PARAOXONASE 1; PON1
Description
パラオキソナーゼ遺伝子は3つの遺伝子を含むファミリーである。染色体7番にある。
PON1は多くの有機リン系殺虫剤（パラチオン、ヂアジノン、クロピリフォス）や、サリン、ソマンなどの神経毒の有毒なオキソン代謝物を加水分解する。芳香族エステルのうち特に酢酸エステルを加水分解する。加えて、多くの芳香族や脂肪族のラクトンを可逆的な反応で加水分解する。（γまたはδ-ヒドロキシカルボン酸のラクトン化反応を触媒）
PON1は肝臓で合成され、血流中に分泌され、HDLと相互作用しアテローム性動脈硬化の発症を抑える。
The paraoxonase (PON) gene family includes 3 genes, PON1, PON2 (602447), and PON3 (602720), aligned next to each other on chromosome 7. PON1 (EC 3.1.1.2) hydrolyzes the toxic oxon metabolites of several organophosphorous insecticides, including parathion, diazinon, and chlorpyrifos, as well as nerve agents, such as sarin and soman. PON1 also hydrolyzes aromatic esters, preferably those of acetic acid. In addition, PON1 hydrolyzes a variety of aromatic and aliphatic lactones, and it also catalyzes the reverse reaction, lactonization, of gamma- and delta-hydroxycarboxylic acids. Human PON1 is synthesized in liver and secreted into blood, where it is associated exclusively with high density lipoproteins (HDLs) and may protect against development of atherosclerosis (Draganov et al., 2005).
Cloning and Expression
ヒト肝臓cDNAライブラリーから1991年にクローニングされた。355アミノ酸でウサギ酵素と85％以上の相同性があった。生成されたヒトとウサギのPON1の解析より開始メチオニン以外のシグナルペプチドは保持されていた。
Hassett et al. (1991) isolated a full-length PON1 cDNA from a human liver cDNA library using rabbit Pon1 as a hybridization probe. The deduced PON1 protein contains 355 amino acids and is more than 85% similar to the rabbit protein. N-terminal sequences derived from purified rabbit and human PON1 proteins suggested that the PON1 signal sequence is retained, except for the initiator methionine. Characterization of the rabbit and human PON1 cDNAs confirmed that the signal sequences are not processed, except for the N-terminal methionine.
SDS-PAGEによる解析で、PON1は39、42kDaの二種類あることが示された。非変性PAGEでダイマーであることが示された。グリコシダーゼ処理により部筆されたPON1は複合型糖鎖を含むことが示された。
Using SDS-PAGE, Draganov et al. (2005) found that PON1 appeared as a doublet of about 39 and 42 kD. However, using nondenaturing PAGE, they observed human serum PON1 and recombinant PON1 at apparent molecular masses of 91.9 and 95.6 kD, respectively, suggesting that PON1 forms dimers. Glycosidase treatment of human serum PON1 suggested that the secreted form of PON1 contains complex carbohydrates.
ヒトの三種類のPONには3つのシステイン残基が保存されている。うち2つは分子間ジスルフィドの形成、残りは抗酸化活性に関与する。
Lu et al. (2006) stated that human PON1, PON2, and PON3 have 3 conserved cysteines. Cys41 and cys351 are predicted to form an intramolecular disulfide bond, and cys283 is predicted to be involved in antioxidant activity.
Gene Structure
28kBに渡る。約300塩基対の5'上流配列、全コーディング領域と2kBの3'隣接配列。9つのエキソンに分断されている。
Clendenning et al. (1996) characterized a 28-kb contig encompassing 300 bp of 5-prime sequence, the entire coding region, and 2 kb of 3-prime flanking sequence of the PON1 gene. The structural portion of the paraoxonase protein is encoded by 9 exons that form the primary transcript through the use of typical splice donor and acceptor sites. Click this to see references in PubMed related to the ones listed in the paragraph above.
Sorenson et al. (1995) showed that the Pon1 gene in mice contains 9 exons spanning approximately 25 to 26 kb.
Mapping
連鎖解析により、嚢胞性線維腫症とPON遺伝子に連鎖が認められることが明らかになった。
Eiberg and Mohr (1979) presented linkage data. No linkage with any of 19 markers was found by Mueller et al. (1983). Eiberg et al. (1985) showed that cystic fibrosis (219700) and PON are linked on chromosome 7 (maximum lod 3.70 at theta = 0.07 in males and 0.00 in females)--the first step in the cloning of the CF gene in 1989. Tsui et al. (1985) confirmed the PON-CF linkage by finding linkage of PON to a DNA marker that is also linked to CF. Schmiegelow et al. (1986) found the PON and CF loci linked with lod score of 3.46 at recombination fraction 0.07 in males and 0.13 in females. By in situ hybridization, Humbert et al. (1993) demonstrated that the PON gene maps to chromosome 7q21-q22. Mochizuki et al. (1998) pointed out that the PON1, PON2, and PON3 genes are physically linked on chromosome 7q21.3. Click this to see references in PubMed related to the ones listed in the paragraph above.
