Recently, we published tantalizing evidence locating a gene affecting susceptibility to systemic lupus erythematosus (SLE), and possibly vitiligo, in vitiligo related lupus families on 17p13 (1). Our goal for this proposal is to narrow the susceptibility region and to identify the susceptibility gene. We will achieve this by iterative reduction in the size of the chromosomal region. To improve the power of the study, specific aim 1 is to first augment our current data with new data, identified from our ongoing SLE genetic linkage projects. We will then narrow our previously identified susceptibility region in two steps. First, in specific aim 2, we will choose microsatellite markers to form a 1-2 cM map across the current susceptibility region and analyse these data using genetic linkage methods. Second, in specific aim 3, we will choose single nucleotide polymorphism (SNP) markers to form a 0.5 cM map across the reduced region from specific aim 2 and analyse these data using linkage disequilibrium methods. In the final step, specific aim 4, we will search the public databases for SNPs in genes known to be located in the narrowed susceptibility region established by specific aim 3 and to analyse these using linkage disequilibrium methods.
Specific aim 5 is to sequence the gene to find the causal mutations. We ascertained families with European American ancestry, multiplex for SLE and each family has at least one member afflicted with vitiligo. Since autoimmune diseases are thought to share some of their genetic origins, decreasing sample heterogeneity would increase the power to identify the susceptibility gene(s). As the presence of vitiligo in the family was used as a pedigree ascertainment criterion, and there was significantly higher risk associated with developing vitiligo among the family members affected with SLE compared to non-SLE family members, we postulated the following hypotheses: SLE and vitiligo may share common autoimmune genetic determinant(s) for their pathophysiology. Alternatively, we may assert that there are genes that lead primarily to develop SLE, which may also modify the risk of developing vitiligo, at least among the ascertained families. Our preliminary results support the hypothesis that SLE and vitiligo may share common genetic determinant(s) (1). This project is directly relevant to the goals of NIAMS SMALL GRANT PROGRAM FOR NEW INVESTIGATORS and has the potential to reveal important, previously unappreciated, susceptibility genes, which contribute toward understanding the etiology of SLE and vitiligo.
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