Systemic Lupus Erythematosus (SLE) is a chronic, multiorgan autoimmune disease, predominantly affecting women, and resulting in significant morbidity and mortality. SLE is a multi-factorial disease whereby multiple genetic factors have been recognized to determine susceptibility. The long term goal of the investigators' studies is to identify genes involved in the etiopathogenesis of human SLE and characterize the mechanisms by which these genes influence disease development. The investigators state that this application is a natural extension of their ongoing work in the mouse models to human SLE. The hypothesis underlying this application is that the genes determining SLE phenotypes are prevalent in families of patients and can be identified using state-of-the-art molecular mapping and linkage analysis techniques. They propose the following: 1) to recruit and collect blood and DNA from 250 multi-case families with SLE; to classify all subjects for clinical and laboratory evidence of SLE, its organ involvement, severity of disease and its complications; this will be accomplished using four recruitment study sites, which are large lupus clinics; 2) conduct a genome wide search for SLE susceptibility loci, employing a multistage strategy beginning with a 20 cM map and using multipoint linkage analysis of affected relatives; efficiency of this search will be optimized by using a liberal significance criterion in the first phase, then revisiting regions identified using stringent significance criteria on multiple closely-spaced markers approximately 2.5 cM apart; 3) conduct multipoint linkage analysis of SLE in regions of the human genome sharing homologies with regions linked to mouse SLE. The studies in these regions of the human genome will use markers spacing and linkage criteria established for the final stage of the genome search. For all marker typing they will use automated fluorescence-based technologies. The investigators point out that this application integrates the talent of a multidisciplinary team, combining clinical expertise with highly qualified basic scientists with genetic, epidemiological, molecular biological and genetic analytic expertise. They further note that their institutional base represent a major and unique resource for the study of the genetics and epidemiology of SLE in humans.
