IgA deficiency (IGAD) is the most common primary immunodeficiency in man, and likely shares genetic susceptibility alleles with the more severe disease common variable immune deficiency (CVID). Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. Each of these disorders has a major MHC genetic component, with recent evidence suggesting important effects in the MHC Class III region in IGAD and MG. In the proposed studies, association signals will be mapped across the MHC region in 500 Swedish MG and 500 Swedish IGAD cases using a dense panel of SNPs. In parallel, these SNPs will be typed in a large set of 1500 Swedish controls. Association signals will be identified and compared to those obtained in other diseases studied as part of the IMAGEN consortium. A number of Swedish multiplex families for IGAD and CVID are available, and these will be used to assess haplotype structure, and to examine segregation of haplotypes and SNP alleles with disease. Additional IGAD and CVID samples from Sweden and the U.S. are also available for typing. Based on the initial association data, we will seek to narrow the associated segments by typing additional SNPs and re-sequencing candidate genes, with a goal of identifying the causal allele(s) for IGAD, CVID and MG. Later in the project, we will study families from the Multiple Autoimmune Disease Genetics Consortium (MADGC) to determine the prevalence and segregation of associated MHC alleles and haplotypes identified in the various consortium projects. Currently, there are 343 MADGC families available, each containing 2 or more individuals with 2 or more major autoimmune diseases (average of about 3.2 affecteds per pedigree). RA, SLE, MS, and autoimmune thyroid disease are well represented in these families, and together there are mpre than 25 autoimmune disorders represented in these families. The studies proposed will be integrated with the other projects of the consortium at many levels, and should advance significantly our understanding of the MHC contribution to IGAD, CVID and MG.
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