Molecular Genetics of HLA and Disease

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DESCRIPTION (provided by applicant): The goal of this application is to identify and characterize the complete repertoire of genes encoded in the MHC region that predispose and/or modulate the expression of autoimmune disease. Following the recent NINDS-sponsored workshop on MHC Genetics in Autoimmune Diseases and the subsequent announcement of an RFA to extend interdisciplinary science in this area, we created a Consortium, named The International MHC and Autoimmunity Genetics Network (IMAGEN) to tackle this problem in a meaningful and decisive manner. The IMAGEN investigators represent a large, diverse, and broad-based collaborative team of scientists at eight academic centers with synergistic skills; demonstrated expertise in MHC genetics and biology; clinical expertise in identifying endophenotypes; history of mutual productive collaborations; and experience in large scale genotyping and state-of-the-art analytical approaches. The basic structure of this collaborative project proposes a common base screen with a panel of more than1500 highly informative SNPs and replication for all diseases. Biologically relevant clinical endpoints will be incorporated into the analysis to assess the role of HLA variants in progression. Specific aim 3 for each project will address disease-specific questions. The primary screen will allow us to: 1) map the association signal(s) across the entire MHC to identify regions of the maximal signal; 2) identify extended MHC haplotypes carrying the strongest association signals; 3) identify recombinant chromosomes that maximally delimit the association; 4) make testable hypotheses as to whether different autoimmune diseases are influenced by a single association with a particular locus, or a single association with an extended haplotype or multiple, independent associations across the MHC. The focus is on Multiple Sclerosis, Rheumatoid Arthritis, IgA Deficiency, Common Variable Immunodeficiency, Myasthenia Gravis, Systemic Lupus Erythematosus and Ulcerative Colitis. We believe that the clinical dataset assembled for this project is unmatched anywhere in the world. An Administrative Core at UCSF will coordinate activities and interactions for the overall project. A second Core at the Broad Institute will be responsible for generation of genotypes, data QC, storage, and interaction with BISC.