Sorenson et al. (1995) mapped the mouse Pon1 gene to the proximal end of chromosome 6 by interspecific backcross analysis. Li et al. (1997) likewise mapped the gene to mouse chromosome 6. Click this to see references in PubMed related to the ones listed in the paragraph above.
Gene Function
血清のアリルエステラーゼ活性が単峰性の分布を示すことを明らかにした。酵素活性に性差は無く、年齢に依存し徐々に活性が増加する。双子による検討で遺伝の寄与する部分は74％。両親のデータから示唆されることは、遺伝の年齢に加えて、それ以外の要因が酵素活性に影響していること。
アリルエステラーゼ活性は、フェニルアセテートを基質にして測定された。パラ置きソナー背活性は同じ遺伝子sにより決定される。
Simpson (1971) found a unimodal distribution of serum arylesterase activity in 176 individuals. There was no difference in enzyme activity between sexes, but the level of activity gradually increased with age. From a study of twins, heritability of arylesterase activity was estimated to be 74%. Data from parent pairs suggested that, in addition to genetic and age factors, unknown nongenetic factors substantially affected enzyme activity.
Eckerson et al. (1983) concluded that arylesterase activity, measured with phenylacetate as substrate, and paraoxonase activity are determined by the same gene. They used the designation esterase A for the paraoxonase/arylesterase enzyme (see HISTORY for information on the identification and classification of esterases). Furlong et al. (1991) also demonstrated that both arylesterase and paraoxonase activities are expressed by a single enzyme. Click this to see references in PubMed related to the ones listed in the paragraph above.
Furlong et al. (1988) studied hydrolysis of an insecticide metabolite, chlorpyrifos oxon, by PON1. Click this to see references in PubMed related to the ones listed in the paragraph above.
パラ置きソナー背の解毒と中間体の代謝における役割はよく分かっていないが、動物実験では、パラオキソンの毒性に対する防御とPONの量を調べた。LD50値とPON活性に相関がある。また、PONを常駐することはパラオキソン毒性に対する耐性をもたらす。ということから血清中のPONは有機リン系の毒物に対する防御をしている。
The physiologic role of paraoxonase in detoxication and in intermediary metabolism is uncertain (La Du, 1988). However, animal studies, including examination of quantitative adequacy of PON and protection against paraoxon toxicity, correlation of LD50 values with PON levels, and demonstration that intravenously injected PON provides protection against paraoxon toxicity, indicate that serum PON is protective against organophosphate poisoning (reviewed by Humbert et al., 1993).
動物実験により、ApoJとPONの比率が増加すると
In a series of animal experiments, Navab et al. (1997) demonstrated that the ratio of Apoj (185430) to Pon was increased in fatty streak-susceptible mice fed an atherogenic diet, in Apoe knockout mice on a chow diet, in LDL receptor (LDLR; 606945) knockout mice on a cholesterol-enriched diet, and in fatty streak-susceptible mice injected with mildly oxidized LDL fed a chow diet. Human studies showed that the APOJ/PON ratio was significantly higher than that of controls in 14 normolipidemic patients with coronary artery disease in whom the cholesterol/HDL ratio did not differ significantly from that of controls. Click this to see references in PubMed related to the ones listed in the paragraph above.
Draganov et al. (2005) found that glycosylation of recombinant PON1 with high-mannose-type sugars did not alter its enzymatic activity, but it may have affected protein stability. They found that PON1, PON2, and PON3, whether expressed in insect or HEK293 cells, metabolized oxidized forms of arachidonic acid and docosahexaenoic acid. Otherwise, the PONs showed distinctive substrate specificities. PON1, but not other PONs, specifically hydrolyzed organophosphates. About 60% of total arylesterase and lactonase activity of PON1-transfected HEK293 cells was secreted into the culture medium. Draganov et al. (2005) found that recombinant PONs did not protect human LDL against Cu(2+)-induced oxidation in vitro, and no antioxidant activity copurified with any of the PONs. They stated that they had previously copurified antioxidant activity with human serum PON1, but that it was attributable to a low molecular mass contaminant and to the detergent in the preparation. Click this to see references in PubMed related to the ones listed in the paragraph above.
Molecular Genetics
Variation in PON1 Enzyme Activity
Geldmacher-von Mallinckrodt et al. (1973) first found polymorphism of paraoxonase activity. Click this to see references in PubMed related to the ones listed in the paragraph above.
