It is well established that genetic predisposition plays a major role in the susceptibility of individuals to systemic lupus erythematosus (SLE). Therefore, definition of the causal mechanisms responsible for this disease will require knowledge of both the genetic alterations and the nature of their contribution to autoimmunity. We have previously identified in (NZBxNZW)F2 mice eight loci designated Lbw1-8 on chromosomes 17, 4, 5, 6, 7, 18, 1 and 11, respectively, that were linked to one or more SLE disease traits. Interval-specific congenic strains for Lbw2 been generated and the specific component phenotypes have been identified. Notably, NZB.NZW-Lbw2 interval congenic mice demonstrated a marked reduction in autoimmune hemolytic anemia (AIHA) and consequent splenomegaly that was not associated with defects in immunoglobulin levels, anti-nuclear antibodies, or B cell activation. Using subcongenic mice it was further revealed that Lbw2 contained at least three loci affecting AIHA. This proposal will use a novel whole genome sequencing approach to first identify predicted genetic variants that affect gene function either by altering protein structure or modifying gene expression, and then identify the most likely candidate 'functional'variant within Lbw2 subloci. This proposal has two specific aims. The first will identify coding-region candidate variants for Lbw2 and other lupus-affecting loci based on the whole genome sequences of the NZB and NZW mice.
The second aim will use the information from aim 1 to further evaluate the coding-region candidate variants, to identify non-coding candidate variants, and to define the mechanisms by which the Lbw2 locus- related variants promote antibodies to RBC. Identification of the susceptibility genes and elucidation of their roles in the induction of lupus should provide significant insights into the etiopathogenesis of genetically- determined autoimmune diseases.
Hemolytic anemia is a common and sometimes severe manifestation of SLE that remains poorly defined in terms of pathogenesis. We have previously identified a locus on chromosome 4, named Lbw2 that is associated with susceptibility to hemolytic anemia. In this application, we propose to identify the genetic variation responsible for this susceptibility using a novel whole genome sequencing approach.