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This paper provides a broad overview of the epidemiological and genetical aspects of common multifactorial diseases in man with focus on three well-studied ones, namely, coronary heart disease (CHD), essential hypertension (EHYT) and diabetes mellitus (DM). In contrast to mendelian diseases, for which a mutant gene either in the heterozygous or homozygous condition is generally sufficient to cause disease, for most multifactorial diseases, the concepts of genetic susceptibility' and risk factors' are more appropriate. For these diseases, genetic susceptibility is heterogeneous. The well-studied diseases such as CHD permit one to conceptualize the complex relationships between genotype and phenotype for chronic multifactorial diseases in general, namely that allelic variations in genes, through their products interacting with environmental factors, contribute to the quantitative variability of biological risk factor traits and thus ultimately to disease outcome. Two types of such allelic variations can be distinguished, namely those in genes whose mutant alleles have (i) small to moderate effects on the risk factor trait, are common in the population (polymorphic alleles) and therefore contribute substantially to the variability of biological risk factor traits and (ii) profound effects, are rare in the population and therefore contribute far less to the variability of biological risk factor traits. For all the three diseases considered in this review, a positive family history is a strong risk factor. CHD is one of the major contributors to mortality in most industrialized countries. Evidence from epidemiological studies, clinical correlations, genetic hyperlipidaemias etc., indicate that lipids play a key role in the pathogenesis of CHD. The known lipid-related risk factors include: high levels of low density lipoprotein cholesterol, low levels of high density lipoprotein cholesterol, high apoB levels (the major protein fraction of the low density lipoprotein particles) and elevated levels of Lp(a) lipoprotein. Among the risk factors which are not related to lipids are: high levels of homocysteine, low activity of paraoxonase and possibly also elevated plasma fibrinogen levels. In addition to the above, hypertension, diabetes and obesity (which themselves have genetic determinants) are important risk factors for CHD. Among the environmental risk factors are: high dietary fat intake, smoking, stress, lack of exercise etc. About 60% of the variability of the plasma cholesterol is genetic in origin. While a few genes have been identified whose mutant alleles have large effects on this trait (e.g., LDLR, familial defective apoB-100), variability in cholesterol levels among individuals in most families is influenced by allelic variation in many genes (polymorphisms) as well as environmental exposures. A proportion of this variation can be accounted for by two alleles of the apoE locus that increase (ε4) and decrease (ε2) cholesterol levels, respectively. A polymorphism at the apoB gene (XbaI) also has similar effects, but is probably not mediated through lipids. High density lipoprotein cholesterol levels are genetically influenced and are related to apoA1 and hepatic lipase (LIPC) gene functions. Mutations in the apoA1 gene are rare and there are data which suggest a role of allelic variation at or linked LIPC gene in high density lipoprotein cholesterol levels. Polymorphism at the apoA1--C3 loci is often associated with hypertriglyceridemia. The apo(a) gene which codes for Lp(a) is highly polymorphic, each allele determining a specific number of multiple tandem repeats of a unique coding sequence known as Kringle 4. The size of the gene correlates with the size of the Lp(a) protein. The smaller the size of the Lp(a) protein, the higher are the Lp(a) levels. (ABSTRACT TRUNCATED)
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PMID:Ionizing radiation and genetic risks. VI. Chronic multifactorial diseases: a review of epidemiological and genetical aspects of coronary heart disease, essential hypertension and diabetes mellitus. 987 81

