Paraoxonase activity and genotype predispose to successful aging

The paraoxonase 1 codon 192 R allele has been previously reported to have a role in successful aging. The relationship between PON1 genotypes, enzymatic activity, and mass concentration was evaluated in a group of 229 participants from 22 to 104 years of age, focusing our attention on nonagenarian/centenarian participants. We found a genetic control for paraoxonase activity that is maintained throughout life, also in the nonagenarians/centenarians. This activity decreases significantly during aging and shows different mean values among R and M carriers, where R+ and M- carriers have the significant highest paraoxonase activity. Results from the multinomial regression logistic model show that paraoxonase activity as well as R+ and M- carriers contribute significantly to the explanation of the longevity phenotype. In conclusion, we show that genetic variability at the PON1 locus is related to paraoxonase activity throughout life, and suggest that both parameters affect survival at extreme advanced age.     

Paraoxonase producing PON1 gene M/L55 polymorphism is related to autopsy-verified artery-wall atherosclerosis

Paraoxonase (PON) is an antioxidative enzyme, which eliminates lipid peroxides. PON has two common polymorphisms (M/L55 and R/Q192) that influence PON concentration and activity. We studied whether the M/L55 or R/Q192 genotype relates with the severity of atherosclerosis of the abdominal aorta, and the mesenteric and common iliac arteries in 123 consecutive autopsy cases (90 males and 33 females, aged 18-93 years). The severity of atherosclerosis in the arteries was evaluated, and the percentage of stenosis was measured. The intimal thickness in the internal elastic lamina (IEL) of the coeliac (CA), superior mesenteric (SMA) and inferior mesenteric (IMA) arteries were measured by light-microscopy. The LL homozygous men had more atherosclerotic plaques and complicated lesions in the common iliac arteries (56.8%) than the M allele carriers (28.3%, P=0.007). In logistic regression analysis, age (P<0.001) and the PON M/L55 genotype (P=0.015) were associated significantly with the severity of atherosclerosis in the common iliac arteries independent of smoking status, R/Q192 genotype, hypertension, diabetes mellitus, BMI and sex. The mean intima of the IMA was significantly thicker (P=0.035) and the number of stenotic lesions in SMAs significantly higher (P=0.008) in the LL homozygous men than M allele carriers. In turn, the R/Q192 genotype was not statistically significantly associated with plaque type, intimal thickness in the IEL or with the number of stenotic lesions. This study demonstrates that PON L55 homozygosity is an independent risk factor for autopsy-verified atherosclerosis in Finns.     

Paraoxonase (PON)1 192R Allele Carriage is Associated with Reduced Risk of Inflammatory Bowel Disease

The paraoxonase (PON) genes family maps to chromosome 7q21-q22, within a loci that also showed evidence of susceptibility genes for both Crohn’s disease (CD) and ulcerative colitis (UC). In this case-control study we investigated the possible relationship between PON1 and PON2 polymorphisms and the risk of inflammatory bowel disease (IBD). PON1 192Q/R, PON1 55L/M, and PON2 311S/C polymorphisms were investigated by RFLP analysis in DNA samples from 224 patients with CD, 58 patients with UC, and 311 healthy controls. The PON1 192R allele was significantly less common among IBD Ashkenazi patients (allelic OR = 0.61, P = 0.004, 95% CI = 0.44–0.85). In agreement with the individual SNP analysis, Ashkenazi IBD patients had a higher frequency of haplotype PON1 192Q/PON1 55L/PON2 311S (26.3% vs 17.3%; P=0.003) and a lower frequency of haplotype PON1 192R/PON1 55L/PON2 311S (18.9% vs 27.7%; P=0.008). Our results suggest that in this Ashkenazi Jewish population, carriage of PON1 R192 allele may confer protection against the development of IBD.     

