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      Human Paraoxonase1 Gene Polymorphisms and the Risk of Coronary Heart Disease: A Community-Based Study

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          Abstract

          Published data on the association between paraoxonase1 (PON1) polymorphisms and coronary heart disease (CHD) have yielded controversial results. The objective of this study was to determine the possible relationship between the two human PON1 amino acid variants, the Leu55Met and the Gln192Arg polymorphism, and the risk of CHD in a community-dwelling cohort of European ancestry. PON1 genotypes of 152 women and 151 men out of 1,998 randomly selected individuals aged 44–75 years were determined by polymerase chain reaction-based restriction enzyme digestion. Study participants underwent cardiological examination including a structured clinical interview, resting ECG, exercise testing and echocardiography. The diagnosis of CHD was based on history and/or appropriate findings during cardiac examination. Evidence for CHD was found in 43 (14.2%) study participants. The Leu/Leu (LL), Leu/Met (LM) and Met/Met (MM) genotypes at position 55 were noted in 131 (43.2%), 128 (42.2%) and 44 (14.5%) subjects; the Gln/Gln (QQ), Gln/Arg (QR) and Arg/Arg (RR) genotypes at codon 192 occurred in 167 (55.1%), 118 (38.9%) and 18 (5.9%) individuals, respectively. Homozygosity for the 55L-allele was significantly associated with CHD (p = 0.02), while the Gln192Arg polymorphism had no effect (p = 0.16). Logistic regression analysis demonstrated age (odds ratio 1.06/year), smoking (odds ratio 2.86), HDL cholesterol (odds ratio 0.94/mg/dl) and the paraoxonase LL genotype (odds ratio 2.25) to be significant predictors of CHD. These data suggest that the paraoxonase LL genotype at position 55 may present a risk factor for CHD.

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          Most cited references 16

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          The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family.

          A physiological role for paraoxonase (PON1) is still uncertain, but it catalyzes the hydrolysis of toxic organophosphates. Evidence that the human genome contains two PON1-like genes, designated PON2 and PON3, is presented here. Human PON1 and PON2 each have nine exons, and the exon/intron junctions occur at equivalent positions. PON1 and PON2 genes are both on chromosome 7 in human and on chromosome 6 in the mouse. Turkey and chicken, like most birds, lack paraoxonase activity and are very susceptible to organophosphates. However, they have a PON-like gene with approximately 70% identity with human PON1, PON2, and PON3. Another unexpected finding is that the deduced amino acid sequences of PON2 in human, mouse, dog, turkey, and chicken and of human PON3 are all missing the amino acid residue 105, which is lysine in human PON1. The expanded number of PON genes will have important implications for future experiments designed to discover the individual functions, catalytic properties, and physiological roles of the paraoxonases.
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            Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification.

            Human serum paraoxonase (PON1) associated with high density lipoprotein (HDL) has been postulated to have a role in protecting low density lipoprotein (LDL) against oxidative modification, which has led to the proposal that PON1 is an anti-atherogenic, anti-inflammatory enzyme. PON1 has two genetically determined polymorphic sites giving rise to amino-acid substitutions at positions 55 (L-->M) and 192 (R-->Q) and therefore 4 potential alloenzymes. We have examined the effects of these molecular polymorphisms 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 at protecting LDL while HDL from RR/LL homozygotes was least effective. Thus after 6 h of co-incubation of HDL and LDL with Cu2+ 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% (P < 0.01) and PON1-RR HDL retained only 0.75 +/- 0.40% (P < 0.005). In similar experiments HDL from LL and LM genotypes retained 21.8 +/- 7.5% and 29.5 +/- 6.6% (P = NS), respectively, of their protective ability, whereas PON1-MM HDL maintained 49.5 +/- 5.3% (P < 0.01). PON1 polymorphisms may affect the ability of HDL to impede the development of atherosclerosis and to prevent inflammation.
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              Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes.

              Paraoxonase is a high-density-lipoprotein-associated enzyme capable of hydrolysing lipid peroxides. Thus it might protect lipoproteins from oxidation. It has two isoforms, which arise from a glutamine (A isoform) to arginine (B isoform) interchange at position 192. The relevance of this polymorphism to coronary heart disease (CHD) in non-insulin-dependent diabetic patients was investigated in case-control study. Of the 434 patients, 171 had confirmed coronary artery disease; the other 263 had no history of such disease. The B allele and AB+BB genotypes were associated with an increased risk of coronary heart disease. Compared with subjects homozygous for the A allele (AA genotype), the odds ratio of CHD for subjects homozygous for the B allele was 2.5 (95% CI 1.2-5.3) and that for those heterozygous for the B allele was 1.6 (95% CI 1.1-2.4), suggesting a codominant effect on cardiovascular risk. When subjected to multivariate analysis, the B allele remained significantly associated with CHD (odds ratio 1.94, p = 0.03). The paraoxonase gene polymorphism is thus an independent cardiovascular risk factor in non-insulin-dependent diabetic patients. A possible explanation for this finding is that activity of the paraoxonase B isotype does not protect well against lipid oxidation, a major atherogenic pathway.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2002
                November 2002
                07 November 2002
                : 98
                : 3
                : 116-122
                Affiliations
                aDepartment of Medicine, Division of Cardiology, bInstitute of Medical Biochemistry and cDepartment of Neurology, Karl Franzens University, Graz, Austria
                Article
                66321 Cardiology 2002;98:116–122
                10.1159/000066321
                12417809
                © 2002 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Tables: 5, References: 47, Pages: 7
                Categories
                General Cardiology

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