Paraoxonase 1 concerning dyslipidaemia, cardiovascular diseases, and mortality in haemodialysis patients.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Aryldialkylphosphatase/*genetics ; Cardiovascular Diseases/*etiology ; Dyslipidemias/*etiology ; Renal Dialysis/*mortality; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alleles ; Aryldialkylphosphatase/metabolism ; Cardiovascular Diseases/metabolism ; Child ; Dyslipidemias/metabolism ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Phenotype ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Young Adult

Paraoxonase 1 (PON1) is known for preventing atherosclerosis through lipid-modifying features, antioxidant activity, anti-inflammatory, anti-apoptosis, anti-thrombosis, and anti-adhesion properties. Uremic patients requiring haemodialysis (HD) are especially prone to atherosclerosis and its complications. We analysed the PON1 gene (PON1) polymorphisms and serum PON1 (paraoxonase) activity concerning dyslipidaemia and related cardiovascular diseases and mortality to show how they associate under uremic conditions modified by maintenance HD treatment. The rs662 AA + AG (OR 1.76, 95%CI 1.10-2.80, P = 0.018), rs854560 TT (OR 1.48, 95%CI 1.04-2.11, P = 0.031), and rs854560 AT + TT (OR 1.28, 95%CI 1.01-1.63, P = 0.040) contributed to the prevalence of atherogenic dyslipidaemia diagnosed by the triglyceride (TG)/HDL-cholesterol ratio ≥ 3.8. The normalized serum PON1 activity positively correlated with atherogenic dyslipidaemia (ẞ 0.67 ± 0.25, P = 0.008). The PON1 rs854560 allele T was involved in the higher prevalence of ischemic cerebral stroke (OR 1.38, 1.02-1.85, P = 0.034). The PON1 rs705379 TT genotype contributed to cardiovascular (HR 1.27, 95% CI 1.03-1.57, P = 0.025) and cardiac (HR 1.34, 95% CI 1.05-1.71, P = 0.018) mortality. All P-values were obtained in multiple regression analyses, including clinical variables. Multifaceted associations of PON1 with dyslipidaemia, ischemic cerebral stroke, and cardiovascular mortality in HD patients provide arguments for the consideration of PON1 and its protein product as therapeutic targets in the prevention of atherosclerosis and its complications in uremic patients.

Ginsberg, G. et al. Genetic polymorphism in paraoxonase 1 (PON1): Population distribution of PON1 activity. J. Toxicol. Environ. Health B 12, 473–507 (2009). (PMID: 10.1080/10937400903158409)
Chistiakov, D. A., Melnichenko, A. A., Orekhov, A. N. & Bobryshev, Y. V. Paraoxonase and atherosclerosis-related cardiovascular diseases. Biochimie 132, 19–27 (2017). (PMID: 2777136810.1016/j.biochi.2016.10.010)
Jaouad, L. et al. Age-related decrease in high-density lipoproteins antioxidant activity is due to an alteration in the PON1’s free sulfhydryl groups. Atherosclerosis 185, 191–200 (2006). (PMID: 1602678910.1016/j.atherosclerosis.2005.06.012)
Aviram, M. et al. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J. Clin. Invest. 101, 1581–1590 (1998). (PMID: 954148750873810.1172/JCI1649)
Jakubowski, H. Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels. FASEB J. 13, 2277–2283 (1999). (PMID: 1059387510.1096/fasebj.13.15.2277)
Jakubowski, H. Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J. Biol. Chem. 275, 3957–3962 (2000). (PMID: 1066055010.1074/jbc.275.6.3957)