对氧磷酶1 192Q/R基因多态性及酶活性与脑梗死的相关性研究

目的探讨对氧磷酶1(paraoxonase1,PON1)192Q/R基因多态性及酶活性在脑梗死发生中的作用。方法将104例脑梗死患者为脑梗死组,并按年龄分为老年脑梗死组(41例)和中青年脑梗死组(63例)2个亚组,同期选择门诊体检的非脑血管疾病患者104例为对照组,并按年龄分为老年对照组(41例)和中青年对照组(63例)2个亚组。入选者按年龄?性别相匹配对分为老年组和中青年组。测定2组PON1 192Q/R基因多态性及酶活性。结果脑梗死组患者PON1酶活性均低于对照组,差异有统计学意义(P<0.001)。老年脑梗死组患者PON1 192 Q/R基因型的分布与老年对照组比较差异无统计学意义(P=0.353)。中青年脑梗死组RR基因型(34例)高于中青年对照组(16例),QQ基因型(3例)低于中青年对照组(9例,P=0.003)。老年组(r=-0.290,P=0.008)和中青年组(r=-0.354,P<0.001)PON1 R基因型与酶活性均呈负相关。老年组(OR=0.823,P<0.001)和中青年组(OR=0.835,P<0.001)PON1酶活性升高,脑梗死发生风险降低。结论PON1 192Q/R基因型可影响PON1酶活性。高PON1酶活性可降低脑梗死的风险,而PON1 192Q/R基因型对脑梗死的发生无影响。     

Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases

Paraoxonase 1 (PON1) is proposed to have an anti-atherogenic action. Two polymorphisms at the PON1 (M/L55 and Q/R192) have been shown to be associated with coronary artery disease (CAD). This conclusion is not drawn universally, however, and specific ethnic characteristics may be important determinants in this association. Recently two homologues of PON1 - PON2 and PON3 - were identified and Sanghera et al. demonstrated C/S311 polymorphism at PON2 was associated with the risk of CAD. Within that context, we investigated the association between the aforementioned three polymorphisms and CAD and ischemic stroke in a Japanese population. The study population included 431 control subjects, 210 CAD patients, and 235 ischemic stroke patients. Genotype distributions and allele frequencies of M/L55 and C/S311 were similar among the control and patient groups, whereas the R192 allele frequency was significantly higher (P<0.001) in CAD (75%) and ischemic stroke (76%) patients than in control subjects (65%). When confounding influences of other risk factors were controlled for by multivariate analysis, R192 remained an independent risk determinant (additive model: OR (95% CI), P value CAD: 2.01 (1.45-2.79), 0.0001; ischemic stroke: 1.84 (1.34-2.52), 0.0002 (three genotypes into calculation)). Taken together, our data indicate that the Q/R192 is principally associated with both CAD and ischemic stroke in Japanese.     

对氧磷酶1基因Gln192Arg多态性与阿尔茨海默病的相关性分析

目的 探讨中国汉族人群中对氧磷酶1（PON1）基因Gln192Arg单核苷酸多态性（SNP）与阿尔茨海默病（AD）的相互关系。方法采用实时定量PCR技术检测521例AD患者和578例健康老年人PON1基因Gln192Arg位点SN-P的分布,并通过OR做疾病关联分析。结果AD组（Q／R＋R／R）基因型频率较对照组低,统计分析差异有统计学意义（X^2=4．68,P=0．03）;等位基因频率差异也存在统计学意义,AD组R等位基因频率明显低于对照组（X^2=3．85,P=o．05）。logistic回归分析表明,调整年龄和性别的影响后,（Q／R＋R／R）基因型患AD的危险性是Q／Q基因型的0．71倍（P=0．044,95％CI=0．51～0．99）。结论中国汉族人群中PON1基因Gln192Arg位点R等位基因可能是AD的保护因素。     

Association of paraoxonase 1 (PON1) gene polymorphisms and concentration with essential hypertension

Human serum paraoxonase 1 (PON1) is carried by high-density lipoprotein in blood circulation and is shown to be effective in preventing oxidized phospholipids carried by low-density lipoprotein particles, thus it acts as an antioxidant. Polymorphism in this gene has been investigated for many metabolic diseases, but it is not thought to be a genetic risk factor for essential hypertension. The aim of this study was to determine whether there was an association between PON1 gene polymorphisms and concentration with essential hypertension. The study population was comprised of 100 patients with essential hypertension and 100 healthy controls. One promoter region [C(-108)T] and two coding region (Q192R and L55M) polymorphisms in the PON1 gene were genotyped in individuals by using the TaqMan assay. Plasma PON1 concentration in all volunteers was also measured spectrophotometrically by the enzyme-linked immunosorbent assay method. The genotype and allele frequencies of the PON1 C(-108)T polymorphism showed significant differences between the essential hypertensive and control groups (CT vs. CC: p<0.001; T allele vs. C allele: p<0.001). There was no significant difference for the PON1 L55M polymorphism between the groups, while the heterozygote genotype of the PON1 Q192R polymorphism showed significant difference (p = 0.03). The PON1 concentration was also found to be significantly lower in hypertensive patients (p < 0.001). Decline in the level of PON1 gene may be one of the main factors in the development of essential hypertension, and the PON1 C(-108)T polymorphism may have a prognostic value in the patients with essential hypertension.     

