Aoki, N., Yoshino, H., Watanabe, G., Ishikawa, K., Ikeda, Y., 1997. A 192Arg variant of the human paraoxonase (HUMPONA) gene polymorphism is associated with an increased risk for coronary artery disease in the Japanese. Arterioscler. Thromb. Vasc. Biol. 17, 3565–3569.
Prakash, M., Phani, N. M., Kavya, R., Supriya, M., 2010. Paraxonase: Its antiatherogenic role in chronic renal failure. Indian J. Nephrology 20, 9-14.
Riedmaier, S., Klein, K., Winter, S., Hofmann, U., Schwab, M., and Zanger, U. M., 2011. Paraoxonase (PON1 and PON3) polymorphisms: impact on liver expression and atorvastatin-lactone hydrolysis. Frontiers in Pharmcology 2, 1- 20.
Eom, S. Y., Yim, D. H., Lee, C. H., Choe, K. H., An, J. Y., Lee, K. Y., Kim, Y. D., Kim, H., 2015. Interactions between Paraoxonase 1 Genetic Polymorphisms and Smoking and Their Effects on Oxidative Stress and Lung Cancer Risk in a Korean Population. Plos One 10 (3): e0119100.
Tiwari, A. K., Prasad, P., Thelma, B. K., Prasanna, K. M., Ammini, A. C., Gupta, A., Gupta, R., 2009. Oxidative stress pathway genes and chronic renal insufficiency in Asian Indians with Type 2 diabetes. J. Diabetes Complicat. 23, 102–111.
Reddy, S. T., Wadleigh, D. J., Grijalva, V., Ng, C., Hama, S., Gangopadhyay, A., Shih, D. M., Lusis, A. J., Navab, M., Fogelman, A. M., 2001. Human. paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler. Thromb. Vasc. Biol. 21, 542–547.
Igyesi, G. T., Molna,´V., Semsei, A. F., Kiszel, P., Ungva´I, Po´cza P., Wiener, Z., Zsolt, I., Komlo´, si., La´szlo´, Kunos., Gabriella, G., Gyorgy, L., Ildiko,´ S., Andra´s, F., and Csaba, S., 2009. Gene expression profiling of experimental asthma reveals a possible role of paraoxonase-1 in the disease. International Immunology 21, 967–975.
Marsillach, J., Ferré, N., Vila, M. C., Lligoña, A., Mackness, B., Mackness, M., Deulofeu, R., Solá, R., Parés, A., Pedro-Botet, J., Joven, J., Caballeria, J., Camps, J., 2007. Serum paraoxonase-1 in chronic alcoholics: Relationship with liver disease. Clin. Biochem. 40, 645-650.
Desai, S., Baker, S. S., Liu, W., Moya, D. A., Browne, R. W., Mastrandrea, L., Baker, R. D., and Zhu. L., 2014. Paraoxonase 1 and oxidative stress in paediatric non-alcoholic steatohepatitis. Liver Int. 34, 110–117.
Quemeneur, T., Martin-Nizard, F., Kandoussi, A., Kyndt, X., Vanhille, P., Hachulla, E., Hatron, P. Y., Fruchart, J. C., Duriez, P., Lambert, M., 2007. PON1, a new biomarker of cardiovascular disease, is low in patients with systemic vasculitis. Semin. Arthritis Rheum. 37, 149–155.
Baskol, G., Demir, H., Baskol, M., Kilic, E., Ates, F., Kocer, D., Muhtaroglu, S., 2005. Assessment of paraoxonase 1 activity and malondialdehyde levels in patients with rheumatoid arthritis. Clin. Biochem. 38, 951–955.
Baskol, G., Karakucuk, S., Oner, A. O., Baskol, M., Kocer, D., Mirza, E., Saraymen, R., Ustdal, M., 2006. Serum paraoxonase 1 activity and lipid peroxidation levels in patients with age-related macular degeneration. Ophthalmologica 220, 12–16.
Hashim, Z., Ilyas, A., Saleem, A., Salim A., Zarina, S., 2009. Expression and activity of paraoxonase 1 in human cataractous lens tissue. Free Radical Biology & Medicine 46, 1089–1095.
Gökçen, S., Cengiz, M., Özaydın, A., 2013. Serum Paraoxonase Levels and PON1 (192) Polymorphism in Type 2 Diabetes Mellitus Patients. G. M. J. 24, 70-73.
Uliano, G., Muniz, L. C., Barros, C. C., Schneider, A., Valle, S. C., 2016. Association between paraoxonase 1 (PON1) enzyme activity, PON1 C −107 T polymorphism, nutritional status, and lipid profile in children. Nutrire 41, 20.
Ray Haldar, S., Chakrabarty, A., Chowdhury, S., Haldar, A., Sengupta, S., & Bhattacharyya, M., 2015. Oxidative Stress-Related Genes in Type 2 Diabetes: Association Analysis and Their Clinical Impact. Biochem. Genet. 53, 93-119.
Sahebkar, A., Hernández-Aguilera, A., Abelló, D., Sancho, E., Camps, J., Joven, J., 2016. Systematic review and meta-analysis deciphering the impact of fibrates on paraoxonase-1 status. Metabolism-Clinical and Experimental 65, 609–622.
