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      Defining the Role of the MHC in Autoimmunity: A Review and Pooled Analysis

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          Abstract

          The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits – multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) – in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.

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          Most cited references 93

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          Gene map of the extended human MHC.

          The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.
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            The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.

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              A genome-wide search for human type 1 diabetes susceptibility genes.

              We have searched the human genome for genes that predispose to type 1 (insulin-dependent) diabetes mellitus using semi-automated fluorescence-based technology and linkage analysis. In addition to IDDM1 (in the major histocompatibility complex on chromosome 6p21) and IDDM2 (in the insulin gene region on chromosome 11p15), eighteen different chromosome regions showed some positive evidence of linkage to disease. Linkages to chromosomes 11q (IDDM4) and 6q (IDDM5) were confirmed by replication, and chromosome 18 may encode a fifth disease locus. There are probably no genes with large effects aside from IDDM1. Therefore polygenic inheritance is indicated, with a major locus at the major histocompatibility complex.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plge
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                April 2008
                April 2008
                25 April 2008
                : 4
                : 4
                Affiliations
                [1 ]Section of Molecular Genetics and Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom
                [2 ]Program in Medical and Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America
                [3 ]Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                [4 ]Harvard Medical School/Partners Healthcare Center for Genetics and Genomics, Boston, Massachusetts, United States of America
                [5 ]Université de Montréal, Montréal Heart Institute, Montréal, Québec, Canada
                [6 ]Harvard Medical School, Division of Rheumatology, Allergy and Immunology, Boston, Massachusetts, United States of America
                University College London, United Kingdom
                Author notes

                ¶ These authors are joint senior authors on this work.

                Article
                07-PLGE-RV-0874R3
                10.1371/journal.pgen.1000024
                2291482
                18437207
                Fernando et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 9
                Categories
                Review
                Genetics and Genomics
                Genetics and Genomics/Complex Traits

                Genetics

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