冠心病患者对氧磷酯酶1基因多态性分析

目的 :探讨冠心病 (CHD)患者对氧磷酯酶 1(Paraoxonase 1,PON1)基因多态性与血脂的关系及其病因学意义。方法 :使用Taqman特异性等位基因鉴别法检测 93例CHD患者和 138例健康对照者的基因组DNA ,测定该基因G 12 6C、L5 5M和Q192R三个多态性的基因型和由三个位点的等位基因组成的单体型。统计分析两组间这些基因型和单体型频率分布差异性 ,以及不同基因型与血脂水平的相关性。结果 :CHD患者中Q192R位点的QQ基因型携带者明显少于健康对照者 (7.5 %∶18.1% ,P <0 .0 5 ) ,各种单体型在两组间差异无显著性意义。各基因型之间血脂水平差异亦无显著性意义。结论 :PON1基因中只有Q192R多态性与CHD的发病相关     

Ethnic variations in paraoxonase1 polymorphism in the Malaysian population

The role of high-density lipoprotein associated paraoxonase (PON) 1 in protection against oxidative stress associated with the development of complications in diabetes mellitus has been reported. Variations in the PON1 gene, 55LM and 192QR have been described in different populations. These variations are known to be risk factors for heart disease, especially the L and R alleles. We have investigated the prevalence of both polymorphisms in the Malaysian population comprising the three major ethnic groups: Malay, Chinese and Indian, using polymerase chain reaction followed by restriction endonuclease digestion. The results show the pooled frequencies of L and R alleles were 0.91 and 0.54, respectively, similar to those in the Asian region. The frequency of the M allele was higher in Indians (p < 0.05), whereas the R allele was higher in both the Chinese and Malays compared to Indians (p < 0.05), indicating ethnic group-dependent genetic differences. The most common genotypic combination was LL/QR, followed by LL/RR. The genotype frequencies for the total Malaysian population showed a significant departure from Hardy-Weinberg equilibrium for the 55LM (p = 0.013) but not the 192QR (p = 0.056) polymorphisms. A strong linkage disequilibrium between L/55 and R/192 alleles was also observed. In the Malaysian population as a whole, Malays and Chinese showed a higher frequency of the R allele which is a risk factor for cardiovascular diseases.     

Polymorphisms in the paraoxonase and endothelial nitric oxide synthase genes and the risk of early-onset myocardial infarction

In young patients, the accumulative burden of traditional cardiovascular risk factors may not be as significant as in an older population. Genetic risk factors were suggested to have a role in the early development of myocardial infarction (MI). However, data about the association between polymorphisms in heart disease-related genes and the early onset of a first MI are limited. In the present study, age at onset of a first MI was related to individual single-nucleotide polymorphisms in each of 18 prespecified candidate genes in a cohort of 814 patients enrolled in the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) Study. Multivariate regression analysis showed in patients who had the high-risk genotypes of paraoxonase 1 (PON1) Q192R and endothelial nitric oxide synthase (eNOS) E298D that ages at onset of a first MI were 1.8 (p = 0.02) and 3.5 years (p = 0.02) earlier than in noncarriers of the genotypes, respectively. Consistently, high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms were significantly associated with onset of a first MI at age <50 years (adjusted odds ratio 1.70, p = 0.005, adjusted odds ratio 2.15, p = 0.01, respectively). In conclusion, our findings suggest that high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms are independently associated with a significantly earlier occurrence of coronary events.     

