Renal disease occurs in up to 75% of the systemic lupus erythematosus (SLE) patients usually appearing shortly after diagnosis. We recently linked a putative susceptibility gene to 10q22.3, which leads to lupus in nephritis related lupus families of European American background (1). Our goal for this proposal is to narrow the susceptibility region and to identify the susceptibility gene. We will achieve this by iterative reduction in the size of the chromosomal region. First, we will choose microsatellite markers to form a 1-2 cM map across the current susceptibility region and analyze these data using genetic linkage methods. Second, we will choose single nucleotide polymorphism (SNP) markers to form a 0.5 cM map across the reduced region and analyze these data using linkage disequilibrium methods. In the final step, we will search the public databases for SNPs in genes known to be located in the narrowed susceptibility region previously established and to analyze these using linkage disequilibrium methods. If this does not locate the functional mutation then the gene will be sequenced to find the causal mutation(s). Since autoimmune diseases are thought to share some of their genetic origins, we ascertained families multiplex for SLE in which at least one affected was diagnosed with nephritis, with the intent of decreasing sample heterogeneity and increasing the power to identify the susceptibility gene(s). Our preliminary results support the hypothesis that SLE and nephritis may share common genetic determinants in families of European American background (1). This project is directly relevant to the goals of NIAMS small grant program for new investigators and has the potential to reveal important, previously unappreciated, susceptibility genes, which contribute toward understanding the etiology of SLE and nephritis. ? ? ?