Gbandjaba, N. Y. et al. Paraoxonase activity in healthy, diabetic, and hemodialysis patients. Clin. Biochem. 45, 470–474 (2012). (PMID: 2228538210.1016/j.clinbiochem.2012.01.005)
Locsey, L. et al. Relationship between serum paraoxonase and homocysteine thiolactonase activity, adipokines, and asymmetric dimethyl arginine concentrations in renal transplant patients. Transplant. Proc. 45, 3685–3687 (2013). (PMID: 2431499710.1016/j.transproceed.2013.10.003)
Dantoine, T. F. et al. Decrease of serum paraoxonase activity in chronic renal failure. J. Am. Soc. Nephrol. 9, 2082–2088 (1998). (PMID: 980809410.1681/ASN.V9112082)
Rajković, M. G. et al. Polymorphisms of pon1 and pon2 genes in hemodialyzed patients. Clin. Biochem. 44, 964–968 (2011). (PMID: 2162081310.1016/j.clinbiochem.2011.05.012)
Miljkovic, M. et al. Activity of paraoxonase 1 (PON1) on HDL2 and HDL3 subclasses in renal disease. Clin. Biochem. 60, 52–58 (2018). (PMID: 3013052110.1016/j.clinbiochem.2018.08.006)
Samouilidou, E. et al. Association of lipid profile with serum PON1 concentration in patients with chronic kidney disease. Ren. Fail. 38, 1601–1606 (2016). (PMID: 2688862510.3109/0886022X.2016.1144031)
Suehiro, T. et al. Serum paraoxonase (PON1) concentration in patients undergoing hemodialysis. J. Atheroscler. Thromb. 9, 133–138 (2002). (PMID: 1222655410.5551/jat.9.133)
Ikeda, Y. et al. Human serum paraoxonase concentration predicts cardiovascular mortality in hemodialysis patients. Clin. Nephrol. 67, 358–365 (2007). (PMID: 1759837110.5414/CNP67358)
Kotur-Stevuljević, J. et al. Hyperlipidemia, oxidative stress, and intima media thickness in children with chronic kidney disease. Pediatr. Nephrol. 28, 295–303 (2013). (PMID: 2311758110.1007/s00467-012-2323-5)
Gouédard, C., Koum-Besson, N., Barouki, R. & Morel, Y. Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. Mol. Pharmacol. 63, 945–956 (2003). (PMID: 1264459610.1124/mol.63.4.945)
Clendenning, J. B. et al. Structural organization of the human PON1 gene. Genomics 35, 586–589 (1996). (PMID: 881249510.1006/geno.1996.0401)
Davies, H. G. et al. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat. Genet. 14, 334–336 (1996). (PMID: 889656610.1038/ng1196-334)
Li, W. F. et al. Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. Pharmacogenetics 10, 767–779 (2000). (PMID: 1119188110.1097/00008571-200012000-00002)
Can Demirdöğen, B. et al. Paraoxonase/arylesterase ratio, PON1 192Q/R polymorphism and PON1 status are associated with increased risk of ischemic stroke. Clin. Biochem. 41, 1–9 (2008). (PMID: 1792057810.1016/j.clinbiochem.2007.08.010)
Furlong, C. E. et al. PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenet. Genomics. 16, 183–190 (2006). (PMID: 1649577710.1097/01.fpc.0000189796.21770.d3)
Nakanishi, M. et al. The ratio of serum paraoxonase/arylesterase activity using an improved assay for arylesterase activity to discriminate PON1(R192) from PON1(Q192). J. Atheroscler. Thromb. 10, 337–342 (2003). (PMID: 1503782210.5551/jat.10.337)
Leviev, I., Negro, F. & James, R. W. Two alleles of the human paraoxonase gene produce different amounts of mRNA. An explanation for differences in serum concentrations of paraoxonase associated with the (Leu-Met54) polymorphism. Arterioscler. Thromb. Vasc. Biol. 17, 2935–2939 (1997). (PMID: 940927910.1161/01.ATV.17.11.2935)
Garin, M. C. 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. 99, 62–66 (1997). (PMID: 901157750776810.1172/JCI119134)
