Systemic lupus erythematosus (SLE) is a complex, autoimmune disorder in which susceptibility isdetermined by a combination of genetic, environmental and stochastic factors. SLE disproportionatelyaffects African-Americans (AA) compared to the people of European descent. For disorders with a poorlyunderstood biochemical basis, like SLE, identification of genes contributing to disease susceptibility is aprerequisite 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 ormore ethnic groups should have an increased probability of inheriting the DMA derived from the ethnicgroup with more risk. Admixture between genetically different populations may produce long-range linkagedisequilibrium (LD) or gametic association between loci as a function of genetic difference between parentalpopulations and the admixture rate. These admixed populations facilitate mapping complex disease genesof 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, theyrequire at least 100 times more markers (300,000 to 500,000) than markers required in admixture mappingapproach (1500 to 3000). The present day AA population is a unique resource for mapping SLEsusceptibility genes with similar effect size.The overall goal of this proposal is to identify SLE susceptibility genes in AA using the admixturemapping approach. To meet this goal, two Specific Aims will be accomplished (1) Perform an admixturegenome scan for finding the candidate SLE susceptibility regions, and (2) Follow up the most convincingsusceptibility region with high-density SNPs using the haplotype-based approach for fine genomic mappingand identify the causal susceptibility gene(s). We will perform admixture mapping on a sample of at least2000 SLE cases and 2000 AA controls, using a recently validated panel of ~2000 highly informativeancestry informative markers (AIM). Using an ideal admixed population in which LD has been sustained atlonger chromosome segments, genotyping sufficient AIMs, controlling for spurious association, andemploying an admixture mapping followed by targeted high-density haplotype-mapping strategies, thisproposal maximizes the opportunity to identify the novel genomic regions that contain SLE susceptibilitygenes. Therefore, identification of these genes will help us understanding the development andpathogenesis of this disease in a minority population, and may lead to novel therapeutic interventions.
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