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Gene Review

PON2  -  paraoxonase 2

Homo sapiens

Synonyms: A-esterase 2, Aromatic esterase 2, PON 2, Serum aryldialkylphosphatase 2, Serum paraoxonase/arylesterase 2
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Disease relevance of PON2


Psychiatry related information on PON2


High impact information on PON2

  • Three polymorphisms in the PON1 (Leu55Met and Gln192Arg) and PON2 (Ser311Cys) genes have been shown to be associated with the risk of CAD in several European or European-derived populations [8].
  • Similarly, the frequency of the PON2 codon 311 Cys/Cys genotype was significantly higher in the group with three-vessel disease than in the other groups combined (15.22% vs. 4.61%; P=.018) [8].
  • Cellular PON2 and PON3 were also shown to reduce oxidative stress [9].
  • Cells that overexpressed PON2 showed significantly less intracellular oxidative stress following treatment with hydrogen peroxide or oxidized phospholipid [10].
  • In the present study, we demonstrate that PON2 (i) is not associated with high density lipoprotein; (ii) has antioxidant properties; and (iii) prevents LDL lipid peroxidation, reverses the oxidation of mildly oxidized LDL (MM-LDL), and inhibits the ability of MM-LDL to induce monocyte chemotaxis [10].

Chemical compound and disease context of PON2


Biological context of PON2


Anatomical context of PON2


Associations of PON2 with chemical compounds

  • We found no association between PON2 variation and plasma glucose or insulin [15].
  • We found novel genetic associations between PON2 variation and variation in fasting plasma concentrations of total cholesterol and apolipoprotein AI [15].
  • PON1 Leu/Leu increases the risk for retinopathy and PON2 Ser/Ser increases the risk for microalbuminuria [19].
  • The PON1 M/L55 mutation (MM genotype) was associated with lower triglyceride levels and the PON2 G/A148 mutation (GG genotype), with higher total and low-density lipoprotein (LDL)-cholesterol levels [17].
  • Supplementation of vitamin E to Balb/C mice inhibited the reduced nicotinamide adenine dinuleotide phosphate (NADPH)-oxidase-dependent increase in cellular superoxide anion production by 50% and down-regulated PON2 mRNA expression and activity by 30 and 60%, respectively [18].

Regulatory relationships of PON2

  • Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein [10].

Other interactions of PON2

  • These results suggested that the PON2 polymorphism might be a risk factor for LOAD independent of ApoE epsilon4 status in Chinese [6].
  • Polymerase chain reaction with specific primers followed by Hsp92, Alw1, DdeI and Fnu4HI restriction digestion were employed to identify the PON1 M/L55 and R/Q192 and the PON2 G/A148 and C/S311 genotypes, respectively [17].
  • In subjects with NIDDM, the PON2 codon 148 G/G homozygotes had significantly higher mean fasting plasma glucose than subjects with the other two genotypes (P < 0.0001) [3].
  • Comment--to: Pinizzotto M, Castillo E, Fiaux M, Temler E, Gaillard RC, Ruiz J (2001) Paraoxonase 2 polymorphisms are associated with diabetic nephropathy in Type II diabetes. Diabetologia 44: 104-107 [20].

Analytical, diagnostic and therapeutic context of PON2

  • In the FH-Symptomatic population, surprisingly, no subjects were homozygous for PON2 Cys311, whereas in the FH-Asymptomatic population nine persons (7.9%) and in the control group 12 persons (6.0%) were homozygous [21].
  • The SOD2 gene was screened by denaturing reversed-phase HPLC, and the PON1 (Q192R and M55L) and PON2 (S311C) polymorphisms were analyzed by PCR amplification followed by digestion with restriction endonucleases [5].
  • INTERPRETATION: In contrast to previous suggestions, this meta-analysis shows no significant association of CHD with the L55M or T(-107)C polymorphism in PON1 or with the S311C polymorphism in PON2 [22].


