Genetic studies of vitiligo

描述（由申请人提供）：这是一份重新提交的更新提案，旨在继续进行全身性白癜风（GV）的遗传学研究，这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，他们经常与社会隔离和精神病共病。此外，GV患者有约30%的风险发展为其他自身免疫性疾病，导致直接的医疗共病。 我们对GV的遗传研究始于15年前的遗传和临床流行病学基础研究，随后是候选基因关联研究和全基因组连锁研究。在过去的资助期间，我们组织了国际VitGene联盟在欧洲白人（EUR）中进行了两次非常成功的GWAS，以及对其他人群的研究，确定了约32个GV易感基因并定义了新的病理生物学途径。除了GWAS之外，我们还对第一个GWAS检测到的大多数基因进行了NextGen重新测序，确定了HLA-A，TYR，NLRP 1和GZMB中常见的（和一些不常见/罕见的）致病变异。迄今为止鉴定的潜在致病变异体，以及本提案中鉴定的那些变异体，在我们的平行项目“白癜风基因的功能分析”（AR 045584）中进行功能分析。 我们的研究结果 为白癜风自身免疫发病机制提供了第一个理论生物学框架的基础，并直接转化为改善患者分类和改善治疗。然而，已知的GV基因座仅占GV遗传力（h2）的~18%，并且大多数致病基因变异仍然未知。对我们组合的GV GWAS数据集的统计遗传分析表明，GV的相当大的“隐藏”h2存在于剩余的数据中，这些数据可以以相对较低的成本进行挖掘。 因此，我们的目标是增加GV的基因和途径的“部件列表”，识别因果变异，将GV遗传和等位基因结构与临床亚表型和疾病生物标志物联系起来，并了解因果功能生物学。发现其他GV基因座的一个强有力的理由是，我们还没有足够的生物学知识来控制黑素细胞介导的自身免疫。如果能够实现这一点，GV将是再生医学最好的AI疾病候选者之一，因为皮肤黑素细胞（或黑素细胞干细胞）库保持完整。 因此，我们建议：1）进行第三次小的EUR GWAS以挖掘额外的GV基因座，动力为OR ~1.2（可能是GWAS的实际限制）; 2）精细定位GV基因座以鉴定特定基因并定义常见和一些不常见的致病变体;随后是两个创新的目的，以3）通过分析多重GV家族来鉴定潜在的不常见/罕见致病变体;和4）将GV的遗传结构与特定的临床和生物标志物亚表型相关联，并测试相同的GV基因座/变体是否也引起相关的表型，节段性白癜风（SV）。我们的目标是，由此产生的生物学知识将为治疗甚至预防GV和相关自身免疫性疾病的新方法提供基础。

DESCRIPTION (provided by applicant): This is a resubmitted renewal proposal to continue genetic studies of generalized vitiligo (GV), 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. Our genetic studies of GV began 15 years ago with basic studies of genetic and clinical epidemiology, followed by candidate gene association studies and genomewide linkage studies. During the past grant period we organized the International VitGene Consortium to perform two highly successful GWAS in European-derived whites (EUR), as well as studies of other populations, identifying ~32 GV susceptibility genes and defining novel pathobiological pathways. Beyond the GWAS, we have gone on to NextGen re-sequencing of most of the genes detected by the first GWAS, identifying common (and some uncommon/rare) causal variants in HLA-A, TYR, NLRP1, and GZMB. Potential causal variants identified in to date, as well as those identified in this proposal, are carried forward to functioal analysis in our parallel project, "Functional Analysis of Vitiligo Genes" (AR045584). Our findings provide the basis of the first theoretical biological framework for vitiligo autoimmune pathogenesis, and have translated directly to improved patient classification and improved treatment. Nevertheless, known GV loci account for only ~18% of GV heritability (h2), and most causal gene variants remain unknown. Statistical genetic analysis of our combined GV GWAS datasets shows that considerable "hidden" h2 for GV resides in the remaining data, which can be mined at relatively low cost. Our goals are thus to augment the GV "parts list" of genes and pathways, identify causal variants, relate GV genetic and allelic architecture to clinical sub-phenotypes and disease biomarkers, and understand causal functional biology. A strong rationale to discover additional GV loci is that we do not yet know enough biology to control melanocyte-directed autoimmunity. If this could be achieved, GV would be one of the best AI disease candidates for regenerative medicine, since the skin melanocyte (or melanocyte stem cell) reservoir remains intact. Here, we thus propose to: 1) carry out a small third EUR GWAS to mine additional GV loci, powered to OR ~1.2 (probably the practical limit of GWAS); 2) fine-map GV loci to identify specific genes and define common and some uncommon causal variants; followed by two innovative Aims, to 3) identify potential uncommon/rare causal variants by analyses of multiplex GV families; and 4) relate the genetic architecture of GV to specific clinical and biomarker sub-phenotypes and test whether the same GV loci/variants also cause a related phenotype, segmental vitiligo (SV). It is our goal that the resultant biological knowledge will provide the basis for new approaches to treatment and even prevention of GV and associated autoimmune diseases.