We propose to identify genes that confer risk for Sjogren's syndrome. For the past ten years, we have been using the advances of the genomic revolution to pursue the genes that predispose to systemic lupus erythematosus. At this juncture, we have established more than 20 genetic effects for lupus and have independently confirmed six of these (see Preliminary Data). Now, a decade after starting the lupus genetics studies, we are ready to begin work with Sj?gren's syndrome, a closely-related disorder. Our progress with Sjogren's syndrome will be accelerated because of the infrastructure available and our experience with lupus. We plan to build the scientific organization that will allow us to evaluate 100 candidate genes for genetic association in 300 Sjogren's syndrome patients, their families, and matched controls. In hopes of concentrating our effort on a more genetically homogeneous phenotype, we will use the new European-American consensus criteria for primary Sjogren's syndrome, with the added requirement that all affecteds evaluated have anti-Ro autoantibody precipitins. We propose to use a genetic association approach in an experimental design that will lead to gene identification by the following experimental steps: assembling the materials from probands, family members and controls; constructing the clinical and demographic database; and genotyping polymorphisms in and nearby candidate genes. Our longer term goal is to perform a reasonably powered genome scan for genetic association, but the technologies and methodologies are not yet proven practical. Consequently, we envision a commitment to this scientific problem over the next decade to accomplish this goal, as may be required. On the other hand, by assembling the needed materials and pursuing candidate genes, we will be specifically poised to exploit a genome scan for genetic association in Sj?gren's syndrome as soon as it is practical to perform. Meanwhile, we will evaluate as many candidate genes as is practically possible with the resources made available to us and with the technologies and methods in hand to elucidate the genetic component of the etiology of Sj?gren's syndrome would provide important new insights into pathogenesis, thereby providing new diagnostic capabilities and previously unexplored therapeutic targets.
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