  1. DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Sanghera, D.K., Aston, C.E., Saha, N., Kamboh, M.I. Am. J. Hum. Genet. (1998) [Pubmed]
  2. The paraoxonase gene family and atherosclerosis. Ng, C.J., Shih, D.M., Hama, S.Y., Villa, N., Navab, M., Reddy, S.T. Free Radic. Biol. Med. (2005) [Pubmed]
  3. Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus. Hegele, R.A., Connelly, P.W., Scherer, S.W., Hanley, A.J., Harris, S.B., Tsui, L.C., Zinman, B. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  4. Association of PON2 variation with birth weight in Trinidadian neonates of South Asian ancestry. Busch, C.P., Ramdath, D.D., Ramsewak, S., Hegele, R.A. Pharmacogenetics (1999) [Pubmed]
  5. Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss. Fortunato, G., Marciano, E., Zarrilli, F., Mazzaccara, C., Intrieri, M., Calcagno, G., Vitale, D.F., La Manna, P., Saulino, C., Marcelli, V., Sacchetti, L. Clin. Chem. (2004) [Pubmed]
  6. Possible association between Cys311Ser polymorphism of paraoxonase 2 gene and late-onset Alzheimer's disease in Chinese. Shi, J., Zhang, S., Tang, M., Liu, X., Li, T., Han, H., Wang, Y., Guo, Y., Zhao, J., Li, H., Ma, C. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  7. Codon 311 (Cys --> Ser) polymorphism of paraoxonase-2 gene is associated with apolipoprotein E4 allele in both Alzheimer's and vascular dementias. Janka, Z., Juhász, A., Rimanóczy A, A., Boda, K., Márki-Zay, J., Kálmán, J. Mol. Psychiatry (2002) [Pubmed]
  8. Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. Chen, Q., Reis, S.E., Kammerer, C.M., McNamara, D.M., Holubkov, R., Sharaf, B.L., Sopko, G., Pauly, D.F., Merz, C.N., Kamboh, M.I. Am. J. Hum. Genet. (2003) [Pubmed]
  9. Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences. Aviram, M., Rosenblat, M. Curr. Opin. Lipidol. (2005) [Pubmed]
  10. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. Ng, C.J., Wadleigh, D.J., Gangopadhyay, A., Hama, S., Grijalva, V.R., Navab, M., Fogelman, A.M., Reddy, S.T. J. Biol. Chem. (2001) [Pubmed]
  11. Decreased macrophage paraoxonase 2 expression in patients with hypercholesterolemia is the result of their increased cellular cholesterol content: effect of atorvastatin therapy. Rosenblat, M., Hayek, T., Hussein, K., Aviram, M. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]
  12. Plasma homocysteine thiolactone adducts associated with risk of coronary heart disease. Yang, X., Gao, Y., Zhou, J., Zhen, Y., Yang, Y., Wang, J., Song, L., Liu, Y., Xu, H., Chen, Z., Hui, R. Clin. Chim. Acta (2006) [Pubmed]
  13. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. Draganov, D.I., Teiber, J.F., Speelman, A., Osawa, Y., Sunahara, R., La Du, B.N. J. Lipid Res. (2005) [Pubmed]
  14. Paraoxonase gene cluster variations associated with coronary heart disease in Chinese Han women. Su, S.Y., Chen, J.H., Huang, J.F., Wang, X.L., Zhao, J.G., Shen, Y., Qiang, B.Q., Gu, D.F. Chin. Med. J. (2005) [Pubmed]
  15. Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with variation in plasma lipoproteins in Alberta Hutterites. Boright, A.P., Connelly, P.W., Brunt, J.H., Scherer, S.W., Tsui, L.C., Hegele, R.A. Atherosclerosis (1998) [Pubmed]
  16. Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence. Mochizuki, H., Scherer, S.W., Xi, T., Nickle, D.C., Majer, M., Huizenga, J.J., Tsui, L.C., Prochazka, M. Gene (1998) [Pubmed]
  17. PON1 M/L55 mutation protects high-risk patients against coronary artery disease. Oliveira, S.A., Mansur, A.P., Ribeiro, C.C., Ramires, J.A., Annichino-Bizzacchi, J.M. International journal of cardiology. (2004) [Pubmed]
  18. Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages. Shiner, M., Fuhrman, B., Aviram, M. Free Radic. Biol. Med. (2004) [Pubmed]
  19. Paraoxonase gene cluster is a genetic marker for early microvascular complications in type 1 diabetes. Kao, Y., Donaghue, K.C., Chan, A., Bennetts, B.H., Knight, J., Silink, M. Diabet. Med. (2002) [Pubmed]
  20. Comment--to: Pinizzotto M, Castillo E, Fiaux M, Temler E, Gaillard RC, Ruiz J (2001) Paraoxonase 2 polymorphisms are associated with diabetic nephropathy in Type II diabetes. Diabetologia 44: 104-107. Canani, L.H., Araki, S., Warram, J.H., Krolewski, A.S. Diabetologia (2001) [Pubmed]
  21. PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. Leus, F.R., Zwart, M., Kastelein, J.J., Voorbij, H.A. Atherosclerosis (2001) [Pubmed]
  22. Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies. Wheeler, J.G., Keavney, B.D., Watkins, H., Collins, R., Danesh, J. Lancet (2004) [Pubmed]
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