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      Matrix GLA Protein Gene Polymorphisms: Clinical Correlates and Cardiovascular Mortality in Chronic Kidney Disease Patients

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          Abstract

          Background: Increased vascular calcification plays an important role in the pathogenesis of cardiovascular events in chronic kidney disease (CKD) patients. It is the result of an active ossification process counteracted by ‘protective’ proteins, such as matrix GLA protein (MGP). Polymorphisms of MGP have been identified. Methods: The aim of this study was to define the distribution of two MGP polymorphisms (–7, –138) in 99 hemodialysis (HD) patients, in 26 patients with CKD stage 3 and in 135 age- and sex-matched healthy controls. Patients were followed up for 12 months to record any cardiovascular deaths. The cause of death was determined by medical doctors, considering the medical history of each patient. The primers were designed with Primer Express software. Results: MGP –138TT homozygotes were more frequent in the HD group versus controls (p = 0.0004). Additionally, the frequency of the T allele was significantly higher in the HD group (p = 0.0006). The frequency of the A allele of MGP-7 was significantly higher both in the HD group (p = 0.033) and in the CKD group (p = 0.0017) versus controls. MGP-7 GG homozygotes were significantly less common in the CKD group than in controls (p = 0.037). Combination –138TT –7AA was significantly more frequent in both CKD patients (p = 0.001) and in HD patients (p = 0.029) than in controls. Seventeen out of 99 HD patients experienced fatal cardiovascular events. Sixteen (94.1%) were –138TT homozygotes and either –7AA homozygotes or –7GA heterozygotes. Conclusion: This study suggests that CKD and HD patients have a different distribution of MGP gene polymorphism as compared with the normal population. Altered MGP gene polymorphism may be a negative prognostic factor for the progression to end-stage renal disease and for cardiovascular events in CKD patients.

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          Most cited references 7

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          Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome.

          Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and midfacial hypoplasia. A genome search using homozygosity mapping provided evidence of linkage to chromosome 12p12.3-13.1 (maximum multipoint lod score, 4.06). MGP was a candidate on the basis of its localization to this chromosomal region and the known function of its protein. MGP maps to chromosome 12p near D12S363. Human MGP is a 10-kD skeletal extracellular matrix (ECM) protein that consists of an 84-aa mature protein and a 19-aa transmembrane signal peptide. It is a member of the Gla protein family, which includes osteocalcin, another skeletal ECM protein, and a number of coagulation factors (factors II, VII, IX, X and proteins S and C). All members of this family have glutamic acid residues modified to gamma-carboxyglutamic acids (Gla) by a specific gamma-carboxylase using vitamin K as a cofactor. The modified glutamic acid residues of Gla proteins confer a high affinity for mineral ions such as calcium, phosphate and hydroxyapatite crystals, the mineral components of the skeletal ECM. The pattern and tissue distribution of Mgp expression in mice suggest a role for Mgp in regulating ECM calcification. Mglap-deficient mice (Mglap-/-) have been reported to have inappropriate calcification of cartilage. Mutational analysis of MGP in three unrelated probands identified three different mutations: c.69delG, IVS1-2A-->G and c.113T-->A. All three mutations predict a non-functional MGP. Our data indicate that mutations in MGP are responsible for KS and confirm its role in the regulation of extracellular matrix calcification.
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            Osteogenic regulation of vascular calcification: an early perspective.

            Cardiovascular calcification is a common consequence of aging, diabetes, hypercholesterolemia, mechanically abnormal valve function, and chronic renal insufficiency. Although vascular calcification may appear to be a uniform response to vascular insult, it is a heterogenous disorder, with overlapping yet distinct mechanisms of initiation and progression. A minimum of four histoanatomic variants-atherosclerotic (fibrotic) calcification, cardiac valve calcification, medial artery calcification, and vascular calciphylaxis-arise in response to metabolic, mechanical, infectious, and inflammatory injuries. Common to the first three variants is a variable degree of vascular infiltration by T cells and macrophages. Once thought benign, the deleterious clinical consequences of calcific vasculopathy are now becoming clear; stroke, amputation, ischemic heart disease, and increased mortality are portended by the anatomy and extent of calcific vasculopathy. Along with dystrophic calcium deposition in dying cells and lipoprotein deposits, active endochondral and intramembranous (nonendochondral) ossification processes contribute to vascular calcium load. Thus vascular calcification is subject to regulation by osteotropic hormones and skeletal morphogens in addition to key inhibitors of passive tissue mineralization. In response to oxidized lipids, inflammation, and mechanical injury, the microvascular smooth muscle cell becomes activated. Orthotopically, proliferating stromal myofibroblasts provide osteoprogenitors for skeletal growth and fracture repair; however, in valves and arteries, vascular myofibroblasts contribute to cardiovascular ossification. Current data suggest that paracrine signals are provided by bone morphogenetic protein-2, Wnts, parathyroid hormone-related polypeptide, osteopontin, osteoprotegerin, and matrix Gla protein, all entrained to endocrine, metabolic, inflammatory, and mechanical cues. In end-stage renal disease, a "perfect storm" of vascular calcification often occurs, with hyperglycemia, hyperphosphatemia, hypercholesterolemia, hypertension, parathyroid hormone resistance, and iatrogenic calcitriol excess contributing to severe calcific vasculopathy. This brief review recounts emerging themes in the pathobiology of vascular calcification and highlights some fundamental deficiencies in our understanding of vascular endocrinology and metabolism that are immediately relevant to human health and health care.
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              Pathogenesis of vascular calcification in chronic kidney disease.

              Pathogenesis of vascular calcification in chronic kidney disease. Background. Hyperphosphatemia and hypercalcemia are independent risk factors for higher incidence of cardiovascular events in patients with chronic kidney disease. In addition to increased calcium-phosphate product, hyperphosphatemia accelerates the progression of secondary hyperparathyroidism with the concomitant bone loss, possibly linked to vascular calcium-phosphate precipitation. Results. The control of serum phosphate levels reduces vascular calcification not only by decreasing the degree of secondary hyperparathyroidism and calcium-phosphate product, but also by reducing the expression of proteins responsible for active bone mineral deposition in cells of the vasculature. The calcium and aluminum-free phosphate-binders provide a new and effective therapeutic tool in preventing vascular calcifications in chronic kidney disease in animal models and in hemodialysis patients. Conclusion. Additional investigations are necessary to examine the benefits of different phosphate-binders in reducing mortality from cardiovascular disease.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2005
                December 2005
                05 October 2005
                : 25
                : 6
                : 548-552
                Affiliations
                aRenal Division and bClinical Chemistry and Microbiology, S. Paolo Hospital, University of Milan, Milan, and cChair of Nephrology, School of Medicine, University Federico II, Naples, Italy
                Article
                88809 Am J Nephrol 2005;25:548–552
                10.1159/000088809
                16210837
                © 2005 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: 2, Tables: 2, References: 15, Pages: 5
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/88809
                Categories
                Original Report: Laboratory Investigation

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