Paraoxonase1 55 and 192 gene polymorphisms in an Egyptian population with diabetic complications

Type 2 diabetes is a polygenic disease characterized by interaction of environmental and genetic factors. The paraoxonase 1 gene (PON1) 55 and 192 polymorphisms have been reported to be associated with type 2 diabetes and its complications. Our aim is to study the PON1 55, 192 gene polymorphisms and enzyme activity in type 2 diabetic Egyptian population with complications. 100 type 2 diabetic patients with complications (34 with cardiac and 66 with microvascular complications (neuropathy, retinopathy and/or nephropathy)). This was in addition to 100 healthy control subjects of matched age and sex were taken. PON1 55 L?M and 192 Q?R gene polymorphisms and PON1 enzyme activity serum levels were detected. The LL genotype of PON1 55 polymorphism and QR and QQ genotypes of PON1 192 polymorphism were more frequent among the patients with diabetic complications. The PON1 enzyme activity levels were lower among the diabetic patients than in control subjects. PON1 55 and 192 polymorphisms and enzyme activity seems to be related to diabetic complications in this population.     

Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia

Human serum paraoxonase (PON) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two frequent mutations at the paraoxonase gene locus (PON1) are the leucine (L allele)-->methionine (M allele) and the glutamine (Q allele)-->arginine (R allele) substitutions at residues 55 and 192, respectively. We have examined the influence of these two polymorphisms on carotid atherosclerosis in familial hypercholesterolemia (FH) patients. The allele frequencies of these two polymorphisms were determined by PCR and restriction fragment analysis, for both the FH population and healthy controls. High resolution B-mode ultrasound was used to assess intima-media wall thickness (IMT) of the carotid artery. No differences were found in allele frequencies between the FH and the control population. In FH patients, the LL, LM and MM genotypes at position 55 occurred in 86 (46.0%), 78 (41.7%) and 23 (12.3%) subjects, respectively, whereas the QQ, QR and RR genotypes at position 192 were found in 90 (48.1%), 79 (42.2%) and 18 (9.6%) individuals. When both polymorphisms were considered separately, no different carotid IMTs were found between the genotype groups. However, our data did show a significant association between the various genotypes of the combined polymorphisms at position 55 and 192 of PON1 and the carotid artery IMT in FH subjects. Subjects with the homozygous wildtype LL/QQ for paraoxonase had the highest mean carotid IMTs when compared to other genotypes, combined. Multiple regression analysis demonstrated age (beta=0.34, P<0.0001), total plasma cholesterol (beta=0.17, P=0. 0109) and the LL/QQ genotype of the PON1 gene (beta=0.22, P=0.0018) to be significant risk factors for carotid atherosclerosis in subjects with FH. The LL/QQ genotype could explain 5.3% of total variance of carotid IMT. In conclusion, this is the first study to report an independent association between the combined PON1 polymorphism genotypes and carotid wall thickness. The homozygous wildtype LL/QQ for PON1 may represent an additional risk factor for carotid atherosclerosis in subjects with FH.     

Association of paraoxonase 1 polymorphism with beta-cell function: a case of molecular heterosis

Paraoxonase 1 (PON1) is an antioxidant enzyme that inhibits the oxidative modification of LDL. Since PON1 has been shown to express in pancreatic islets and oxidative stress plays a role in beta-cell dysfunction, we investigated the impact of the PON1 polymorphisms on beta-cell function. This study included 84 healthy and glucose-tolerant white subjects who underwent an oral glucose tolerance test. Beta-cell function (1stPHS and 2ndPHS) was estimated according to the formulae published by Stumvoll et al. The relationship of the L55M and Q192R polymorphisms to beta-cell function was examined. Allelic frequency in this population was 0.37 for the M allele and 0.30 for the R allele. For the L55M polymorphism, the LM genotype had the lowest 1stPHS (P = 0.009) and 2ndPHS (P = 0.007), indicating molecular heterosis. Multivariate analyses confirmed that the L55M polymorphism was an independent determinant for 1stPHS (P = 0.016) and 2ndPHS (P = 0.009), after adjustment for covariates. For the Q192M polymorphism, no difference was noted in 1stPHS and 2ndPHS. We observed the L55M polymorphism of the PON1 gene as an independent determinant for beta-cell function in glucose-tolerant whites. Our observations suggest that this polymorphism could play a role in beta-cell dysfunction.     

