Systemic lupus erythematosus (SLE) is a multifactorial disease that is the result of an interaction between environmental factors and multiple genes involved in the generation of the immune and inflammatory responses. New molecular and genetic approaches have provided a means for mapping genetic loci contributing to SLE in humans as well as in animal models. The hypothesis for this study is that potential loci identified from association and linkage studies in humans and animals can be used to identify candidate genes and/or chromosomal regions contributing to SLE susceptibility, autoantibody production, and the development of coronary vasculitis/atherosclerosis, autoantibody production, and lipid alterations in the MRL/lpr mouse model for SLE can be identified using quantitative trait locus (QTL) mapping. These murine loci can then be tested for linkage in the human SLE multiplex families.
The specific aims for this proposed study are the following: 1. Initiate linkage studies in human SLE multiplex families using candidate genes and chromosomal regions linked to autoantibody production and GN in murine models of SLE. Testing for linkage to SLE susceptibility, development of GN, and autoantibody production in these families will performed using sib-pair linkage analysis with microsatellite markers. Initial candidate genes and regions to be tested include the MHC Class II region on chromosome 6p, selected regions of chromosome 1q, chromosome 10q23-24, and chromosome 19q13. 2. Complete QTL mapping of murine loci in the F2 intercross progeny from MRL/lpr x BALB/c contributing to coronary vasculitic/therosclerotic lesion development; anti-ssDNA and anti-dsDNA antibodies; and cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels. A complete genomic linkage map using microsatellite markers at 10-20 cM intervals will be generated and used for mapping. 3. Novel loci identified in the MRL/lpr cross contributing to the autoantibody production will be used to identify candidate genes or chromosomal regions to be tested for linkage in the SLE multiplex families.
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