Systemic lupus erythematosus (SLE) appears to be one of the better-behaved complex disease phenotypes. Indeed, genetic linkages have been established with pedigree collections of a practical size (100 to 300 pedigrees); and more importantly, of the six established linkages with SLE, nearly all have been independently confirmed to be present in the genomic region of the originally identified effect. This unusual degree of consensus of results among the SLE genetic investigators augers well for continued success in the effort to find and exploit the genes that predispose to SLE. Project #2 continues the efforts underway under the previous SCOR for SLE by proposing to sustain the effort to enlarge the collection of simplex pedigrees containing an SLE proband. The materials and data collected would be used to further build the infrastructure needed to explain the genetics of SLE. These materials would make it possible to assess associations in sporadic cases in Projects #1 and #3, as well as #2. In Project #2, we would use the simplex pedigree collection to test the associations found with the familial cases of SLE in the 4p 16-15 support interval for linkage. Indeed,the linkage at 4p 16-15 was established (lod=3.8) and confirmed (lod=1.5) using the collections available and the cooperating project investigators of the previous SCOR for SLE. Fine mapping has further confirmed the linkage effect at another marker, has improved the evidence for linkage (lod=4.3), and has reduced the region potentially containing the gene with >95% confidence to a 9.25 cM region of 4pl6-15.33 composed of about 6 mb of DNA. In Project #2, we propose to search for association in this interval using the pedigrees linked here, in order to improve power to detect association. Then, we hope to use linkage disequilibrium to localize and identify the gene and its polymorphisms responsible for the genetic risk for SLE. We will use additional pedigrees multiplex for SLE to confirm associations. We will use the simplex pedigrees and case-control pairs available in Oklahoma and Alabama (including those described elsewhere in this Program Project) to assess potential role of these genes in the sporadic cases of SLE. Finding the gene responsible for the 4p 16-15 linkage will provide a fundamental advance in our efforts to understand and defeat this disease.
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