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

描述(由申请人提供)： 泛发性白癜风(GV)是一种常见的自身免疫性疾病，皮肤和头发上的白色斑块是黑素细胞破坏的结果。GV中显著的皮肤脱色尤其影响有色人种，经常与社会隔离和精神疾病并存。此外, GV患者有约30%的风险发展为其他自身免疫性疾病，导致直接的医学共发病。通过对欧洲衍生的白人(EUR)个体进行GV的两个GWA，我们已经识别了至少32个GV易感基因，定义了疾病的病理生物学途径，并直接转化为改善患者分类和改善治疗。大约90%的GV易感基因编码免疫调节蛋白，其中一些也与其他自身免疫(AI)疾病有关，其余的编码黑素细胞蛋白，似乎介导黑素细胞特异性自身免疫的触发和靶向。统计分析表明，这些GV基因座仅占GV遗传力(H2)的~18%的共同因果变异。虽然其他GV易感基因无疑仍有待发现，但这些已知基因座罕见的病理变异很可能解释了额外的“缺失”遗传性。这项建议侧重于对免疫调节GV易感基因之一SLA的遗传和功能分析，我们有很好的证据表明该基因混合了常见和罕见的因果等位基因。SLA位于染色体8q24.22上，编码类Src适配器蛋白(SLA)。SLA是一种同源二聚体适配器蛋白，在T细胞中高表达，负向调节T细胞受体(TCR)信号。条件分析表明，SLA区域包含两个独立的GV关联信号。关联信号1由共同的SNP rs853308(MAF 0.48，或1.22)表示，它位于SLA下游的一个明显的转录增强子中。关联信号2由位于SLA编码区内的不常见的非同义SNP rs4486183 SNP(Pro15Thr；MAF 0.025，或1.80)表示。在这项建议中，我们的目标是1)对GV病例和对照中的SLA重新排序，以识别额外的罕见变异，并在GV病例和对照中测试额外的罕见功能变异；2)对SLA关联信号1进行功能分析，测试与高风险和低风险信号单倍型相关的差异增强子活性；以及3)对SLA关联信号2进行功能分析，测试与低风险和高风险Pro15Thr亚型相关的差异SLA功能。在适当的情况下，我们还将把在目标1中发现的新的明显有害的二语习得变体编程到目标2和目标3的功能研究中。

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.