Disease relevance of PON2

• DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease [1].
• While the physiological function of these proteins is unknown, studies currently underway using PON2 and PON3 knockout and transgenic mice should enable us to tease out the apparently redundant functions of these three proteins and yield clues as to their physiological function as well as their role in atherogenesis [2].
• Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus [3].
• Association of PON2 variation with birth weight in Trinidadian neonates of South Asian ancestry [4].
• We evaluated whether susceptibility to noise-induced hearing loss (NIHL) is associated with SOD2, PON1, and PON2 polymorphisms in workers exposed to prolonged loud noise [5].

Psychiatry related information on PON2

• The common polymorphism at codon 311 (C311S) of paraoxonase 2 gene (PON2) was investigated in 165 patients with sporadic late-onset Alzheimer's disease (LOAD) and 174 controls in Chinese. The PON2*C allele frequency was significantly increased in the patients as compared with controls [6].
• Codon 311 (Cys --> Ser) polymorphism of paraoxonase-2 gene is associated with apolipoprotein E4 allele in both Alzheimer's and vascular dementias [7].

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

• CONCLUSIONS: HMDM-PON2 expression is reduced in patients with hypercholesterolemia as a result of their increased cellular cholesterol content [11].
• CONCLUSIONS: High plasma homocysteine thiolactone adducts and the CC 311 genotype of paraoxonase-2 gene may be the emerging risk factor for coronary heart disease [12].

Biological context of PON2

• Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities [13].
• Haplotype analyses indicated that there might be some synergistic effects between the PON1 -107C > T and PON2 S311C polymorphisms [14].
• With the recent cloning of the PON1-related gene PON2, we undertook studies of the association between genetic variation in PON2 and variation in plasma quantitative traits variation in a sample of 745 Alberta Hutterites [15].
• Furthermore, there was almost complete linkage disequilibrium between PON2 alleles G148 and C311 [15].
• 3. PON2 is ubiquitously expressed and we identified several mRNA forms produced by alternative splicing, or by the use of a second transcription start site [16].

Anatomical context of PON2

• The PON2 protein was overexpressed in HeLa cells using the tetracycline-inducible ("Tet-On") system, and its antioxidant capacity was measured in a fluorometric assay [10].
• Recently, an association between PON2 and quantitative metabolic phenotypes, such as plasma lipoproteins, plasma glucose, and coronary artery disease (CAD), has been reported [17].
• The PON1 gene is regulated by Sp1 and protein kinase C, whereas the PON2 gene in macrophages is regulated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [9].
• PON2 expression was analyzed in vitro in THP-1 cells differentiated with 1alpha,25-dihydroxyvitamin D3 and in vivo in mouse peritoneal macrophages (MPM) isolated at increasing time intervals after intraperitoneal thioglycollate injection [18].
• Atorvastatin therapy reduced both macrophage oxidative stress and cholesterol content, and upregulated PON2 expression, thus contributing to attenuation of foam cells formation [11].

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].

References