Brophy, V. H. et al. Effects of 5’ regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. Am. J. Hum. Genet. 68, 1428–1436 (2001). (PMID: 11335891122612910.1086/320600)
Feingold, K. R., Memon, R. A., Moser, A. H. & Grunfeld, C. Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 139, 307–315 (1998). (PMID: 971233710.1016/S0021-9150(98)00084-7)
Van Lenten, B. J., Wagner, A. C., Navab, M. & Fogelman, A. M. Oxidized phospholipids induce changes in hepatic paraoxonase and ApoJ but not monocyte chemoattractant protein-1 via interleukin-6. J. Biol. Chem. 276, 1923–1929 (2001). (PMID: 1103499610.1074/jbc.M004074200)
Kumon, Y., Suehiro, T., Ikeda, Y. & Hashimoto, K. Human paraoxonase-1 gene expression by HepG2 cells is downregulated by interleukin-1beta and tumor necrosis factor-alpha, but is upregulated by interleukin-6. Life Sci. 73, 2807–2815 (2003). (PMID: 1451176610.1016/S0024-3205(03)00704-5)
Deakin, S., Leviev, I., Guernier, S. & James, R. W. Simvastatin modulates expression of the PON1 gene and increases serum paraoxonase: A role for sterol regulatory element-binding protein-2. Arterioscler. Thromb. Vasc. Biol. 23, 2083–2089 (2003). (PMID: 1450029010.1161/01.ATV.0000096207.01487.36)
Dirican, M., Akca, R., Sarandol, E. & Dilek, K. Serum paraoxonase activity in uremic predialysis and hemodialysis patients. J. Nephrol. 17, 813–818 (2004). (PMID: 15593056)
Marsillach, J. et al. Administration of exogenous erythropoietin beta affects lipid peroxidation and serum paraoxonase-1 activity and concentration in predialysis patients with chronic renal disease and anaemia. Clin. Exp. Pharmacol. Physiol. 34, 347–349 (2007). (PMID: 1732414810.1111/j.1440-1681.2007.04552.x)
Rahimi-Ardabili, B. et al. Paraoxonase enzyme activity is enhanced by zinc supplementation in hemodialysis patients. Ren. Fail. 34, 1123–1128 (2012). (PMID: 2295060010.3109/0886022X.2012.717479)
Hsu, S. P. et al. Chronic green tea extract supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am. J. Clin. Nutr. 86, 1539–1547 (2007). (PMID: 1799167010.1093/ajcn/86.5.1539)
Ghorbanihaghjo, A., Argani, H., Rahbaninoubar, M. & Rashtchizadeh, N. Effect of nandrolonedecanonate on paraoxonase activity in hemodialysis patients. Clin. Biochem. 38, 1076–1080 (2005). (PMID: 1615362810.1016/j.clinbiochem.2005.08.006)
Kuo, C. L. & La Du, B. N. Calcium binding by human and rabbit serum paraoxonases. Structural stability and enzymatic activity. Drug Metab. Dispos. 26, 653–660 (1998). (PMID: 9660847)
Public Health Statement: Acrolein—ATSDR. https://www.atsdr.cdc.gov › phs › phs. https://www.atsdr.cdc.gov/ToxProfiles/tp124-c1-b.pdf . Accessed 16 Jan 2020 (2007).
Gugliucci, A. et al. Acrolein inactivates paraoxonase 1: Changes in free acrolein levels after hemodialysis correlate with increases in paraoxonase 1 activity in chronic renal failure patients. Clin. Chim. Acta. 384, 105–112 (2007). (PMID: 1763209410.1016/j.cca.2007.06.012)
Hanak, V., Munoz, J., Teague, J., Stanley, A. & Bittner, V. Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am. J. Cardiol. 94, 219–222 (2004). (PMID: 1524690710.1016/j.amjcard.2004.03.069)
Kidney Disease Outcomes Quality Initiative (K/DOQI) Group. K/DOQI clinical practice guidelines for managing dyslipidemia in chronic kidney disease. Am. J. Kidney Dis. 41, 1–237 (2003).
