Functional Genomic Determinants of B cell Homeostasis and Susceptibility to SLE

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The overall goal of this pilot and feasibility study is to facilitate the understanding of genetic susceptibility to SLE through the independent and joint effects of select candidate genes and their biological effects. The hypothesis is that functional variation in TNFfTNFR superfamily genes that encode BLyS, BAFF-R, BCMA, TACI and APRIL, associated with enhanced B cell survival, correlate with the presence of SLE and among these patients, renal involvement. To address this hypothesis, (1) genotype-disease phenotype and (2) genotype-immunophenotype relationships of B cell homeostasis and SLE pathogenesis will be characterized. Because the natural history of SLE is complex involving concurrent protean clinical manifestations of multiple organ systems, the generalizability of findings can be limiting. Using a candidate gene approach, we intend to capitalize on a unique opportunity to explore functional genomics in an existing large, ethnically diverse, well-characterized population of SLE and to take advantage of recent advances in human genome resequencing and biologic plausibility of the TNF/TNFR superfamily in SLE pathogenesis. Haplotype analyses based on predicted phase, permutation testing and logistic or linear regression will be used to exploit differences in frequencies using case-control, case-only and cross-sectional approaches. Immunophenotyping will be conducted using flow cytometry. The extensive characterization of the SLE phenotype and related risk factors from an existing well-defined study population coupled with a candidate functional genomics approach that exploits the expertise of the Epitope Recognition Immunoreagent Core, the Analytic and Preparative Flow Cytometry Core, the General Clinical Research Center and the investigative team will facilitate a rigorous evaluation. Together these approaches offer the best opportunity to rapidly exploit targeted relationships of B cell homeostasis and SLE and to generate preliminary data necessary to investigate functional genomics as a tool for targeting high-risk populations who may benefit from individualized clinical management or therapeutic intervention. The candidate is a new independent investigator without current or past extramural NIH research support who will translate their demonstrated expertise in molecular epidemiology and immunogenetics to the understanding of common pathways involved in the activation of genes important for B cell autoreactivity and homeostasis in SLE.