Playfer et al. (1976) found bimodality for plasma paraoxonase activity in British and Indian persons, defining low and high activity phenotypes. Study of 40 British families confirmed this genetic polymorphism. Two phenotypes controlled by 2 alleles at 1 autosomal locus were defined. The frequency of the low activity phenotype was lower in the Indian population than in the British population. Malay, Chinese, and African populations failed to show clear bimodality. Possibly multiple alleles are present in these populations and result in a continuous distribution. Click this to see references in PubMed related to the ones listed in the paragraph above.
Mueller et al. (1983) described a test based on the differential inhibition of EDTA of plasma paraoxonase from persons with the high activity allele. With this test, trimodality of activity levels was suggested by population studies. The gene frequency of the low activity allele in 531 Seattle blood donors of European origin was 0.72. Family studies were consistent with codominant autosomal inheritance of 2 alleles encoding products with low and high activity levels. Click this to see references in PubMed related to the ones listed in the paragraph above.
Eckerson et al. (1983) could clearly distinguish heterozygotes from both homozygous phenotypes on the basis of the ratio of paraoxonase to arylesterase activities. Click this to see references in PubMed related to the ones listed in the paragraph above.
Ortigoza-Ferado et al. (1984) concluded that albumin has paraoxonase activity and proposed that an optimal assay of polymorphic paraoxonase activity should be based on activity of the nonalbumin fraction. Click this to see references in PubMed related to the ones listed in the paragraph above.
Nielsen et al. (1986) reexamined extensive family data and reaffirmed that segregation into high and low paraoxonase activity is largely or exclusively due to a 1-locus system. Click this to see references in PubMed related to the ones listed in the paragraph above.
Humbert et al. (1993) found that arginine at position 192 of PON1 specifies high-activity plasma paraoxonase, whereas glutamine at this position specifies a low-activity variant (Q192R; 168820.0001). This polymorphism is also referred to as gln191 to arg. Adkins et al. (1993) demonstrated that glutamine or arginine at amino acid 191 determines the A and B allozymes, respectively, of PON1. Click this to see references in PubMed related to the ones listed in the paragraph above.
In a study of 376 white individuals, Brophy et al. (2001) determined the genotypes of 3 regulatory region polymorphisms and examined their effect on plasma PON1 levels as indicated by rates of phenylacetate hydrolysis. The -108C-T polymorphism (168820.0003) had a significant effect on PON1 activity level, whereas a polymorphism at position -162 had a lesser effect. A polymorphism at position -909, which is in linkage disequilibrium with the other sites, appeared to have little or no independent effect on PON1 activity level in vivo. Brophy et al. (2001) presented evidence that the effect of the L55M (168820.0002) polymorphism on lowered paraoxonase activity is not due primarily to the amino acid change itself but to linkage disequilibrium with the -108C-T regulatory region polymorphism. The L55M polymorphism marginally appeared to account for 15.3% of the variance in PON1 activity, but this dropped to 5% after adjustments for the effects of the -108C-T and Q192R polymorphisms were made. The -108C-T polymorphism accounted for 22.8% of the observed variability in PON1 expression levels, which was much greater than that attributable to other PON1 polymorphisms. Click this to see references in PubMed related to the ones listed in the paragraph above.
Using a validated microsomal expression system of metabolizing enzymes, Bouman et al. (2011) identified PON1 as the crucial enzyme for the bioactivation of the antiplatelet drug clopidogrel, with the common Q192R polymorphism determining the rate of active metabolite formation. Analysis of patients with coronary artery disease who underwent stent implantation and received clopidogrel therapy revealed that Q192 homozygotes were more likely to undergo stent thrombosis than patients with the RR192 or QR192 genotypes (odds ratio, 3.6; p = 0.0003). Click this to see references in PubMed related to the ones listed in the paragraph above.
Susceptibility to Organophosphate Poisoning
PON1 hydrolyzes diazinonoxon, the active metabolite of diazinon, which is an organophosphate used in sheep dip. Cherry et al. (2002) studied PON1 polymorphisms in 175 farmers with ill health that they attributed to sheep dip and 234 other farmers nominated by the ill farmers and thought to be in good health despite having also dipped sheep. They calculated odds ratios for the Q192R (168820.0001) and L55M (168820.0002) polymorphisms, and for PON1 activity with diazinonoxon as substrate. Cases were more likely than referents to have at least 1 R allele at position 192 (odds ratio 1.93), both alleles of type LL (odds ratio 1.70) at position 55, and to have diazoxonase activity below normal median (odds ratio 1.77). The results supported the hypothesis that organophosphates contribute to the reported ill health of people who dip sheep. Click this to see references in PubMed related to the ones listed in the paragraph above.