Huen, K., Ritcher, R., Furlong, C., Eskenazi, B., Holland, N., 2009. Validation of PON1 enzyme activity assays for longitudinal studies. Clin. Chim. Acta 402, 67–74.
Ferré, N., Camps, J., Cabré, M., Paul, A., Joven, J., 2001. Hepatic paraoxonase activity alterations and free radical production in rats with experimental cirrhosis. Metabol. 50, 997–1000.
Costa L. G., Vitalone, A., Cole, T., Furlong, C., 2005. Modulation of paraoxonase (PON1) activity. Biochem. Pharmacol. 69, 541–550.
Browny, R. W., Koury, S. T., Marion, S., Wilding, G., Muti, P., and Trevisan, M., 2007. Accuracy and Biological Variation of Human Serum Paraoxonase 1 Activity and Polymorphism (Q192R) by Kinetic Enzyme Assay. Clinical Chemistry 53, 310-317.
Flekac M., Skrha, J., Zidkova, K., Lacinova, Z., Hilgertova, J., 2007. Paraoxonase 1 gene polymorphisms and enzyme activities in diabetes mellitus. Physiology Res. 717-726.
Singh, S., Verma, N., Nain, C. K., Co, L., Goel, R. C., Sharma B. K., 1998. Paraoxonase polymorphism in north west Indians. Int. J. Clin. Pharmacol. Ther. 36, 545-548.
Marsillach, J., Aragonès, G., Mackness, B., Mackness, M., Rull, A., Beltrán-Debón, R., Pedro-Botet, J., Alonso-Villaverde, C. A., Joven, J., Camps, J., 2010. Decreased paraoxonase-1 activity is associated with alterations of high-density lipoprotein particles in chronic liver impairment. Lipids in Health and Disease9, 46.
Marsillach, J., Bertran, N., Camps, J., Ferré, N., Riu, F., Tous, M., Coll, B., Alonso- Villaverde, C., Joven, J., 2005. The role of circulating monocytes chemoattractant protein-1 as a marker of hepatic inflammation in patients with chronic liver disease. Clin. Biochem. 38, 1138-1140.
Ikeda., Y., Suehiro T., Itahara T., Inui Y., Chikazawa H., Inoue M., Arii K., and Hashimoto K., 2007. Human serum paraoxonase concentration predicts cardiovascular mortality in hemodialysis patients. Clin. Nephrol. 67, 358–365.
Suvarna, R., Rao, S. S., Joshi, C. et al., 2011. Serum Paraoxonase activity in type 2 diabetes Mellitus patients with and without Complications. J. C. D. R. 5, 63-65.
Arai, K., Maguchi, S., Fujii, S., Ishibashi, H., Oikawa, K., Taniguchi, N., 1987. Glycation and inactivation of human Cu-Zn-superoxide dismutase. Identification of the in vitro glycated sites. J. Biol. Chem. 262, 16969.
Vlassara, H., Brownlee, M., Cerami, A., 1986. Nonenzymatic glycosylation: role in the pathogenesis of diabetic complications. Clin. Chem. 32, B37.
Reiser, K. M., Amigable, M. A., Last, J. A., 1992. Nonenzymatic glycation of type 1 collagen. The effects of aging on preferential glycation sites. J. Biol. Chem. 267, 24207.
Hedrick, C. C., Thorpe, S. R., Fu, M. X., Harper, C. M., Yoo, J., Kim, S. M., Wong, H., Peters, A. L., 2000. Glycation impairs high-density lipoprotein function. Diabetologia 43, 312–320.
Yeung, D. T., Josse, D., Nicholson, J. D., Khanal, A., McAndrew, C. W., Bahnson, B. J., Lenz, D. E., Cerasoli, D. M., 2004. Structure/function analyses of human serum paraoxonase (HuPON1) mutants designed from a DFPase-like homology model. Biochim. Biophys. Acta. 1702, 67–77.
Harel, M., Aharoni, A., Gaidukov, L., Brumshtein, B., Khersonsky, O., Meged, R., Dvir, H., Ravelli, R. B., McCarthy, A., Toker, L., Silman, I., Sussman, J. L., Tawfik, D. S., 2004. Structure and evolution of the serum paraoxonase family of detoxifying and antiatherosclerotic enzymes. Nat. Struct. Mol. Biol. 11, 412–419.
Januszek, R., 2016. Paraoxonase-1 and Simvastatin Treatment in Patients with Stable Coronary Artery Disease. Int. J. Vas. Med. 1, 1-10.
Atamer, Y., Atamer, A., Can, A. S., lu, A. H., Ihan, N. I., Yenice, N., and Kocyigit, Y., 2013. Effects of rosiglitazone on serum paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus. Brazilian Journal of Medical and Biological Research 46, 528-532.
Saikawa, Y., Price, K., Hance, K. W., Chen, T. Y., Elwood, P. C., 1995. Structural and functional analysis of the human KB cell folate receptor gene P4 promoter: cooperation of three clustered Sp1-binding sites with initiator region for basal promoter activity. Biochemistry 34, 9951–9961.
Ikeda, Y., Suehiro, T., Arii, K., Kumon, Y., Hashimoto K., 2008. High glucose induces transactivation of the human paraoxonase 1 gene in hepatocytes. Metabolism 57, 1725–32.
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