Paraoxonase is an HDL-associated enzyme implicated in the pathogenesis of atherosclerosis by protecting lipoproteins against peroxidation. Its biallelic gene polymorphism at codon 192 (glutamine/arginine) has been associated with coronary artery disease (CAD). To further evaluate the role of this paraoxonase gene polymorphism for CAD in type 2 diabetes, we determined the paraoxonase genotype in 288 type 2 diabetic patients (170 with and 118 without angiographically documented CAD). The paraoxonase 192 Gln/Arg genotype was assessed using polymerase chain reaction followed by AlwI digestion. The frequency of the Gln allele was 0.656 in the CAD patients and 0.746 in the controls (chi2 = 5.36, P = 0.02). Compared with the Gln/Gln genotypes, the age-adjusted odds ratio for CAD was 1.78 (95% CI 1.08-2.96, P = 0.02) in subjects carrying at least one Arg allele. In the multivariate analysis, this association was even stronger after correction for the possible confounders age, sex, smoking history, and hypertension. Among current and former smokers, the odds ratio (OR) for having CAD among patients with at least one Arg allele was 3.58 (1.45-9.53, P < 0.01). The paraoxonase Arg allele was not associated with the history of myocardial infarction (OR 1.20 [0.73-1.99, NS]), but was with the extent of CAD (OR for three-vessel disease 1.92 [1.15-3.27, P = 0.01]). Our data indicate that the 192 Arg allele of the human paraoxonase gene is a risk factor for CAD but not myocardial infarction in type 2 diabetic patients, a risk factor further modified by cigarette smoking. This risk could possibly be explained by a reduced ability of the paraoxonase Arg isoform to protect lipoproteins against peroxidation.
Diabetes 1999 Mar
PMID:Paraoxonase 192 Gln/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes. 1007 66

Oxidative damage is a major cause of atherosclerosis. Since human paraoxonase has been postulated as a factor which plays a role in protection from low density lipoprotein oxidation, recent studies have dealt with the impact of hereditary PON1 gene polymorphisms as risk factors for coronary artery disease (CAD). The results from these studies are conflicting. In a case-control study, 1000 Caucasian patients with angiographically confirmed CAD were recruited and matched by age and gender to 1000 control individuals. PON1 mutations in codons 55 and 192 were evaluated by polymerase chain reaction-restriction fragment length polymorphism and allocated to defined haplotypes *1 (55L/192Q), *2 (55L/192R), and *3 (55M/192Q). Frequency of PON1 genotypes without any mutation (PON1*1/*1, wild-type) in CAD cases was 16.9% versus 17.1% in control individuals. PON1*2/*2 showed a frequency of 6.6% versus 7.3% (P = 0.68 compared to wild-type), and PON1*3/3 occurred in 11.8% in CAD cases versus 10.3% among control individuals (P = 0.40). There was also no difference in the distribution of carriers heterozygous for *2 or *3 among cases and control individuals. A haplotype containing both mutations 55M and 192R was not observed. None of the investigated genotypes demonstrated association with early manifestation, severity of disease, acute coronary syndromes, or myocardial infarction. Logistic regression analysis with adjustment for age, gender, diabetes, hypertension, hypercholesterolemia and smoking revealed no evidence of increased coronary risk associated with PON1 genotypes. These results suggest that PON1 polymorphisms are not major genetic determinants of CAD.
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PMID:Mutations in the human paraoxonase 1 gene: frequencies, allelic linkages, and association with coronary artery disease. 1063 38

Recent studies indicate that the enzyme paraoxonase may be an important modulator of cardiovascular disease risk because of its ability to protect LDL from oxidation. We tested for association between two functional variants of the paraoxonase gene (Met-55/Leu and Gln-192/Arg) and both all-cause mortality and fatal cardiovascular disease. This was done within a population-based study among subjects aged 85 years and over in a cross-sectional and a prospective design. In the cross-sectional analysis, the distribution of both paraoxonase genotypes was found to be similar in the subset of 364 elderly subjects who were born in Leiden, The Netherlands, as compared with 250 young subjects whose families originated from the same geographical region. The polymorphisms were in strong linkage disequilibrium (P<0.00001) and the frequency of the haplotype carrying both risk alleles was not lower in the elderly than in the young (0.313 vs. 0.284). The complete cohort of 666 elderly subjects was followed over 10 years. The risk of all-cause and cardiovascular mortality was not increased in elderly subjects with the paraoxonase Leu/Leu (RR, 1.1 [95% CI, 0.9-1.5] and 1.3 [95% CI, 0.8-2.0], respectively) or the Arg/Arg genotype (RR, 0. 9 [95% CI, 0.7-1.2] and 0.7 [95% CI, 0.4-1.3], respectively). In a subset of patients with diabetes, the all-cause mortality risk was elevated in Arg/Arg carriers (RR, 2.1 [95% CI, 0.8-5.8]) but this did not reach statistical significance. Analysis of genotype combinations did not yield significant associations with mortality. The paraoxonase gene variants, previously associated with coronary artery disease, are thus not likely to have a major effect on the risk of fatal cardiovascular disease in the population at large. Adverse effects of the gene variants might be observed in subjects exposed to factors that enhance oxidative stress such as diabetes.
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PMID:Common paraoxonase gene variants, mortality risk and fatal cardiovascular events in elderly subjects. 1070 19