Susceptibility to Coronary Artery Disease
Serrato and Marian (1995), who referred to the gln192-to-arg (Q192R; 168820.0001) polymorphism as the A/G polymorphism or the A/B polymorphism, demonstrated a relationship to coronary artery disease. The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. Individuals with the A genotype have a lower enzymatic activity than those with the B genotype. Serrato and Marian (1995) determined the genotypes in 223 patients with angiographically documented coronary artery disease and in 247 individuals in the general population. The distribution of genotypes was in Hardy-Weinberg equilibrium in both groups. Genotypes A and B were present in 49% and 11% of control individuals and in 30% and 18% of patients with coronary artery disease, respectively (p = 0.0003). The frequency of the A allele was 0.69 in controls and 0.56 in patients (p = 0.0001). There was no difference in the distribution of PON genotypes in the subgroups of patients with restenosis, myocardial infarction, or any of the conventional risk factors for coronary artery disease as compared with corresponding subgroups. Click this to see references in PubMed related to the ones listed in the paragraph above.
The L55M and Q192R polymorphisms in the PON1 gene and the ser311-to-cys (S311C; 602447.0001) polymorphism in the PON2 gene are associated with the risk of coronary artery disease in several European or European-derived populations. Chen et al. (2003) examined the association between these 3 markers and the severity of coronary artery disease as determined by the number of diseased coronary artery vessels in 711 women. No significant association was found between the PON polymorphisms and stenosis severity in either white or black women. However, among white women, when data were stratified by the number of diseased vessels, the frequency of the PON codon 192 arg/arg genotype was significantly higher in the group with 3-vessel disease than in the other groups (those with 1-vessel and 2-vessel disease) combined. Similarly, the frequency of the PON2 codon 311 cys/cys genotype was significantly higher in the group with 3-vessel disease than in the other groups combined. The adjusted odds ratio for the development of 3-vessel disease was 2.80 for PON1 codon 192 arg/arg and 3.68 for PON2 codon 311 cys/cys. The data indicated that the severity of coronary artery disease, in terms of the number of diseased vessels, may be affected by common genetic variation in the PON gene cluster on chromosome 7. Click this to see references in PubMed related to the ones listed in the paragraph above.
Garin et al. (1997) identified homozygosity for the leu54 allele of PON1 (168820.0002), which is associated with high paraoxonase activity, as an independent risk factor for cardiovascular disease. A linkage disequilibrium was apparent between the polymorphisms giving rise to leu54 and arg191. Garin et al. (1997) stated that their study underlined the fact that susceptibility to cardiovascular disease correlated with high-activity paraoxonase alleles. Linkage disequilibrium could explain the association between both the leu54 and the arg191 polymorphisms and cardiovascular disease. Click this to see references in PubMed related to the ones listed in the paragraph above.
Susceptibility to Coronary Artery Spasm
Ito et al. (2002) found that the incidence of the PON1 192R allele was significantly higher in a cohort of 214 Japanese patients with coronary spasm than in 212 control subjects. They speculated that the high frequency of the PON1 arg192 allele may be related to the higher prevalence of coronary spasm among Japanese than among Caucasians. Click this to see references in PubMed related to the ones listed in the paragraph above.
Susceptibility to Microvascular Complications of Diabetes 5
Kao et al. (1998) found an association between the L55M polymorphism in the PON1 gene (168820.0002) and diabetic retinopathy (MVCD5; 603933) in patients with type 1 diabetes (222100). Click this to see references in PubMed related to the ones listed in the paragraph above.
Kao et al. (2002) confirmed the association between L55M and diabetic retinopathy, finding increased susceptibility for retinopathy with the leu/leu genotype (odds ratio 3.34; p less than 0.0001). Click this to see references in PubMed related to the ones listed in the paragraph above.
Other Associations
Ikeda et al. (2001) found that the distribution of the Q192R and L55M (168820.0002) polymorphisms in the PON1 gene was significantly different between Japanese patients with exudative age-related macular degeneration (ARMD; see 153800) and age- and sex-matched controls. The BB genotype at position 192 and the LL genotype at position 55 occurred at higher frequency in patients with ARMD compared to controls (p = 0.0127 and p = 0.0090, respectively). The mean oxidized LDL level in patients was significantly higher than in controls (p less than 0.01). Ikeda et al. (2001) concluded that the PON1 gene polymorphisms might represent a genetic risk factor for ARMD and that increased plasma oxidized LDL might be involved in the pathogenesis of ARMD. Click this to see references in PubMed related to the ones listed in the paragraph above.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Genotype/Phenotype Correlations
Davies et al. (1996) analyzed the paraoxonase catalytic activity against the toxic oxon forms which result from the bioactivation of the organophosphorus insecticides parathion, chloropyrifos, and diazinon in the P450 system. They also analyzed the hydrolytic activity of PON1 against the nerve agents soman and sarin. Davies et al. (1996) reported a simple enzyme analysis that provided a clear resolution of PON1 genotypes and phenotypes. The plot of diazoxon hydrolysis versus paraoxon hydrolysis clearly resolved all 3 genotypes (Q192Q192, Q191R192, R192R192; see 168820.0001) and at the same time provided important information about the level of enzyme activity in an individual. They observed the reversal of the effect of PON1 polymorphisms for diazoxon hydrolysis relative to paraoxon hydrolysis. RR homozygotes (high paraoxonase activity) had lower diazoxonase activity than the QQ homozygotes (low paraoxonase activity). They reported that the effect was also reversed for the nerve gases soman and sarin (sarin was the nerve gas released in the Tokyo subway in March 1995). The mean value of sarin hydrolysis was only 38 U per liter for the R192 homozygotes compared with 355 U per liter for the Q192 homozygotes. Davies et al. (1996) observed an increased frequency for the R192 allele (0.41) in the Hispanic population compared with a frequency of 0.31 for populations of northern European origin. These frequencies result in approximately 16% of individuals of Hispanic origin being homozygous for the R192 PON1 isoform compared with 9% of individuals of northern European origin. They noted that newborns have very low activities of PON1, leading them to predict that newborns would be significantly more sensitive to organophosphorus compounds than adults. The authors cited studies showing that injected PON1 protects against organophosphorus poisoning in rodents (Li et al., 1995). Click this to see references in PubMed related to the ones listed in the paragraph above.
