Systemic lupus erythematosus is a complex, autoimmune disease with a suspected multifactorial etiology. Work during the previous funding cycle has defined several genomic areas that are important and has identified a candidate molecular mechanism for the development and pathogenesis of SLE through the anti-Sm and anti-nRNP autoimmune responses. At least 12 different regions with LOD>3.3 have been identified, several of which are supported by separate pedigree collections and by scientifically independent investigators. Now the time has come to build on this early success. We hope to apply strategies to identify the genes underlying one of these areas of interest. In particular, we have used an immunochemical approach to implicate Epstein-Barr virus in the pathogenesis of lupus, most obviously through the autoantibody response against the nRNP and Sm autoantigens. Now, we wish to extend our interest in the host response against Sm and nRNP to understand its genetics in the hope that we will be working toward a more comprehensive explanation of anti-Sm and anti-nRNP autoimmunity in SLE. Due to the extremely varied presentation of SLE and the likelihood that many different genes contribute to this disease process, we have stratified pedigrees and selected a lupus sub-phenotype for further evaluation. Our laboratory has a long-standing interest in patients with anti-Sm and anti-nRNP (or anti-spliceosomal) autoantibodies (1 -20). These patients are of special interest because of their association with a more severe disease course (21, 22), of the higher prevalence of these specificities in patients of African-American descent (23), clinical homogeneity of the affected patients (22, 24, 25), and the development of these autoantibodies in close proximity to disease onset (26). Indeed, patients with anti-Sm now have perhaps the most sophisticated conceptual construct to explain the development and pathogenesis of any group with SLE. In Project #3 of the Program project, we will focus upon enlarging a case-control cohort (enriched for anti-spliceosomal autoantibody positive SLE patients) that can be used for Project #3, as well as making a contribution to the infrastructure of the Program and toward the genetic solution of SLE. We will utilize this resource, as well as others in the program, to confirm linkage in the 20q 12 region that is of sufficient magnitude to be considered established (lodmax=4.3). We will then narrow the area of interest, assess association with this interval and identify the gene(s) responsible for this effect in African-American pedigrees with anti-spliceosomal autoantibodies.
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