The serum enzyme paraoxonase (PON) protects LDLs from oxidative stress. We recently identified promoter polymorphisms of the PON gene that strongly affect gene expression and serum levels of the enzyme. The present study tested the hypothesis that promoter polymorphism T(-107)C could be a risk factor for vascular disease in type 2 diabetic patients by virtue of its ability to modulate serum concentrations of the antioxidant enzyme. The low-expressor genotype (TT) was associated with significantly lower serum PON concentrations, and it was over-represented in type 2 diabetic patients with coronary heart disease (CHD) (TT vs. TC+CC: odds ratio [OR] 1.64 [95% CI 1.03-2.61], P < 0.05). The association of the low-expressor genotype with an increased risk of disease was independent of other risk factors, including the coding region Q191R polymorphism (OR 2.12 [95% CI 1.19-3.70], P = 0.01). However, an interaction of the promoter polymorphism with the Q191R polymorphism, which was previously identified as an independent risk factor, was observed. The low-expressor promoter allele (-107T) associated with the high-risk 191R allele showed a lower-than-expected level of risk (OR 2.21 vs. the expected 4.76). The data are consistent with the hypothesis that low expression of the antioxidant enzyme PON increases the risk of CHD. Moreover, the promoter polymorphism appears to have a modulating effect on risk that is associated with the coding region polymorphism Q191R. This study indicates a strong genetic component to the antioxidant capacity of HDLs.
Diabetes 2000 Aug
PMID:Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients. 1092 42

Human paraoxonase (PON1) is a calcium-dependent esterase closely associated with high density lipoprotein (HDL)-containing apolipoprotein AI (apoAI), which has been shown to confer antioxidant properties to HDL. PON1 has been recently implicated in the pathogenesis of atherosclerosis. Low PON1 activities have been found in familial hypercholesterolemia (FH) and diabetes mellitus. We have undertaken a study of the effect of the lipid-lowering drug simvastatin on serum PON1 activity (in relation to paraoxon and arylesterase activity), on apoAI-containing and apolipoprotein B (apoB)-containing lipoproteins, and on lipid peroxide concentrations in 64 (39 women and 25 men) unrelated FH patients. We have also analyzed the influence of the PON1-192 and PON1-55 genetic polymorphisms on the response of PON1 activity to simvastatin therapy. A venous blood sample for a baseline analysis and another after 4 months of simvastatin therapy at a dosage of 20 mg per day were taken. The major effect of simvastatin on lipid traits was to decrease serum cholesterol, low density lipoprotein (LDL) cholesterol, and lipid peroxide concentrations by 19.9%, 26.3%, and 37.3%, respectively. There was also a significant decrease in serum apoB, LDL apoB, and triglyceride concentrations (20.5%, 21.1%, and 15.6%, respectively). Conversely, simvastatin had no significant influence on very low density lipoprotein-lipid content, HDL cholesterol, apoAI concentrations, and lipoprotein AI and AI:AII particles. Remarkably, serum PON1 activity toward paraoxon significantly increased during treatment with simvastatin (168. 7+/-100.3 U/L before therapy versus 189.5+/-116.5 U/L after therapy, P:=0.005). Arylesterase activity displayed only a nonsignificant trend to increase after therapy. Whereas PON1 activity levels were significantly lower in FH patients before simvastatin therapy compared with those of 124 normolipidemic subjects (168.7+/-100.3 versus 207.6+/-125.2 U/L, respectively; P:<0.05), this difference disappeared after simvastatin therapy. After simvastatin therapy, a significantly negative correlation between PON1 activity and lipid peroxide concentration was observed (r=-0.35, P:=0.028). The latter also strongly correlated with LDL cholesterol concentration (r=0.64, P:<0.001). Serum PON1 activity levels were significantly lower in the low-activity PON1-192 QQ and PON1-55 M carriers than in R carriers and in LL carriers, respectively. No significant differences were found in the therapeutic response of PON1 activity between genotype groups (8.5% and 11.1% increase for QQ homozygous and R-carrier FH patients, respectively, and 12.7% and 9.5% increase for LL homozygotes and M carriers, respectively). We conclude that simvastatin may have important antioxidant properties through increasing serum PON1 activity, perhaps as a consequence of reducing oxidative stress, by a mechanism independent of apoAI-containing lipoprotein concentration and without the influence of PON1-192 and PON1-55 genetic polymorphisms. Further studies are clearly warranted to clarify the precise mechanism by which simvastatin therapy is associated with increased PON1 activity.
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PMID:Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. 1097 57

