LUPUS SUSCEPTIBILITY LOCI IN NEW-ZEALAND MICE

Susceptibility to systemic lupus erythematosus has been uuequivocally established to be an inherited trait, but the exact genes and how they confer susceptibility remain largely unknown. In this study of(NZB x NZW)F-2 intercross mice, we used linkage analysis of markers covering >90% of the autosomal genome and identified eight susceptibility loci (Lbw1 to -8, chromosomes 17, 4-7, 18, 1, 11, respectively) associated with antichromatin autoantibody production, glomerulonephritis, and/or mortality. Only one locus, the major histocompatibility complex, was linked to all three traits. Two other loci were associated with both g lomerulonephritis and mortality, whereas the remaining loci were linke d to one of the above traits. Two additional loci (Sbw1 and -2) that c ontributed to splenomegaly were also identified. The Sbw2 locus mapped to the identical region as Lbw2, a locus on chromosome 4 linked to gl omerulonephritis and mortality, suggesting a single locus with pleiotr opic effects. The results indicate that the immunopathologic features of lupus are affected by distinct, but additive, genetic contributions . Studies to determine the nature of the genes associated with these l oci should help define the genetic mechanisms involved in this systemi c autoimmune disease.