Functional Genomics of Alopecia Areata

斑秃的功能基因组学

• 批准号: 9521505
• 负责人: Angela M Christiano
• 金额: $ 54.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9521505
• 关键词: Affect; Alleles; Alopecia Areata; Autoimmune Diseases; Autoimmunity; Automobile Driving; Avidity; Biological; Biological Assay; Biology; Biometry; Candidate Disease Gene; Cell Line; Cells; Cellular biology; Chemistry; Code; Collaborations; Consultations; Custom; DNA Sequence Alteration; Data Set; Developmental Biology; Disease; Ethnic group; Exons; Family; Foundations; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genome; Genomic Segment; Genomics; Genotype; Goals; Grant; Hair follicle structure; Human; Immune; Immunology; In Vitro; Individual; Investigation; Ligand Binding; Ligands; MicroRNAs; Nature; Network-based; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Public Health; Registries; Research Personnel; Resources; Risk; Sampling; Sequence Analysis; Signal Pathway; Social Impacts; Susceptibility Gene; Systems Biology; T-Lymphocyte; Targeted Resequencing; Testing; The Sun; Time; Transcriptional Regulation; Universities; Untranslated RNA; Variant; Work; analytical tool; cell killing; cohort; deep sequencing; economic impact; exome; exome sequencing; functional genomics; genetic architecture; genetic linkage analysis; genetic variant; genome wide association study; indexing; innovation; insight; lifetime risk; multidisciplinary; novel therapeutics; proband; public health relevance; rare variant

 DESCRIPTION (provided by applicant): Alopecia Areata (AA) is one of the most common autoimmune diseases in the US, with a lifetime risk of 1.7%, it affects approximately 5.3 million individuals across all ethnic groups. We recently carried out a genome-wide association study (GWAS) to identify common alleles that contribute to risk of AA, and identified several genomic regions harboring potential susceptibility genes. In our Preliminary Studies, we have generated a significant and unique resource of genomic and genetic datasets in alopecia areata patient samples using several approaches, including GWAS genotyping on >1000 individuals, ImmunoChip on >400 individuals, Linkage analysis on >50 families, Gene expression profiling on >100 individuals, Targeted resequencing in GWAS regions in 124 individuals, and Whole exome sequencing in >10 alopecia areata probands selected from linkage families. These robust and highly integrated datasets provide a rich foundation from which to interrogate the functional significance of variants in AA candidate genes in the context of this innovative proposal. As a first step towards understanding the biological significance of these results, we must now perform deep sequencing analysis in these regions to identify causal variants that are driving the association of tagSNPs. The emerging picture of the genetic architecture of common diseases contains niches for both common and rare variants acting independently or in concert to influence phenotypes. Understanding the impact of these variants in disease pathogenesis is the first key step in moving toward novel therapies for AA. These studies are extremely timely, and will allow us to place AA into the context of other autoimmune diseases in which GWAS and deep sequencing is already underway. We postulate that causal variants in candidate genes underlie the susceptibility to develop AA. This grant is focused on carrying out deep sequencing studies to identify new variants in candidate genes, followed by functional genomics of variants in several in vitro contexts, which will allow us to determine: 1) the nature of the specific variats contributing to AA susceptibility; and 2) the mechanism(s) by which they contribute to disease pathogenesis. In this proposal, we will carry out Exome-plus sequencing with enrichment in our previous GWAS regions to identify causal variants. We will then interrogate the functional consequences of variants within candidate genes expressed in both the hair follicle and immune cells, with an emphasis on the NKG2D pathway.

 描述（由适用提供）：脱发Areata（AA）是美国最常见的自身免疫性疾病之一，终身风险为1.7％，在所有族裔群体中影响约530万人。我们最近进行了一项全基因组关联研究（GWAS），以识别导致AA风险的常见等位基因，并确定了具有潜在易感基因的几个基因组区域。 In our Preliminary Studies, we have generated a significant and unique resource of genomic and genetic datasets in alopecia area patient samples using several approaches, including GWAS genotyping on >1000 individuals, ImmunoChip on >400 individuals, Linkage analysis on >50 families, Gene expression profiling on >100 individuals, Targeted resequencing in GWAS regions in 124 individuals, and Whole exome sequencing in >10 alopecia areata从连锁家庭中选择的证据。这些坚固且高度集成的数据集为在此创新建议的背景下询问AA候选基因中变体的功能意义的丰富基础。作为了解这些结果的生物学性的第一步，我们现在必须在这些区域进行深入的测序分析，以识别推动Tagsnps关联的毒性变体。常见疾病的遗传结构的新兴图片包含独立作用或共同作用以影响表型的常见变体和稀有变体的壁ni。了解这些变体在疾病发病机理中的影响是朝着新型AA疗法发展的第一步。这些研究非常及时，将使我们能够将AA置于其他自身免疫性疾病的背景下，其中GWAS和深层测序已经进行。我们假设候选基因中的因果变异是发展AA的敏感性。该赠款的重点是进行深入的测序研究，以鉴定候选基因中的新变体，然后在几种体外情况下进行变体的功能基因组学，这将使我们确定：1）有助于AA敏感性的特定变异的性质； 2）它们有助于疾病发病机理的机制。在此提案中，我们将在以前的GWAS区域进行富集，以识别因果变异。然后，我们将询问在毛囊和免疫细胞中表达的候选基因中变体的功能后果，并重点介绍NKG2D途径。

项目成果

An Imperative Need for Further Genetic Studies of Alopecia Areata.

• DOI: 10.1016/j.jisp.2020.04.003
• 发表时间: 2020-11
• 期刊: The journal of investigative dermatology. Symposium proceedings
• 作者: Petukhova L

Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82.

• DOI: 10.1038/s41467-022-28343-3
• 发表时间: 2022-02-10
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Erjavec SO;Gelfman S;Abdelaziz AR;Lee EY;Monga I;Alkelai A;Ionita-Laza I;Petukhova L;Christiano AM
• 通讯作者: Christiano AM