Systemic lupus erythematosus (SLE) is a complex, autoimmune disorder in which susceptibility is determined by a combination of genetic, environmental and stochastic factors. SLE disproportionately affects African-Americans (AA) compared to the people of European descent. For disorders with a poorly understood biochemical basis, like SLE, identification of genes contributing to disease susceptibility is a prerequisite to understanding its biological basis. Admixture mapping is a promising 'new'tool for discovering genes that contribute to complex traits. The idea is simple?near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the DMA derived from the ethnic group with more risk. Admixture between genetically different populations may produce long-range linkage disequilibrium (LD) or gametic association between loci as a function of genetic difference between parental populations and the admixture rate. These admixed populations facilitate mapping complex disease genes of small effect size (risk ~ 1.5 fold), which is beyond the current power of family-based linkage approach. Though haplotype-based or direct association methods are able to detect these genes, however, they require at least 100 times more markers (300,000 to 500,000) than markers required in admixture mapping approach (1500 to 3000). The present day AA population is a unique resource for mapping SLE susceptibility genes with similar effect size. The overall goal of this proposal is to identify SLE susceptibility genes in AA using the admixture mapping approach. To meet this goal, two Specific Aims will be accomplished?(1) Perform an admixture genome scan for finding the candidate SLE susceptibility regions, and (2) Follow up the most convincing susceptibility region with high-density SNPs using the haplotype-based approach for fine genomic mapping and identify the causal susceptibility gene(s). We will perform admixture mapping on a sample of at least 2000 SLE cases and 2000 AA controls, using a recently validated panel of ~2000 highly informative ancestry informative markers (AIM). Using an ideal admixed population in which LD has been sustained at longer chromosome segments, genotyping sufficient AIMs, controlling for spurious association, and employing an admixture mapping followed by targeted high-density haplotype-mapping strategies, this proposal maximizes the opportunity to identify the novel genomic regions that contain SLE susceptibility genes. Therefore, identification of these genes will help us understanding the development and pathogenesis of this disease in a minority population, and may lead to novel therapeutic interventions.
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