Identification and Functional Analyses of Common and Rare Causal Variants in SLA

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DESCRIPTION (provided by applicant): 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.