The overall goal of this competitive renewal of our Program Project in the Genetics of SLE is to identify the genes responsible for susceptibility to and severity of SLE in ethnic minorities. Our scientific strategy involves three approaches: (1) to use genome-wide linkage data, developed during the first project period, to define regions with significant genetic effects, to use fine mapping of single nucleotide polymorphisms to narrow the interval, and then to focus on candidate genes and their haplotypes to identify risk alleles (haplotypes);(2) to use genotypic information, developed during the first project period, in both families and collections of individuals on established candidate gene families which suggest a role for copy number variation and to establish the range of variation and its contribution to SLE;and (3) to examine the genetic contribution to disease severity and outcome over time by continuing to build our longitudinal collaborative cohort (PROFILE) and assessing the impact of genotype on the phenotype of clinical outcomes. To implement our scientific strategy, we propose four projects and two cores. Project No. 1 (Kimberly, PI) will examine the role of structural variants (copy number variation) in the classical Fc receptor cluster in contributing to SLE risk and outcomes in different ethnic groups. Project No. 2 (Harley, PI) will define the strong association at 12q24 with SLE in Hispanics and test the hypothesis that this effect reflects variants of TCF1. Project No. 3 (Nath, PI) will use an admixture mapping approach to discover new genes contributing to lupus in African Americans and to test their contribution to the more severe outcome in this ethnic group. And Project No. 4 (Alarcon, PI) will examine the relationship between biologic ancestry, SES variables and outcomes in a test of gene environment relationships. Each of these Projects is coordinated through an Administrative Core and a vigorous Genetic Epidemiology and Biostatistics Core which serves each project. Working together, the investigators of this P01 anticipate making major advances in our understanding of the genetic variants underlying SLE in ethnic minorities.
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