Paraoxonase is a serum enzyme with an anti-oxidant function, protecting low density lipoproteins (LDL) from oxidative modifications. Diabetic patients are suggested to be at greater risk of oxidative stress, which may contribute to the significantly higher incidence of vascular disease in this population. Less efficient protection mechanisms may be one feature of the greater susceptibility to oxidation in diabetes. In this context, the present study examined the hypothesis that serum paraoxonase is reduced in type 1 (insulin-dependent) diabetic patients and that the reduction can affect the anti-oxidant capacity of HDL. Serum paraoxonase concentrations and activities were compared in type 1 patients and first degree, non-diabetic relatives with particular attention paid to the confounding effects of paraoxonase gene polymorphisms. In addition, the ability of HDL-paraoxonase to protect low density lipoproteins from oxidation was analysed in an in vitro system. Serum concentrations and enzyme activities of paraoxonase were significantly lower in type 1 patients compared to non-diabetic, first degree relatives. The differences were independent of promoter and coding region polymorphisms, which influence serum concentrations and activities of the enzyme. Overall, paraoxonase concentrations were a mean 13.3+/-4.5% lower (P<0.02) in type 1 patients. Specific activities did not differ between diabetic and non-diabetic groups. The concentration ratios of LDL cholesterol:paraoxonase (1.37+/-0.51 vs. 1.18+/-0.37, P=0.003) and apolipoprotein B:paraoxonase (0.84+/-0.33 vs. 0.71+/-0.40; P=0.012) were significantly higher in diabetic patients, consistent with a reduced capacity to protect LDL from oxidation. In vitro oxidation studies showed that a significantly higher level of lipid hydroperoxides was generated in LDL in the presence of HDL, containing paraoxonase levels equivalent to those of type 1 patients, compared to HDL containing paraoxonase levels equivalent to those of control subjects (mean difference 8.1%, P<0.05). The study demonstrates that serum concentrations of the antioxidant enzyme paraoxonase are significantly lower in type 1 (insulin-dependent) diabetic patients compared to non-diabetic, first-degree relatives, independently of known gene polymorphisms. Concentrations are reduced to an extent that can affect its anti-oxidant capacity. The results are consistent with the contention that modifications to serum paraoxonase in type 1 patients can increase risk of lipoprotein oxidation and, consequently, risk of vascular disease.
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PMID:Serum paraoxonase is reduced in type 1 diabetic patients compared to non-diabetic, first degree relatives; influence on the ability of HDL to protect LDL from oxidation. 1122 46

There is considerable evidence that the antioxidant activity of high density lipoprotein (HDL) is largely due to the paraoxonase-1 (PON1) located on it. Experiments with transgenic PON1 knockout mice indicate the potential for PON1 to protect against atherogenesis. This protective effect of HDL against low density lipoprotein (LDL) lipid peroxidation is maintained longer than is the protective effect of antioxidant vitamins and could thus be more important. There is evidence that the genetic polymorphisms of PON1 least able to protect LDL against lipid peroxidation are overrepresented in coronary heart disease, particularly in association with diabetes. However, these polymorphisms explain only part of the variation in serum PON1 activity; thus, a more critical test of the hypothesis is likely to be whether low serum PON1 activity is associated with coronary heart disease. Preliminary case-control evidence suggests that this is indeed the case and, thus, that the quest for dietary and pharmacological means of modifying serum PON1 activity may allow the oxidant model of atherosclerosis to be tested in clinical trials.
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PMID:Paraoxonase and atherosclerosis. 1130 60