Pan, L. et al. The prevalence, awareness, treatment and control of dyslipidemia among adults in China. Atherosclerosis 248, 2–9 (2016). (PMID: 2697858110.1016/j.atherosclerosis.2016.02.006)
Sanchis-Gomar, F., Perez-Quilis, C., Leischik, R. & Lucia, A. Epidemiology of coronary heart disease and acute coronary syndrome. Ann. Transl. Med. 4, 256 (2016). (PMID: 27500157495872310.21037/atm.2016.06.33)
Roger, V. L. et al. Heart disease and stroke statistics–2012 update: A report from the American Heart Association. Circulation 125, e2–e220 (2012). (PMID: 22179539)
Ribeiro, S. et al. Main determinants of PON1 activity in hemodialysis patients. Am. J. Nephrol. 36, 317–323 (2012). (PMID: 2300707410.1159/000342235)
Regieli, J. J. et al. Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein-bound antioxidant in secondary prevention. J. Am. Coll. Cardiol. 54, 1238–1245 (2009). (PMID: 1977866310.1016/j.jacc.2009.05.061)
Bhattacharyya, T. et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 299, 1265–1276 (2008). (PMID: 1834908810.1001/jama.299.11.1265)
Hegele, R. A., Brunt, J. H. & Connelly, P. W. A polymorphism of the paraoxonase gene associated with variation in plasma lipoproteins in a genetic isolate. Arterioscler. Thromb. Vasc. Biol. 15, 89–95 (1995). (PMID: 774982010.1161/01.ATV.15.1.89)
Imai, Y. et al. Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases. Atherosclerosis 149, 435–442 (2000). (PMID: 1072939510.1016/S0021-9150(99)00340-8)
Vaisi-Raygani, A. et al. ParaoxonaseArg 192 allele is an independent risk factor for three-vessel stenosis of coronary artery disease. Mol. Biol. Rep. 38, 5421–5428 (2011). (PMID: 2146516510.1007/s11033-011-0696-3)
Durrington, P. N., Mackness, B. & Mackness, M. I. Paraoxonase and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 21, 473–480 (2001). (PMID: 1130446010.1161/01.ATV.21.4.473)
Ruiz, J. et al. Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet 346, 869–872 (1995). (PMID: 756467110.1016/S0140-6736(95)92709-3)
Pfohl, M. et al. Paraoxonase 192 Gln/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes. Diabetes 48, 623–627 (1999). (PMID: 1007856610.2337/diabetes.48.3.623)
Gardemann, A. et al. The paraoxonase Leu-Met54 and Gln-Arg191 gene polymorphisms are not associated with the risk of coronary heart disease. Atherosclerosis 152, 421–431 (2000). (PMID: 1099847110.1016/S0021-9150(99)00489-X)
Zhang, G. et al. Association between paraoxonase gene and stroke in the Han Chinese population. BMC Med. Genet. 28, 14–16 (2013).
Baráth, A. et al. Roles of paraoxonase and oxidative stress in adolescents with uraemic, essential or obesity-induced hypertension. Kidney Blood Press. Res. 29, 144–151 (2006). (PMID: 1691251210.1159/000095124)
Dronca, M., Paşca, S. P., Nemeş, B., Vlase, L. & Vladutiu, D. Serum paraoxonase 1 activities and homocysteinemia in hemodialysis patients. Clin. Chem. Lab. Med. 46, 880–881 (2008). (PMID: 1860161610.1515/CCLM.2008.164)
Gugliucci, A., Schulze, J., Kinugasa, E., Ogata, H. & Kimura, S. The free fraction of paraoxonase 1 is not increased in patients with end stage renal disease undergoing hemodialysis. Clin. Chim. Acta. 402, 209–210 (2009). (PMID: 1915044310.1016/j.cca.2008.12.023)
Varga, Z. et al. Hyperleptinemia is not responsible for decreased paraoxonase activity in hemodialysis patients. Nephron. Clin. Pract. 103, c114-120 (2006). (PMID: 1653423510.1159/000092020)
