This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.For disorders with a poorly known biochemical basis, like Systemic Lupus Erythematosus (SLE), identification of the genes is a prerequisite or key to understanding biological basis. Therefore, identification of the genes contributing to susceptibility in SLE will help us to understand the development and pathogenesis of the disease, and may lead to novel therapeutic interventions. The overall goal of this proposal is to identify the SLE susceptibility genes in African-Americans (AA) using the admixture mapping approach. Admixture between genetically different populations may produce linkage disequilibrium (LD) or gametic association between gene loci as a function of genetic difference between parental populations and the admixture rate. The method tests for association of the allele ancestry with the disease and for the situation in AA is applicable at loci that have different allele frequencies in the ancestral Africans and Europeans. Although the idea for admixture mapping has been around for more than half a century, the genomic tools are only now becoming available to make this a feasible and attractive option for complex-trait mapping. Analytical as well as empirical simulation-based approaches show that the admixed population facilitates mapping complex disease genes of moderate effect size (1.5 to 2 fold risk), which is beyond the power of current family-based linkage approach. Additionally, for loci at which the underlying risk-allele frequencies are substantially different in the ancestral populations, the power of admixture mapping can be comparable to that of whole genome association-based mapping but with a far smaller number of markers (~2000 markers compared to ~500,000 markers). Today's African-American population is a unique and ideal resource for mapping the SLE susceptibility genes with similar effect size. We hope to detect many of the novel SLE susceptibility loci using the admixture mapping approach. In aggregate, we plan to begin with 400 SLE cases with AA background and to enlarge the study to 1000 AA cases. Therefore, to meet this goal, the Specific Aim 1 is to perform a whole genome admixture scan to find the candidate regions that confer the SLE susceptibility.
Specific Aim 2 is to follow up the most convincing susceptibility region with high-density SNPs using the haplotype-based approach for fine genomic mapping. Consequently, we hope to make this a cooperative SLE mapping project involving multiple sites.
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