Four independent genome-wide scans indicate several genetic effects for SLE on the long arm of human chromosome I in the region of I q2l-24. We have now demonstrated linkage, family-based association and case-control association to activating receptors (FcgammaRIIIA and FcgammaRIIA) in the low affinity classical FCgamma receptor cluster in this region. Based on the recognition that lupus is a complex genetic trait and based on the precedents of multiple genetic components within a region and of gene clusters within each component in murine models of lupus, we hypothesize that there are additional disease susceptibility and severity genes on chromosome Iq. From the perspective of functional candidates (and preliminary results), we anticipate that structural and functional homologues of the Fcgamma receptors with activating and/or inhibitory function that have polymorphic variants will contribute to the genetic predisposition to SLE. Furthermore, noting that this region of Iq is paralogous to other regions in the human genome rich in immunologically relevant genes, we anticipate that other genes, known from pathophysiology and from homology to murine candidate genes, will also contribute to the lupus diathesis. Therefore, through direct sequencing of genomic and cDNA template from affected individuals of differing ethnicities, and using all available bioinformatics tools, we will identify candidate genes for SLE susceptibility and severity on chromosome lq2l-24. Single nucleotide polymorphisms (SNPs) in these genes will be tested both for linkage and for family-based and case-control association with SLE, using single-point and haplotype-based approaches. The corresponding biologies of the most pertinent SNPs will be defined and related to clinical outcome. These studies will draw on the collaborative, assembled resources and expertise of each of the projects in this Program Project as well as the Genetic Epidemiology and Biostatistics Core.
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