Itahara, T. et al. Serum paraoxonase and arylesterase activities in hemodialysis patients. J. Atheroscler. Thromb. 7, 152–158 (2000). (PMID: 1148045610.5551/jat1994.7.152)
Zhang, B. et al. Paraoxonase (Pon1) Q192R polymorphism and serum Pon1 activity in diabetic patients on maintenance hemodialysis. Clin. Nephrol. 60, 257–265 (2003). (PMID: 1457994010.5414/CNP60257)
Abdallah, E., El-Shishtawy, S., Sherif, N., Ali, A. & El-Bendary, O. Assessment of the relationship between serum paraoxonase activity and epicardial adipose tissue in hemodialysis patients. Int. Urol. Nephrol. 49, 329–335 (2017). (PMID: 2787875110.1007/s11255-016-1465-y)
Gugliucci, A. et al. Paraoxonase-1 concentrations in end-stage renal disease patients increase after hemodialysis: correlation with low molecular AGE adduct clearance. Clin. Chim. Acta. 377, 213–220 (2007). (PMID: 1711835210.1016/j.cca.2006.09.028)
Dirican, M., Sarandol, E., Serdar, Z., Ocak, N. & Dilek, K. Oxidative status and prevalent cardiovascular disease in patients with chronic renal failure treated by hemodialysis. Clin. Nephrol. 68, 144–150 (2007). (PMID: 1791561610.5414/CNP68144)
Razavi, A. E., Ani, M., Pourfarzam, M. & Naderi, G. A. Associations between high density lipoprotein mean particle size and serum paraoxonase-1 activity. Res. Med. Sci. 17, 1020–1026 (2012).
Henning, B. F., Holzhausen, H. & Tepel, M. Continuous reduction of plasma paraoxonase activity with increasing dialysis vintage in hemodialysis patients. Ther. Apher. Dial. 14, 572–576 (2010). (PMID: 2111836510.1111/j.1744-9987.2010.00844.x)
Ferretti, G., Bacchetti, T., Masciangelo, S. & Pallotta, G. Lipid peroxidation in hemodialysis patients: Effect of vitamin C supplementation. Clin. Biochem. 41, 381–386 (2008). (PMID: 1819467210.1016/j.clinbiochem.2007.12.011)
Sztanek, F. et al. Effect of nutritional status on human paraoxonase-1 activity in patients with chronic kidney disease. Kidney Blood Press. Res. 36, 310–319 (2012). (PMID: 2323528510.1159/000343383)
Harel, M. et al. 3-D structure of serum paraoxonase 1 sheds light on its activity, stability, solubility and crystallizability. Arh. Hig. Rada Toksikol. 58, 347–353 (2007). (PMID: 1791369010.2478/v10004-007-0028-0)
Vlagopoulos, P. T. & Sarnak, M. J. Traditional and nontraditional cardiovascular risk factors in chronic kidney disease. Med. Clin. NorthAm. 89, 587–611 (2005). (PMID: 10.1016/j.mcna.2004.11.003)
Seaman, V. Y., Bennett, D. H. & Cahill, T. M. Origin, occurrence, and source emission rate of acrolein in residential indoor air. Environ. Sci. Technol. 41, 6940–6946 (2007). (PMID: 1799313210.1021/es0707299)
Mathew, A. T., Fishbane, S., Obi, Y. & Kalantar-Zadeh, K. Preservation of residual kidney function in hemodialysis patients: Reviving an old concept for contemporary practice. Kidney Int. 90, 26271 (2016). (PMID: 10.1016/j.kint.2016.02.037)
Shafi, T. et al. Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: The CHOICE (Choices for Healthy Outcomes in Caring for End-Stage Renal Disease) Study. Am. J. Kidney Dis. 56, 348–358 (2010). (PMID: 20605303291083510.1053/j.ajkd.2010.03.020)
Saeed, S. A., Elsharkawy, M., Elsaeed, K. & Fooda, O. Paraoxonase-1 (PON1) activity as a risk factor for atherosclerosis in chronic renal failure patients. Hemodial. Int. 12, 471–479 (2008). (PMID: 1909087010.1111/j.1542-4758.2008.00311.x)