Phuntuwate et al. (2005) studied the activity of 4 PON1 polymorphisms towards paraoxon, phenylacetate, and diazoxon. They found that the L55M, Q192R, and -909G-C polymorphisms significantly and variably affected serum PON1 activity towards the substrates, whereas the -108C-T polymorphism had no significant effect on serum PON1 activity towards any substrate. Phuntuwate et al. (2005) suggested that the physiologic relevance of the PON1 polymorphisms is that they are associated with significant differences in serum PON1 activity that are substrate dependent. Click this to see references in PubMed related to the ones listed in the paragraph above.
Mackness et al. (1998) examined the effects of the 2 common polymorphisms in PON1 on the ability of HDL to protect LDL from oxidative modification. HDL protected LDL from oxidative modification, whatever the combination of PON1 alloenzymes present in it. However, HDL from QQ/MM homozygotes was most effective in protecting LDL, while HDL from RR/LL homozygotes was least effective. Thus after 6 hours of coincubation of HDL and LDL with Cu(2+), PON1-QQ HDL retained 57 +/- 6.3% of its original ability to protect LDL from oxidative modification, while PON1-QR HDL retained less at 25.1 +/- 4.5% and PON1-RR HDL retained only 0.75 +/- 0.40%. In similar experiments, HDL from LL and LM genotypes retained 21.8 +/- 7.5% and 29.5 +/- 6.6%, respectively, of their protective ability, whereas PON1-MM HDL maintained 49.5 +/- 5.3%. PON1 polymorphisms may affect the ability of HDL to impede the development of atherosclerosis and to prevent inflammation. Click this to see references in PubMed related to the ones listed in the paragraph above.
Animal Model
To study the role of PON1 in vivo, Shih et al. (1998) created Pon1-knockout mice by gene targeting. Compared with their wildtype littermates, Pon1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from Pon1-deficient mice were unable to prevent LDL oxidation in a cocultured cell model of the artery wall, and both HDLs and LDLs isolated from Pon1-knockout mice were more susceptible to oxidation by cocultured cells than were lipoproteins from wildtype littermates. When fed on a high-fat, high-cholesterol diet, Pon1-null mice were more susceptible to atherosclerosis than were their wildtype littermates. Click this to see references in PubMed related to the ones listed in the paragraph above.
Watson et al. (2001) identified a serum paraoxonase polymorphism in rabbit with functional characteristics similar to those of human Q192R. They suggested that the rabbit may serve as a model in examining the effect of human PON1 polymorphisms in disease development. Click this to see references in PubMed related to the ones listed in the paragraph above.
History
Identification and Classification of Esterases
Using azo dye coupling techniques and electrophoresis, Tashian (1965) defined several different esterases in human red cells. Three main groups, differing as to electrophoretic properties, substrate specificities and inhibition characteristics, were A, B, and C esterases. Variants of esterase A were reported by Tashian and Shaw (1962) and Tashian (1965). Click this to see references in PubMed related to the ones listed in the paragraph above.
Using starch-gel electrophoresis, Coates et al. (1975) identified multiple esterase isozymes in every human tissue, and they characterized the isozymes in terms of electrophoretic mobility, tissue distribution, developmental changes in utero, substrate specificity, inhibition properties, and molecular weight. On these criteria, 13 sets of esterase isozymes were identified, in addition to the esterase isozymes due to cholinesterase and carbonic anhydrase. The data suggested that the 13 sets of isozymes are determined by at least 9 different genes. The acetylesterases, which prefer acetate esters as substrates, were divided into 9 sets of isozymes, designated ESA1 to ESA7, ESC (133270), and ESD (133280). Coates et al. (1975) divided the butyrylesterases, which prefer butyrate esters as substrates, into 4 sets of isozymes, designated ESB1 to ESB4. Click this to see references in PubMed related to the ones listed in the paragraph above.
