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      Plasma C-Reactive Protein and 5-Lipoxygenase-Activating Protein Gene Promoter Poly-A Polymorphism in Patients with Coronary Artery Disease

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          Abstract

          Objectives: The purpose of this study was to explore the possible associations of the 5-lipoxygenase-activating protein (FLAP) poly-A genotype, plasma high-sensitivity C-reactive protein (hsCRP) and the extent score of coronary artery disease (CAD). Methods: The 17A/21A genotypes and plasma hsCRP levels were determined in 555 Chinese patients, 424 with and 131 without CAD. The luciferase reporter assay was performed to explore the functional significance of promoter poly-A polymorphism. Results: CAD patients showed significantly higher plasma hsCRP (p = 0.007) than non-CAD subjects, but no differences in the 17A allele carriers and frequency. The extent score of CAD was significantly correlated with plasma hsCRP (p = 0.03). Furthermore, the 17A allele carriers showed significantly higher hsCRP than the 21A homozygotes (p = 0.02). Multiple linear regression analysis documented an impact of the poly-A genotype on plasma hsCRP (p = 0.03). In vitro, the 17A construct was found to have greater promoter activity than the 21A construct (p = 0.02). Conclusions: The present study demonstrated a significant correlation of FLAP gene promoter 17A allele carriers with higher plasma hsCRP levels in patients with CAD. This association might be related to the increased transcriptional activity of the FLAP gene and the resulting pro-inflammatory effect on the 5-lipoxygenase pathway.

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          Most cited references 21

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          The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.

          We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
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            Production of C-reactive protein and risk of coronary events in stable and unstable angina

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              Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis.

              Leukotrienes are inflammatory mediators generated from arachidonic acid (polyunsaturated n-6 fatty acid) by the enzyme 5-lipoxygenase. Since atherosclerosis involves arterial inflammation, we hypothesized that a polymorphism in the 5-lipoxygenase gene promoter could relate to atherosclerosis in humans and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates. We determined 5-lipoxygenase genotypes, carotid-artery intima-media thickness, and markers of inflammation in a randomly sampled cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis Study. Dietary arachidonic acid and marine n-3 fatty acids (including a competing 5-lipoxygenase substrate that reduces the production of inflammatory leukotrienes) were measured with the use of six 24-hour recalls of food intake. Variant 5-lipoxygenase genotypes (lacking the common allele) were found in 6.0 percent of the cohort. Mean (+/-SE) intima-media thickness adjusted for age, sex, height, and racial or ethnic group was increased by 80+/-19 microm (95 percent confidence interval, 43 to 116; P<0.001) among carriers of two variant alleles, as compared with carriers of the common (wild-type) allele. In multivariate analysis, the increase in intima-media thickness among carriers of two variant alleles (62 microm, P<0.001) was similar in this cohort to that associated with diabetes (64 microm, P=0.01), the strongest common cardiovascular risk factor. Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of genotype, whereas increased dietary intake of n-3 fatty acids blunted the effect. Finally, the plasma level of C-reactive protein, a marker of inflammation, was increased by a factor of 2 among carriers of two variant alleles as compared with that among carriers of the common allele. Variant 5-lipoxygenase genotypes identify a subpopulation with increased atherosclerosis. The observed diet-gene interactions further suggest that dietary n-6 polyunsaturated fatty acids promote, whereas marine n-3 fatty acids inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2008
                December 2007
                10 July 2007
                : 109
                : 1
                : 25-32
                Affiliations
                Division of Cardiology, Department of Internal Medicine, Buddhist Tzu-Chi General Hospital, Tzu-Chi University, Hualien, Taiwan, ROC
                Article
                105323 Cardiology 2008;109:25–32
                10.1159/000105323
                17627106
                © 2007 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
                Figures: 1, Tables: 3, References: 34, Pages: 8
                Categories
                Original Research

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