Variations in the copy number of a given gene, also known as copy number variation (CNV) or copy numberpolymorphisms (CNP), when the frequency exceeds 1%, is a heritable property. CNVs of specific targetgenes have been associated with complex phenotypes such as cancer and inflammatory bowel disease.Indeed, CNV of the target gene, TLR7, has been associated with the autoimmune phenotype in BXSB mice,and recent data in the human Fc receptor locus suggest that CNV of a neutrophil specific gene in this regionmay also be important in autoimmune diseases. We now have data that demonstrate that there are multipletypes of structural variation in the Fc receptor region, both deletions of varying extents and duplications.Furthermore, since the genes immediately adjacent FCGR3B are pathophysiologically important, wehypothesize that the full repertoire of activating and inhibitory FcR genes involved in these structuralvariations may be most important. In particular, FCGR2C, thought by most to be a pseudogene, encodes aprotein expressed on B cells and provides a counterbalancing signal to the classical concept of theFCGR2B-mediated 'brake' on immune complex driven B cell activity. We hypothesize that the nature andfrequency of these CNVs will be distinct in African Americans, and perhaps Hispanics, compared toCaucasians and that these differences will contribute to the severity of the disease phenotype over time inboth of these groups. In this Program Project, we have the unique opportunity to define the structuralvariations of this genetically and pathophysiologically important region, in ethnic minorities, and to relate thisvariation to both disease susceptibility and disease severity over time.
Our Specific Aims are 1) To definethe nature of copy number variation in the classical Fc receptor cluster and its relationship to SLE, 2) Todefine the relationship between ancestry and the types of copy number variants and 3) To examine othergenes in the 'opsonin / immune complex' pathway for copy number variation and relate this variation tooverall SLE risk. Relationship of Project with Overall PPG Priorities. The proposed research plan willexamine the importance of CNV in Fc receptors and other pathway genes. The project will also look atinteractions between genetic ancestry markers and CNV for SLE susceptibility and severity. This researchplan will (1) work with Projects 2 and 3 to identify regional AIMs, (2) draw on the expertise of the GeneticEpidemiology and Biostatistics Cores in the design and analysis of CNV in relation to regional AIMs,increase collaboration between partner institutions, (3) foster the continued development of an effectiveRheumatic Diseases Research Program, (4) enhance research efforts toward SLE-related health disparitiesand (5) provide novel insight to the genetic etiology of SLE as an autoimmune phenotype that isdisproportionately more frequent and severe among ethnic minority populations.
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