ALLELIC VARIANTS (3 Selected Examples):
Table View
.0001 PON1 ENZYME ACTIVITY, VARIATION IN
CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED
CORONARY ARTERY SPASM 2, SUSCEPTIBILITY TO, INCLUDED
PON1, GLN192ARG [dbSNP:rs662] [ClinVar]
Humbert et al. (1993) found that arginine at position 192 of PON1 specifies high-activity plasma paraoxonase, whereas glutamine at this position specifies a low-activity variant. They showed that allele-specific probes or restriction enzyme analysis of amplified DNA could be used for genotyping of individuals. This polymorphism is also referred to as GLN191ARG. Adkins et al. (1993) also demonstrated that glutamine or arginine at amino acid 191 determines the A and B allozymes, respectively, of PON1. Click this to see references in PubMed related to the ones listed in the paragraph above.
Serrato and Marian (1995), who referred to the gln192-to-arg (Q192R) polymorphism as the A/G polymorphism or the A/B polymorphism, demonstrated a relationship to coronary artery disease. The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. Individuals with the A genotype have a lower enzymatic activity than those with the B genotype. Serrato and Marian (1995) determined the genotypes in 223 patients with angiographically documented coronary artery disease and in 247 individuals in the general population. The distribution of genotypes was in Hardy-Weinberg equilibrium in both groups. Genotypes A and B were present in 49% and 11% of control individuals and in 30% and 18% of patients with coronary artery disease, respectively (p = 0.0003). The frequency of the A allele was 0.69 in controls and 0.56 in patients (p = 0.0001). There was no difference in the distribution of PON genotypes in the subgroups of patients with restenosis, myocardial infarction, or any of the conventional risk factors for coronary artery disease as compared with corresponding subgroups. Click this to see references in PubMed related to the ones listed in the paragraph above.
Antikainen et al. (1996) referred to this polymorphism as gln191 to arg (Q191R). In Finns they were unable to confirm an association with the risk of coronary artery disease. The most common genotype found in both 380 well-characterized CAD patients and 169 controls was AA (gln/gln). The frequency of the A allele was 0.74 in both patients and controls. The genotype distributions of the 2 groups did not differ and were similar to those reported earlier in other caucasoid populations. Click this to see references in PubMed related to the ones listed in the paragraph above.
Odawara et al. (1997) performed an association study of the arg192 polymorphism with coronary heart disease (CHD) in Japanese noninsulin-dependent diabetes mellitus (NIDDM; 125853) subjects. They genotyped 164 NIDDM patients (42 with and 122 without CHD). Other known risk factors for CHD were matched between the 2 groups. AB + BB isoforms were detected in 41 of 42 NIDDM patients with CHD. The proportion of B allele carriers (AB + BB) was significantly higher than that of AA carriers among NIDDM patients with CHD compared to those without CHD (chi square = 7.68, p = 0.003). Multivariate logistic regression analyses showed an increased odds ratio (8.8; CI, 1.1-69) in B allele carriers, while odds ratios of other risk factors remained between 1.0 and 1.9. The authors concluded that Japanese NIDDM patients who are carriers of the B allele of the gln192-to-arg polymorphism have an increased risk for developing CHD independent of other known risk factors for CHD. Click this to see references in PubMed related to the ones listed in the paragraph above.
The arg192 isoform of paraoxonase hydrolyzes paraoxon more rapidly than the gln192 isoform. However, with respect to hydrolysis of toxic nerve agents, such as sarin, the arg192 isoform displays a lower activity than the other isoform. Yamasaki et al. (1997) found that the arg192 allele is more common in the Japanese (allele frequency, 0.66) than in people of other races (range, 0.24 to 0.31). In Japanese, 41.4% of subjects were homozygous for the arg192 allele, which shows a very low hydrolysis activity for sarin. Thus, there seems to be a racial difference in vulnerability to toxic nerve agents, such as sarin. The dominance of the arg192 allele in the Japanese population probably worsened the tragedy of March 1995 in the Tokyo subway. Click this to see references in PubMed related to the ones listed in the paragraph above.
Heinecke and Lusis (1998) reviewed the results of previous studies of the PON1 Q192R polymorphism in CHD and raised the question of whether these PON polymorphisms support the oxidative damage hypothesis of atherosclerosis. Click this to see references in PubMed related to the ones listed in the paragraph above.
