Unraveling the molecular causes of alopecia areata (AA): whole-genome sequencing in patients with AA plus other autoimmune diseases

揭示斑秃 (AA) 的分子原因：对 AA 及其他自身免疫性疾病患者进行全基因组测序

• 批准号: 497768231
• 负责人: Dr. Buket Basmanav, Ph.D.
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497768231?language=en
• 关键词: Unraveling; molecular; causes; alopecia; areata

Alopecia areata (AA) is a common autoimmune-mediated disorder in humans with an estimated lifetime risk of approximately 2 %. Episodes of hair loss usually begin with the development of isolated hairless patches that may spread centrifugally and progress to complete hair loss over the entire body. If symptoms persist for a long time, the prognosis is unfavorable with regard to therapeutic responsiveness or spontaneous remission. The psychological impact on affected individuals is severe, including increased rates of clinically relevant anxiety and depression. AA is generally thought to be a multifactorial disorder involving both environmental and genetic factors. Genome-wide association studies (GWAS) of AA have so far identified 14 susceptibility loci, demonstrating the polygenic nature of the disease. Little attention has been paid in the field of AA genetics to the fact that AA can also occur as an associated clinical feature of a number of monogenic syndromes that severely compromise the immune system and lead to immunodeficiency and/or autoimmunity. These syndromes are caused by mutations in key immune genes. Particularly intriguing is the incomplete penetrance of some of these mutations and/or the variable expression of clinical phenotypes. These observations and the fact that a subset of AA patients (more than 400 patients out of our total cohort of 2.500) are affected by additional autoimmune diseases -we refer to this as AAPAD (alopecia areata plus other autoimmune disease(s))- may open a whole new avenue in the field of AA genetics. We hypothesize that AAPAD cases are due to specific genetic causes and are intermediate between the very rare autoimmune syndromes and the multifactorial AA cases, representing a continuous spectrum of autoimmunity with AA as the common feature. Therefore, the aim of the present proposal is to detect rare variants in the coding and noncoding genome with moderate to large effects by whole-genome sequencing (WGS) in our AAPAD group. Briefly, a total of 400 AAPAD patients will be subjected to WGS and then screened for candidate mutations by use of diverse bioinformatic analyses. As next step, we aim to perform targeted sequencing of the most promising 10 genes emerging from WGS data in the rest of the AA cohort with help of single molecule Molecular Inversion Probe (smMIP) technology. 2-3 genes/variants gaining robust evidence for causality from WGS and targeted sequencing data will be functionally characterized by in vitro experiments. The identification of such rare variants and the mechanistic concepts derived from them would i) provide important insights into the etiology of AA and general autoimmunity, paving the way for the development of novel therapeutics and ii) could significantly impact the way we clinically diagnose AA in the future.

斑秃（AA）是人类常见的自身免疫介导的疾病，估计终生风险约为2%。脱发的发作通常开始与孤立的无毛补丁的发展，可能会蔓延离心和进展，以完成整个身体的脱发。如果症状持续很长时间，预后是不利的治疗反应或自发缓解。对受影响个人的心理影响是严重的，包括临床相关的焦虑和抑郁的比率增加。AA通常被认为是一种涉及环境和遗传因素的多因素疾病。AA的全基因组关联研究（GWAS）迄今已确定了14个易感基因座，表明该疾病的多基因性质。在AA遗传学领域，很少有人注意到AA也可以作为许多严重损害免疫系统并导致免疫缺陷和/或自身免疫的单基因综合征的相关临床特征而发生。这些综合征是由关键免疫基因的突变引起的。特别令人感兴趣的是这些突变中的一些的不完全突变和/或临床表型的可变表达。这些观察结果以及AA患者的一个子集（我们的2500名总队列中有400多名患者）受到其他自身免疫性疾病的影响-我们将其称为AAPAD（斑秃加其他自身免疫性疾病）-可能会在AA遗传学领域开辟一条全新的途径。我们假设AAPAD病例是由于特定的遗传原因，介于非常罕见的自身免疫综合征和多因素AA病例之间，代表了以AA为共同特征的连续自身免疫谱。因此，本提案的目的是在我们的AAPAD组中通过全基因组测序（WGS）检测编码和非编码基因组中具有中等至大影响的罕见变异。简而言之，总共400名AAPAD患者将接受WGS，然后通过使用不同的生物信息学分析筛选候选突变。下一步，我们的目标是在单分子分子反转探针（smMIP）技术的帮助下，对AA队列其余部分中WGS数据中出现的最有希望的10个基因进行靶向测序。2-3从WGS和靶向测序数据获得因果关系的有力证据的基因/变体将通过体外实验进行功能表征。这种罕见变异体的鉴定和由此衍生的机制概念将i）提供对AA和一般自身免疫的病因学的重要见解，为开发新的治疗方法铺平道路，和ii）可以显著影响我们未来临床诊断AA的方式。