Low density lipoprotein (LDL) oxidation is a crucial step in the atherosclerotic process. High density lipoprotein (HDL)-associated enzymes such as paraoxonase could exert a protective effect on LDL oxidation in the arterial wall, an effect which could be impaired in Type 2 diabetes mellitus (T2DM). We studied copper-induced oxidation in LDL and HDL isolated from 17 T2DM patients with fair glycaemic control and HDL-cholesterol within normal range and 17 healthy normolipidaemic control subjects. To evaluate the effect of HDL on LDL oxidation in diabetic and control subjects, we assessed copper-induced oxidation in HDL/LDL mixtures, with each lipoprotein isolated from the same subject. Relationships with HDL chemical composition, alpha-tocopherol content and serum paraoxonase activity were investigated. Oxidation was promoted by lipoprotein incubation with copper and then thiobarbituric acid reactive substances (TBARS), conjugated diene production and electrophoretic mobility in agarose gel were measured. In T2DM subjects HDL oxidation was higher than in controls. However, HDL from diabetics was as effective as control HDL to inhibit LDL oxidation. Neither HDL chemical composition nor serum paraoxonase activity showed any difference as compared to control subjects. In contrast, HDL from T2DM subjects showed a higher alpha-tocopherol content which positively correlated with HDL oxidability. Paraoxonase activity positively and strongly correlated with HDL inhibitory effect on LDL oxidation in patients and controls belonging to the heterozygous activity phenotype. Besides, LDL oxidability showed no differences between patients and controls. These results suggest that fairly-controlled T2DM patients with HDL-cholesterol levels within normal range show: 1) normal HDL ability to inhibit LDL oxidation related to normal paraoxonase activity; 2) higher HDL oxidability in spite of its high alpha-tocopherol content, which could favour tocopherol-mediated peroxidation and 3) normal LDL oxidability possibly due to the lack of significant lipoprotein structural alterations.
Diabetes Nutr Metab 2001 Feb
PMID:HDL oxidability and its protective effect against LDL oxidation in Type 2 diabetic patients. 1134 63

In vivo supplementation studies of the antioxidant alpha-tocopherol in human Type II diabetes have used surrogate, rather than direct, markers of oxidative damage/antioxidant protection and have used higher doses of alpha-tocopherol than used in coronary secondary prevention trials. We tested the hypothesis that oral alpha-tocopherol in a dosage regimen used in secondary prevention trials would reduce directly observed oxidatively induced single-strand breaks in lymphocyte DNA in Type II diabetes. We studied 40 people with Type II diabetes and 30 controls in a randomized, double-blind, placebo-controlled trial of 400 i.u. of oral alpha-tocopherol daily for 8 weeks. Lymphocyte DNA single-strand breaks and low-density lipoprotein (LDL) particle size and oxidizability were measured at baseline, after 8 weeks, and after 4 weeks washout. Polymorphisms in the gene for the antioxidant enzyme paraoxonase-1 gene (position 192) were measured. The diabetics had increased DNA oxidative susceptibility (P=0.008), without increased LDL oxidative susceptibility. There was a direct relationship between DNA oxidative susceptibility and baseline plasma alpha-tocopherol in the diabetes group alone (r=0.421, r(2)=0.177 and P=0.023), but DNA and LDL oxidative susceptibility were not influenced by alpha-tocopherol supplementation in either group in this regimen. Paraoxonase-1 gene polymorphisms did not contribute to LDL or DNA oxidative susceptibility or response to alpha-tocopherol. Increased DNA oxidative susceptibility, therefore, can occur in Type II diabetes without increased LDL oxidative susceptibility, but alpha-tocopherol supplementation in this regimen has no influence on DNA or LDL oxidative susceptibility in Type II diabetes or controls. Polymorphisms in the paraoxonase gene (position 192) are not associated with differences in oxidative susceptibility or responses to alpha-tocopherol.
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PMID:Increased DNA oxidative susceptibility without increased plasma LDL oxidizability in Type II diabetes: effects of alpha-tocopherol supplementation. 1152 40


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