Paolisso et al. (2001) investigated the relationship between a PON1 polymorphism and brachial reactivity in healthy adult subjects in the presence of acute hypertriglyceridemia as a prooxidant factor. In 101 healthy subjects the response to flow-induced vasodilation was measured before and after Intralipid infusion. In the same subjects the A/B PON1 polymorphism was genotyped. The frequency was 0.545 for the AA genotype, 0.356 for the AB genotype, and 0.099 for the BB genotype. At baseline all genotype groups had similar increases in brachial artery diameter and flow. After Intralipid infusion, subjects sharing the BB genotype had a significant decrease versus baseline values in changes in brachial artery diameter, but not in flow. In a subgroup of 55 subjects distributed along the 3 PON1 genotypes the same study protocol was repeated by buccal nitroglycerine administration to study the endothelium-independent vasodilation. Again, subjects with the BB genotype had the worse vasodilation. The authors concluded that transient hypertriglyceridemia decreases vascular reactivity more in subjects with the PON1 BB genotype than in those with the other PON1 genotypes. Click this to see references in PubMed related to the ones listed in the paragraph above.
Ito et al. (2002) found that the incidence of the PON1 192R allele was significantly higher in a cohort of 214 Japanese patients with coronary spasm than in 212 control subjects. They speculated that the high frequency of the PON1 arg192 allele may be related to the higher prevalence of coronary spasm among Japanese than among Caucasians. They also noted that cigarette smoking reduces serum PON1 activity in patients with coronary artery disease, and that cigarette smoking is highly prevalent in the Japanese. Click this to see references in PubMed related to the ones listed in the paragraph above.
PON1 hydrolyzes diazinonoxon, the active metabolite of diazinon, which is an organophosphate used in sheep dip. Cherry et al. (2002) studied PON1 polymorphisms in 175 farmers with ill health that they attributed to sheep dip and 234 other farmers nominated by the ill farmers and thought to be in good health despite having also dipped sheep. They calculated odds ratios for the Q192R and L55M (168820.0002) polymorphisms, and for PON1 activity with diazinonoxon as substrate. Cases were more likely than referents to have at least 1 R allele at position 192 (odds ratio 1.93), both alleles of type LL (odds ratio 1.70) at position 55, and to have diazoxonase activity below normal median (odds ratio 1.77). The results supported the hypothesis that organophosphates contribute to the reported ill health of people who dip sheep. Click this to see references in PubMed related to the ones listed in the paragraph above.
Bonafe et al. (2002) examined the Q192R polymorphism in 308 Italian unrelated centenarians and 579 Italian individuals aged 20 to 65 years. The percentage of carriers of the R192 allele was significantly higher in centenarians than in young people (0.539 vs 0.447, p = 0.011). No significant difference between centenarians and young individuals was observed for the PON1 L55M polymorphism (168820.0002). The authors proposed that the R192 allele decreases mortality in carriers, but that the effect of PON1 variability on the overall population mortality is rather slight. The findings suggested that PON1 is one of the genes affecting the individual adaptive capacity and is therefore one of the genes affecting rate and quality of aging (152430). Click this to see references in PubMed related to the ones listed in the paragraph above.
In a longitudinal study of survival involving 1,932 Danish individuals, Christiansen et al. (2004) found that women homozygous for the R192 allele had a poorer survival rate compared to Q192 homozygotes (hazard ratio, 1.38; p = 0.04). An independent sample of 541 Danish individuals confirmed the findings for R192 homozygous women, with a hazard ratio of 1.38 (p = 0.09). Combining the 2 samples did not change the risk estimate, but increased the statistical significance (p = 0.008). Using self-reported data on ischemic heart disease, the authors found only a nonsignificant trend of R192 homozygosity in women being a risk factor. Christiansen et al. (2004) concluded that PON1 R192 homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to the development of CHD. Click this to see references in PubMed related to the ones listed in the paragraph above.
Using a validated microsomal expression system of metabolizing enzymes, Bouman et al. (2011) identified PON1 as the crucial enzyme for the bioactivation of the antiplatelet drug clopidogrel, with the common Q192R polymorphism determining the rate of active metabolite formation. A case-cohort study of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy revealed that Q192 homozygotes were more likely to undergo stent thrombosis than patients with the RR192 or QR192 genotypes (odds ratio, 3.6; p = 0.0003). In addition, PON1 QQ192 homozygotes showed a considerably higher risk than RR192 homozygotes of lower PON1 plasma activity, lower plasma concentrations of active metabolite, and lower platelet inhibition. Click this to see references in PubMed related to the ones listed in the paragraph above.
.0002 PON1 ENZYME ACTIVITY, VARIATION IN
CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED
MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 5, INCLUDED
PON1, LEU55MET [dbSNP:rs854560] [ClinVar]
This polymorphism was originally designated MET54LEU (M54L; Garin et al., 1997) and has also been designated MET55LEU (M55L; e.g., Kao et al., (1998, 2002)). It is referred to here as LEU55MET (L55M) because Brophy et al. (2001) noted that leucine is the more frequent amino acid at position 55 (or 54, depending on the numbering system). Click this to see references in PubMed related to the ones listed in the paragraph above.
