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      The Genetics of SystemicLupus erythe matosus

      ,

      Cardiorenal Medicine

      S. Karger AG

      SLE, MHC, Genetic linkage, Mouse, Autoantibodies, Autoimmunity

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          Abstract

          Background: There is a genetic predisposition to human systemic lupus erythematosus (SLE). The genes that contribute to susceptibility are, for the most part, unknown. The introduction of new gene mapping techniques has opened the way to explore lupus genetics on a genome-wide basis. Methods: Microsatellites are simple sequence repeats widely distributed throughout eukaryotic genomes. They exhibit length variation. This polymorphism can be exploited to provide a panoply of genome-wide markers. Thereby, loci linked with lupus have been mapped in lupus-prone mouse strains and in recently published studies in multi-case human families. Results: More than 20 non-MHC (major histocompatibility complex) loci have now been linked with murine lupus. Nine non-MHC loci have been corroborated in human SLE. Some of the mouse intervals are syntenic with human loci raising the tantalizing possibility of common suspectibility genes. Although we await the results of formal gene identification, functional studies in back-cross and congenic analyses indicate that, in the mouse at least, disease genes act at multiple levels in disease development. Conclusions: A large number of genes are involved in the pathogenesis of SLE. The data also suggest that even the MHC contribution is multiple. Having mapped disease loci, geneticists now face the task of closing down on the actual aetiological alleles and demonstrating how they might operate. This undertaking will add significantly to our understanding of disease development.

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          Most cited references 6

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          Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis.

          The (NZB x NZW)F1 hybrid mouse develops a severe autoimmune disease similar to systemic lupus erythematosus in humans. Both the human and murine form of the disease show strong associations with alleles of the major histocompatibility complex (MHC) gene products. The severe form of the disease found in F1 mice is due, in part, to dominant NZW gene(s) mapping with the H-2 complex (the murine MHC). Here we present evidence that the tumour necrosis factor (TNF-alpha) gene, which is located within the H-2 complex (the murine major histocompatibility complex), could be involved in the pathogenesis of lupus nephritis in F1 mice. Thus, a restriction fragment length polymorphism in the TNF-alpha gene correlates with the reduced levels of TNF-alpha produced by NZW mice. Furthermore, replacement therapy with recombinant TNF-alpha induces a significant delay in the development of the nephritis.
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            Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

            Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.
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              A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families.

              Systemic lupus erythematosus (SLE) is an autoimmune multisystem inflammatory disease characterized by the production of pathogenic autoantibodies. Previous genetic studies have suggested associations with HLA Class II alleles, complement gene deficiencies, and Fc receptor polymorphisms; however, it is likely that other genes contribute to SLE susceptibility and pathogenesis. Here, we report the results of a genome-wide microsatellite marker screen in 105 SLE sib-pair families. By using multipoint nonparametric methods, the strongest evidence for linkage was found near the HLA locus (6p11-p21) [D6S257, logarithm of odds (lod) = 3.90, P = 0.000011] and at three additional regions: 16q13 (D16S415, lod = 3.64, P = 0.000022), 14q21-23 (D14S276, lod = 2.81, P = 0.00016), and 20p12 (D20S186, lod = 2.62, P = 0.00025). Another nine regions (1p36, 1p13, 1q42, 2p15, 2q21-33, 3cent-q11, 4q28, 11p15, and 15q26) were identified with lod scores >/=1.00. These data support the hypothesis that multiple genes, including one in the HLA region, influence susceptibility to human SLE.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2000
                October 2000
                31 July 2000
                : 8
                : 4-5
                : 194-202
                Affiliations
                Rheumatology Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Campus, London, UK
                Article
                20668 Exp Nephrol 2000;8:194–202
                10.1159/000020668
                10940716
                © 2000 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: 22, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20668
                Categories
                Minireview

                Cardiovascular Medicine, Nephrology

                SLE, Autoimmunity, Autoantibodies, Mouse, Genetic linkage, MHC

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