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

SLA 中常见和罕见因果变异的识别和功能分析

• 批准号: 8829758
• 负责人: RICHARD ANDREW SPRITZ
• 金额: $ 40.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829758
• 关键词: Accounting; Adaptor Signaling Protein; Adaptor Signaling Protein Gene; Affect; Alleles; Amino Acid Substitution; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Binding Sites; Biological; Cell Line; Cell physiology; Chromosomes; Classification; Color; Comorbidity; Complex; DNA; DNA Sequence Analysis; Data; Development; Disease; Disease Pathway; EMSA; Employee Strikes; Enhancers; European; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Hair; Haplotypes; Heritability; Human; Incidence; Individual; Inflammatory; Intervention; Mediating; Medical; Missense Mutation; Molecular; Mus; Open Reading Frames; Pathologic; Pathway interactions; Patients; Persons; Predisposition; Protein Isoforms; Protein Region; Proteins; Receptor Activation; Receptor Signaling; Relative (related person); Rest; Risk; Role; Signal Transduction; Skin; Social isolation; Structural Genes; Susceptibility Gene; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Translating; Tumor Necrosis Factor-alpha; Variant; Vitiligo; adapter protein; case control; chromatin immunoprecipitation; cytokine; gain of function; genetic analysis; genetic variant; genome wide association study; high risk; improved; in vivo; inhibitor/antagonist; melanocyte; mutant; novel; programs; protein function; public health relevance; rare variant; reconstitution; skin patch; transcription factor

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.

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，其中皮肤和毛发的白色斑块是由黑素细胞破坏引起的。GV中引人注目的皮肤色素脱失特别影响有色人种，经常与社会隔离和精神病共病。此外，本发明还提供了一种方法， GV患者有约30%的风险发展为其他自身免疫性疾病，导致直接的医疗共病。 通过在欧洲来源的白色（EUR）个体中的两个GV GWAS，我们已经确定了至少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。这些GV易感基因中约90%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，而其余编码黑素细胞蛋白，似乎介导黑素细胞特异性自身免疫触发和靶向。统计分析表明，这些GV位点的共同因果变异仅占GV遗传力（h2）的~18%。尽管其他GV易感基因座无疑仍有待发现，但这些已知基因座的罕见病理变异可能是额外的“缺失”遗传性的原因。 这项建议的重点是遗传和功能分析的免疫调节GV易感基因座之一，SLA，我们有很好的证据，常见和罕见的致病等位基因的混合物。SLA位于染色体8q24.22，编码Src样衔接蛋白（SLA）。SLA是在T细胞中高度表达的同源二聚体衔接蛋白，其负调节T细胞受体（TCR）信号传导。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由常见SNP rs 853308（MAF 0.48，OR 1.22）表示，其位于SLA下游的表观转录增强子内。关联信号2由位于SLA编码区内的不常见的非同义SNP rs 4486183 SNP（Pro 15 Thr; MAF 0.025，OR 1.80）表示。在该提案中，我们的目标是1）重新测序GV病例和对照中的SLA以鉴定额外的罕见变体，并测试GV病例与对照中过量的罕见功能变体; 2）进行SLA关联信号1的功能分析，测试与高风险与低风险信号单倍型相关的差异增强子活性;和3）进行SLA关联信号2的功能分析，测试与低风险和高风险Pro 15 Thr同种型相关的不同SLA功能。在适当的情况下，我们还将在目标1中发现的新的明显有害的SLA变体编程到目标2和3的功能研究中。