Kim, D. S. et al. Dietary cholesterol increases paraoxonase 1 enzyme activity. J. Lipid Res. 53, 2450–2458 (2012). (PMID: 22896672346601410.1194/jlr.P030601)
Gupta, N., Singh, S., Maturu, V. N., Sharma, Y. P. & Gill, K. D. Paraoxonase 1 (PON1) polymorphisms, haplotypes and activity in predicting CAD risk in North-West Indian Punjabis. PLoS ONE 6, e17805 (2011). (PMID: 21629682310120210.1371/journal.pone.0017805)
James, R. W. et al. Promoter Polymorphism T(−107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients. Diabetes 49, 1390–1393 (2000). (PMID: 1092364210.2337/diabetes.49.8.1390)
Grzegorzewska, A. E. et al. Paraoxonase 1 gene polymorphisms concerning non-insulin-dependent diabetes mellitus nephropathy in hemodialysis patients. J. Diabetes Complic. 34, 107687 (2020). (PMID: 10.1016/j.jdiacomp.2020.107687)
Richter, R. J. & Furlong, C. E. Determination of paraoxonase (PON1) status requires more than genotyping. Pharmacogenetics 9, 745–753 (1999). (PMID: 1063413710.1097/00008571-199912000-00009)
Jarvik, G. P. et al. Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype. Arterioscler. Thromb. Vasc. Biol. 20, 2441–2447 (2000). (PMID: 1107385010.1161/01.ATV.20.11.2441)
Richter, R. J., Jarvik, G. P. & Furlong, C. E. Determination of paraoxonase 1 status without the use of toxic organophosphate substrates. Circ. Cardiovasc. Genet. 1, 147–152 (2008). (PMID: 20031556303562810.1161/CIRCGENETICS.108.811638)
Mackness, B. et al. Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype?. Arterioscler. Thromb. Vasc. Biol. 21, 1451–1457 (2001). (PMID: 1155767110.1161/hq0901.094247)
Taylor, J. K. et al. Paraoxonase responses to exercise and niacin therapy in men with metabolic syndrome. Redox Rep. 20, 42–48 (2015). (PMID: 2518082710.1179/1351000214Y.0000000103)
Harper, C. R. & Jacobson, T. A. Managing dyslipidemia in chronic kidney disease. J. Am. Coll. Cardiol. 51, 2375–2384 (2008). (PMID: 1856539310.1016/j.jacc.2008.03.025)
Gupta, S., Vaidya, S. R., Arora, S., Bahekar, A. & Devarapally, S. R. Type 2 versus type 1 myocardial infarction: a comparison of clinical characteristics and outcomes with a meta-analysis of observational studies. Cardiovasc. Diagn. Ther. 7, 348–358 (2017). (PMID: 28890871558206310.21037/cdt.2017.03.21)
Torun, E. et al. Serum paraoxonase 1 activity and oxidative stress in pediatric patients with pulmonary tuberculosis. Med. Princ. Pract. 23, 426–431 (2014). (PMID: 25034194558696910.1159/000363700)
Yılmaz, A. et al. Protective effects of caffeic acid phenethyl ester on fluoxetine-induced hepatotoxicity: An experimental study. Biomed. Res. Int. 2016, 1247191 (2016). (PMID: 27144157484203410.1155/2016/1247191)
Zhao, F., Song, M., Wang, Y. & Wang, W. Genetic model. J. Mol. Mol. Med. 20, 765 (2016).
Lewis, C. M. Genetic association studies: Design, analysis and interpretation. Brief. Bioinform. 3, 146–153 (2002). (PMID: 1213943410.1093/bib/3.2.146)
Bae, H., Perls, T., Steinberg, M. & Sebastiani, P. Bayesian polynomial regression models to fit multiple genetic models for quantitative traits. Bayesian Anal. 10, 53–74 (2015). (PMID: 2602931610.1214/14-BA880)
Manly, K. F. Reliability of statistical associations between genes and disease. Immunogenetics 57, 549–558 (2005). (PMID: 1608617210.1007/s00251-005-0025-x)

EC 3.1.8.1 (Aryldialkylphosphatase)
EC 3.1.8.1 (PON1 protein, human)

Date Created: 20210325 Date Completed: 20211022 Latest Revision: 20230129

20230130

PMC7990965

10.1038/s41598-021-86231-0

33762698