Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with both genetic andenvironmental risk factors that remain incompletely defined. Alterations in the immune regulatorypathways are believed to play an important role in disease pathogenesis, and hundreds of studieshave examined the role of potential candidate genes in populations of varying ethnicity and size,often with conflicting results. Hundreds of other candidate genes in immune regulatory pathwaysappear ripe for study as well, especially since no results have been published regarding their role inSLE. The purpose of this feasibility project is to winnow down our long list of interesting candidatesto a few genes worthy of dedicated study in future large proposals.
In Specific Aim 1, we will test acohort of European-American samples consisting of 400 SLE cases and 400 matched controls at384 SNPs chosen within genes in our candidate lists through the SNP-Gen Core. We have 400African-American cases and nearly 300 matched controls on hand, and for Specific Aim 2 we willrecruit additional African-American patients and controls for testing on the same array.
For SpecificAim 3 we utilize on the results of these European-American and African-American cohorts to selectgenes with promising associations for further study and test them on a confirmation containing bothfamily-based and case-control samples from European-American, African-American, and Hispanicfamilies. For those associations confirmed in this phase, Specific Aim 4 will examine the genes tofind functional polymorphisms in cases where the associated SNP does not encode a structuralvariant or a known regulatory site. These results will enable identification of indisputable geneticrisk factors for SLE. The finding of a functional polymorphism associated with SLE would be theperfect springboard for more extensive structure/function studies and the starting point ofsubsequent applications for funding.
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