Similar to many multifactorial complex human diseases, SLE becomes clinically manifest when an individual either inherits a critical number of susceptibility genes or has an adequate number which interact with environmental factors. These susceptibility genes, however, remain elusive. SLE susceptibility loci on mouse chromosomes 1,4,7, and 17 were repeatedly identified by linkage analysis in multiple inbred strains prone lupus-like disease. Their syntenic locations on human chromosome are 1q21-q42, 1p22-p36, 11p15 or 19q12-q13, and 6p21, three of which are implicated in human SLE. Therefore, these murine susceptibility regions and their syntenic human chromosomal regions are likely to contain important disease-causing genes. We hypothesize that 1) important SLE susceptibility genes are conserved between mouse and man, and 2) if one or more loci are conserved across species, they are likely to be conserved across several ethnic groups. We now have very promising preliminary data showing evidence of linkage of the candidate chromosome 1 region. We propose to determine whether these human chromosomal regions contain SLE susceptibility genes by both linkage and association studies in SLE multiplex families. To reduce genetic heterogeneity, most SLE patients can be classified into clinical subsets characterized y autoantibo es of restricted specificities and damage to a limited number of organs. To accomplish our goal, we will 1) accumulate 300 multiplex families containing two or more first or second degree relatives with SLE (emphasis on collecting affected sib pairs) and classify all individuals into a more homogeneous population for clinical or laboratory evidence of SLE, GN or no GN, and presence and titers of autoantibodies (to dsDNA, Ro, La, Sm, RNP, cardiolipin, chromatin, or ANA). 2) genotype each family member for genetic markers located on these human chromosomal regions, 3) identify chromosomal regions containing SLE susceptibility genes by linage analysis, and 4) localize the primary susceptibility gene(s) within each linked region by association. Our ultimate goal is to identify individual genes that increase the risk for SLE, then determine how these genes influence immune responses.
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