Chromosome 1 Regions Linked to SLE in Multiplex Families

点击翻译按钮获取中文摘要

DESCRIPTION (provided by the applicant): Systemic lupus erythematosus (SLE) is a hetereogeneous autoimmune disease characterized by a plethora of immunopathologic manifestations including the production of autoantibodies to various nuclear components. Genetic predisposition clearly plays an important role in risk for developing SLE, however, many remain elusive. Genome scans have mapped many SLE susceptibility loci in both murine and human SLE. One genomic region on the distal end of mouse chromosome 1 and its syntenic human counterpart 1q23-44 has shown strong evidence to harbor SLE susceptibility genes in multiple independent genome scans of both mice and humans. We have observed evidence for linkage to SLE at 1q23 and 1q41-42 in our cohort of affected sibpair families. In this application, we propose to identify genetic polymorphisms within 1q21-44 that are associated with SLE or SLE subsets in our cohort, and to explore if the same or functionally related genes contribute to syntenic conservation in susceptibility intervals between mice and humans. Our aims are as follows: 1) To continue family ascertainment for an additional 150 SLE multiplex families and an additional 500 simplex families and to assess familiality of SLE manifestations. The enlarged multiplex families will allow more samples in each stratified subset (by ethnicity, SLE-manifestations, or age of disease-onset), hence greater statistical power to localize the linked interval. The enlarged simplex families will allow greater statistical power for association studies in each ethnic group. Familial SLE manifestations will be used in stratification of our family collection to reduce genetic heterogeneity in subsequent linkage and association studies. 2) To perform a targeted genome scan of chromosome 1q21-44 and to narrow the intervals linked to SLE susceptibility. 3) To perform linkage disequilibrium mapping of the narrowed genomic intervals to eventually localize genetic polymorphisms associated with SLE susceptibility. 4) To assess human homologues of candidate murine SLE susceptibility genes (Sle1d, Nba2, and Lbw7) for evidence of association in our cohort. The identification of SLE susceptibility genes can reveal underlying mechanisms in the pathogenesis of autoimmunity and provide potential targets for disease management.