Association between paraoxonase-1 gene Q192R and L55M polymorphisms in systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS) in a population from Cairo of Egypt

Paraoxonase-1 (PON1) is involved in the oxidative stress process that cause tissue damage observed in systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS). The aim of the present study was to investigate the association of PON1 Q192R and L55M polymorphisms with risk of SLE and associated APS among Egyptian sample. The study included 120 SLE patients (45 without APS and 75 with APS) and 120 healthy subjects. PON1 Q192R and L55M polymorphisms were genotyped by real-time PCR. No significant differences in Q192R genotypes or allele frequencies were found between patients and controls (p = 0.5 and 0.1, respectively). The frequency of the 55M allele was significantly higher in SLE patients than in controls (66.6 vs. 43.3%), while the 55L allele was more frequent in controls (56.6%) than in patients (33.3%) (p = 0.03). The LL genotype was more frequent in controls (21.6%) than in patients (10%) while M allele carrier genotypes (LM + MM) were more frequent among patients (90%) than controls (78.3%), p = 0.04. Also, the 55M allele was more frequent in APS patients (73.3%) than in patients without APS (55.6%), p = 0.004. M allele carrier genotypes (LM + MM) was significantly higher among APS patients (95.4%) than in non-APS patients (80%), p = 0.008. Our results indicated that the PON1 L55M polymorphism associated with SLE and associated APS in a population from Cairo of Egypt, while the Q192R polymorphism plays no role in disease susceptibility. A large scale study to assess PON1 polymorphisms, PON1 activity, and markers of oxidative stress interaction is needed to clarify the role of PON-1 polymorphisms in the pathogenesis of SLE and associated APS.     

老年脑出血患者对氧磷酯酶1基因192位Gln-Arg多态性的研究

目的　探讨对氧磷酯酶 1(PON1)基因 192位Gln Arg(Q R192 )多态性与老年脑出血的关系。方法　本研究采用病例对照设计 ,对 170例脑出血患者 (脑出血组 )和 2 0 4例健康体检者 (对照组 )进行研究。采用聚合酶链反应 限制性片段长度多态性方法测定PON1Q R192基因多态性。结果　在脑出血组中 ,PON1Q R192 3种基因型频率分别为QQ12 .4 %、QR5 0 .6 %和RR37.1%。PON1Q R192基因型和等位基因频率分布在脑出血组与对照组间差异无显著性意义 ;各基因型之间血脂水平差异无显著性意义。结论　PON1Q R192基因多态性与老年脑出血不存在相关关系。     

2型糖尿病合并冠心病患者对氧磷酶1基因多态性分析

目的探讨对氧磷酶1(PON1)基因多态性与2型糖尿病合并冠心病的相关性。方法使用变性高效液相色谱分析方法检测了202例2型糖尿病合并冠心病患者、177例单纯2型糖尿病患者和206名健康对照者;共检测了PON1基因G-126C、L55M和Q192R 3个多态性的基因型,比较分析3组间各基因型和等位基因频率分布的差异。结果 2型糖尿病合并冠心病组的Q192R位点R等位基因频率明显高于对照组(67.1%比60.2%,P=0.024),其他位点在各组间差异无统计学意义。结论PON1基因Q192R位点R等位基因与2型糖尿病合并冠心病发病相关。     

Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese

Serum paraoxonase (PON) is a high-density lipoprotein-bound enzyme that can prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides and thus exert an anti-atherogenic effect. Recent studies have suggested that glutamine(Q isoform)/arginine(R isoform) polymorphism at position 192 of PON(1) gene is associated with macrovascular disease of type 2 diabetes mellitus (T2DM). We re-investigated this relationship using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. The genotype and allele frequency of PON(1) 192 Q/R polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism in 152 type 2 diabetic patients and 128 healthy subjects from a population of Chinese Han nationality in ChengDu area. The carotid IMT was measured by B-mode ultrasonography in type 2 diabetic patients. No differences were found in PON(1) gene Q/R polymorphism in the type 2 diabetic patients when compared with the control group. The mean carotid IMT in type 2 diabetic subjects with the QQ, QR and RR genotype was 0.65+/-0.27, 0.83+/-0.27 and 1.05+/-0.32 mm, respectively. One-way ANOVA showed that IMT was significantly greater in the RR subgroup than in both QR and QQ subgroups (P<0.01). Multivariate logistic regression analysis showed R allele to be the main determinant of IMT variability (OR 4.0 95% CI 2.10-7.40 P=0.005). Our data support the view that 192 R allele of PON(1) gene is a risk factor for macrovascular disease of T2DM in Chinese.     

