Generalized vitiligo (GV) is a common autoimmune disease in which white patches of skin and hair result from destruction of melanocytes. Striking skin depigmentation in GV particularly impacts persons of color, with frequent social isolation and psychiatric co-morbidity. In addition, GV patients have ~30% risk of developing other autoimmune diseases, resulting in direct medical co-morbidity. By means of two GWAS of GV in European-derived white (EUR) individuals, we have identified at least 32 GV susceptibility genes, defining pathobiological pathways of disease and translating directly to improved patient classification and improved treatment. About 90% of these GV susceptibility genes encode immunoregulatory proteins, a number of which have also been implicated in other autoimmune (AI) disease, while the rest encode melanocyte proteins that appear to mediate melanocyte-specific autoimmune triggering and targeting. Statistical analysis indicates that common causal variation that these GV loci account for only ~18% of GV heritability (h2). Whereas additional GV susceptibility loci undoubtedly remain to be discovered, it is likely that rare pathologic variation at these known loci account for additional """"""""missing"""""""" heritability. This proposal focuses on genetic and functiona analyses of one of the immunoregulatory GV susceptibility loci, SLA, for which we have good evidence of a mixture of both common and rare causal alleles. SLA, located in chromosome 8q24.22, encodes Src-like adaptor protein (SLA). SLA is a homodimeric adapter protein, highly expressed in T cells, which negatively regulates T cell receptor (TCR) signaling. Conditional analysis shows that the SLA region contains two independent GV association signals. Association signal 1 is represented by the common SNP rs853308 (MAF 0.48, OR 1.22), located downstream of SLA within an apparent transcriptional enhancer. Association signal 2 is represented by the uncommon non-synonymous SNP rs4486183 SNP (Pro15Thr;MAF 0.025, OR 1.80), located within the SLA coding region. In this proposal we aim to 1) re-sequence SLA in GV cases and controls to identify additional rare variants and test for excess rare functional variants in GV cases versus controls;2) carry out functional analyses of SLA association signal 1, testing for differential enhancer activity associated with the high-risk versus low-risk signal haplotypes;and 3) carry out functional analyses of SLA association signal 2, testing for differential SLA function associated with the low-risk versus high-risk Pro15Thr isoforms. As appropriate, we will also program novel apparently deleterious SLA variants we discover in Aim 1 into the functional studies of Aims 2 and 3.
Vitiligo (GV) is the most common pigmentary disorder, with autoimmune destruction of skin melanocytes resulting in patches of white skin and hair, particularly impacting persons of color, and high incidence of other autoimmune diseases. By previous genetic studies, we have identified a parts list of GV susceptibility genes and biological pathways. One of these genes is SLA, encoding SLAP, a key regulator of T cell receptor activation, in which we have found evidence of at least two independent causal variants, one common variant that likely affects transcription and a rare variant that results in an amino acid substitution within the SLAP protein. Here, we plan to re-sequence the SLA gene in GV patients and carry out genetic analyses to identify additional rare causal variants in SLA, and to carry out functional studies of both the common SLA transcriptional variant and the rare SLAP protein variant, with our long-term goal being to discover key biological information that facilitates the development of new treatments that re-regulate melanocyte-targeted autoimmunity.