Garin et al. (1997) investigated this polymorphism in 408 diabetic patients with or without vascular disease. There were highly significant differences in plasma concentrations and activities of paraoxonase between genotypes defined by the met54-to-leu polymorphism. On the other hand, the arg191 variant (168820.0001) had little impact on paraoxonase concentration. Homozygosity for the leu54 allele was an independent risk factor for cardiovascular disease. A linkage disequilibrium was apparent between the mutations giving rise to leu54 and arg191. Garin et al. (1997) stated that their study underlined the fact that susceptibility to cardiovascular disease correlated with high-activity paraoxonase alleles. The M54L polymorphism appeared to be of central importance to paraoxonase function by virtue of its association with modulated concentrations. Linkage disequilibrium could explain the association between both the leu54 and the arg191 polymorphisms and CVD. Click this to see references in PubMed related to the ones listed in the paragraph above.
Brophy et al. (2001) presented evidence that the L55M effect of lowered activity is not due primarily to the amino acid change itself but to linkage disequilibrium with the -108 regulatory region polymorphism (168820.0003). The -108C/T polymorphism accounted for 22.8% of the observed variability in PON1 expression levels, which was much greater than that attributable to other PON1 polymorphisms. Click this to see references in PubMed related to the ones listed in the paragraph above.
Deakin et al. (2002) analyzed glucose metabolism as a function of PON1 polymorphisms in young healthy nondiabetic men from families with premature coronary heart disease (CHD) and matched controls. The L55M PON1 polymorphism was independently associated with the glucose response to an oral glucose tolerance test. LL homozygotes had significantly impaired glucose disposal (p = 0.0007) compared with LM and MM genotypes. It was particularly marked for subjects from high CHD risk families and differentiated them from matched controls (p = 0.049). The area under the glucose curve (p = 0.0036) and the time to peak glucose value (p = 0.026) were significantly higher in the LL carriers, whereas the insulin response was slower (p = 0.013). The results showed that an association exists between PON1 gene polymorphisms and glucose metabolism. The authors also concluded that the L55M-glucose interaction differentiated offspring of high CHD risk families, suggesting that it may be of particular relevance for vascular disease and possibly other diabetic complications. Click this to see references in PubMed related to the ones listed in the paragraph above.
Barbieri et al. (2002) investigated association of the M54L polymorphism with the degree of insulin resistance (IR) in 213 healthy subjects by the homeostasis model assessment. The frequency was 0.366 for the LL genotype, 0.469 for the LM genotype, and 0.164 for the MM genotype. Comparing the 3 genotype groups, LL genotype had the more severe degree of IR. Subjects carrying the LL genotype were associated with the IR syndrome picture more than individuals carrying the M allele because they were more overweight and had the highest levels of triglycerides and blood pressure and the lowest values of plasma high density lipoprotein cholesterol. In a multivariate stepwise regression analysis, LL genotype was a significant predictor of IR, independent of age, sex, body mass index, fasting plasma triglycerides, and high density lipoprotein cholesterol. The authors concluded that the presence of LL PON genotype is associated with a more severe degree of IR. Thus, IR might be the possible missing link between the M54L polymorphism and the increased cardiovascular risk. Click this to see references in PubMed related to the ones listed in the paragraph above.
Kao et al. (1998) investigated the potential significance of these PON1 polymorphisms in the pathogenesis of diabetic retinopathy in IDDM (MVCD5; 612633). They analyzed samples from 80 patients with diabetic retinopathy and 119 controls. The allelic frequency of the leu54 (L) polymorphism was significantly higher in the group with retinopathy than in the group without retinopathy (73% vs 57%, p less than 0.001). Kao et al. (1998) concluded that the genotype L/L was strongly associated with the development of diabetic retinopathy (p less than 0.001), but a similar association was not found with the arg192 polymorphism. Click this to see references in PubMed related to the ones listed in the paragraph above.
Kao et al. (2002) analyzed the M54L PON1 polymorphism in 372 adolescents with type 1 diabetes (222100) and confirmed increased susceptibility to diabetic retinopathy with the leu/leu genotype (odds ratio, 3.4; p less than 0.0001) independent of age, duration of disease, and cholesterol. Click this to see references in PubMed related to the ones listed in the paragraph above.
.0003 PON1 ENZYME ACTIVITY, VARIATION IN
PON1, -108C-T [dbSNP:rs705379] [ClinVar]
Brophy et al. (2001) concluded that the -108C/T polymorphism in the 5-prime regulatory region of the PON1 gene accounts for 22.8% of the observed variability in PON1 expression levels, which is much greater than that attributable to other PON1 polymorphisms. Click this to see references in PubMed related to the ones listed in the paragraph above.
See Also:
Augustinsson and Henricson (1966); Eckerson et al. (1983); Geldmacher-von Mallinckrodt (1978); Neel et al. (1977)