Paraoxonase-1 L55M polymorphism is associated with an abnormal oral glucose tolerance test and differentiates high risk coronary disease families

Polymorphisms of the gene for the antioxidant enzyme, paraoxonase-1 (PON1), have been identified as risk factors for coronary disease (CHD), notably in diabetic patients. The polymorphisms have also been linked with other diabetic complications. The present study analyzed glucose metabolism as a function of PON1 polymorphisms in young healthy nondiabetic men from families with premature 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+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). Insulin resistance did not differ between L55M genotypes. There was a trend for reduced pancreatic beta-cell function as measured by glucose-induced insulin secretion (LL vs. LM vs. MM, 20.26 vs. 23.74 vs. 25.60; P = 0.077). The frequency of the L55 allele decreased significantly (P = 0.028) across regions defining a north-south European axis. No significant differences for the glucose response or case-control populations were observed as a function of the PON1 Q192R polymorphism. The study demonstrates an association between PON1 gene polymorphisms and glucose metabolism. 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.     

PON1 M/L55 mutation protects high-risk patients against coronary artery disease

The paraoxonase (PON) gene family contains at least three members: PON1, PON2, and PON3. The enzyme PON1 has been implicated in the pathogenesis of atherosclerosis. Recently, an association between PON2 and quantitative metabolic phenotypes, such as plasma lipoproteins, plasma glucose, and coronary artery disease (CAD), has been reported. We analyzed two common polymorphisms in PON1 (i.e., M/L55 and R/Q 192 mutations) and PON2 (i.e., G/A148 and C/S311 mutations) in 352 high-risk patients with angiographically defined CAD. These results were compared to those in 380 age- and sex-matched control subjects at high risk for CAD. 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. Univariate analysis showed a higher prevalence of the MM genotype (12% vs. 5%; p=0.004) for the PON1 M/L55 polymorphism and the GG genotype (21% vs. 15%; p=0.047) PON2 G/A148 polymorphism in the control subjects. 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. No mutation was associated with the number of major coronary artery vessels with a >50% reduction in lumen diameter. Multiple regression analysis disclosed smoking, a family history of CAD, high-density lipoprotein (HDL)-cholesterol and the PON1 M/L55 mutation [OR=0.59 (CI95%: 0.42-0.82); p=0.002] as independent markers for CAD. In contrast to traditional coronary risk factors, the PON1 M/L mutation can be considered predictive of protection against CAD.     

Q192R polymorphism of the paraoxanase 1 gene and its association with serum lipoprotein variables and carotid artery intima-media thickness in young adults from a biracial community. The Bogalusa Heart Study

Paraoxanase (PON 1), a high-density lipoprotein-associated enzyme, exerts an antiatherogenic effect by protecting low-density lipoproteins (LDL) against oxidation. A common polymorphism at codon 192(Q/R) of the PON 1 gene has been shown to be associated with an adverse lipoprotein profile and increased coronary artery disease (CAD) risk. However, these observations are based mostly on case-control studies involving relatively older adults. This study examined the frequency and phenotypic (lipoprotein variables) effect of the Q192R variant in a community-based sample of 1786 black and white young adults (mean age: 32.5 years; 69% white, 44% males). In addition, the genotypic effect of this polymorphism on ultrasonographically measured carotid artery intima-media thickness (IMT), a surrogate measure of CAD risk, was examined in a subsample of 436 young adults (mean age: 32.6 years; 70% white, 42% male). The frequency of the variant allele (R192) was higher in blacks than in whites (0.668 versus 0.297, P <0.001). After adjusting for age, sex, body mass index, and smoking status, the R versus Q allele was associated with increased HDL cholesterol in whites (P=0.041), whereas the opposite was true in blacks (P=0.008). Neither the Q nor the R allele was associated with LDL cholesterol and triglycerides in both races. The genotypic effect on the carotid IMT adjusted for the covariates including lipoprotein variables was not apparent in whites or blacks. However, among whites, the carotid IMT was lower in carriers (QR + R) versus non-carriers (QQ) of the variant allele among females (P=0.008) and non-smokers (P=0.026). In addition, the variant allele negated the adverse positive relationship between the carotid IMT and triglycerides among whites (P=0.212 for carriers versus P <0.001 for non-carriers). These results indicate a differential effect of the Q192R variant on HDL cholesterol in whites versus blacks and a beneficial interaction effect of the variant allele with individual's sex, smoking status or triglyceride levels on the carotid IMT among whites.