The contribution of common and rare variants to autoimmunity in African Americans

常见和罕见变异对非裔美国人自身免疫的贡献

• 批准号: 8320110
• 负责人: Jorge R. Oksenberg
• 金额: $ 33.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320110
• 关键词: Affect; African; African American; Alleles; Alzheimer' s Disease; American; Architecture; Asians; Autoimmune Process; Autoimmunity; B-Lymphocytes; Back; Benign; Binding Sites; Biological Assay; Biological Markers; Blood specimen; CD4 Positive T Lymphocytes; CD8B1 gene; Central Nervous System Diseases; Child; Chromosomes; Chronic; Chronic Disease; Clinical; Code; Coupled; DNA; Data; Data Set; Disease; Disease susceptibility; Elements; Environmental Risk Factor; Ethnic group; Etiology; European; Exons; Family; Family member; Female; Gene Expression Profile; Genes; Genetic; Genetic Heterogeneity; Genetic Research; Genetic Risk; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Geographic Locations; Goals; HLA-DRB1; Health Care Costs; Heritability; Heterogeneity; High Prevalence; Human Genome; Immune; In Vitro; Incidence; Individual; Inflammation; Inherited; Interruption; Knowledge; Laboratories; Life Style; Link; Linkage Disequilibrium; Mediating; Molecular Genetics; Multiple Sclerosis; Myelin; Neuraxis; Neurologic; Neurologic Dysfunctions; Nucleic Acid Regulatory Sequences; Oligodendroglia; Oncogenes; Parents; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Production; Promoter Regions; Proteins; Recording of previous events; Recruitment Activity; Reporting; Research; Resolution; Risk; Risk Assessment; Role; Sampling; Social isolation; Susceptibility Gene; Symptoms; Synapses; T-Cell Lymphoma; T-Cell Proliferation; Technology; Testing; Therapeutic; Translating; Trauma; Twin Multiple Birth; Unemployment; United States; Validation; Variant; Woman; Work; case control; clinical phenotype; cohort; cytokine; disability; disorder risk; experience; follow-up; genetic variant; genome sequencing; genome wide association study; genome-wide; high risk; immunological synapse; immunological synapse formation; improved; insight; interest; medical attention; nervous system disorder; novel; outcome forecast; research study; socioeconomics; synaptogenesis; tool; young adult

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a common and severe CNS disorder that is characterized by myelin loss, chronic inflammation, axonal and oligodendrocyte pathology, and progressive neurological dysfunction. While the exact cause of MS is unknown, there is an unequivocal, albeit partial, genetic contribution to its pathogenesis. In spite of intensive long-standing efforts, the knowledge of MS genetics remains incomplete. Our overall goal is to contribute to the understanding of MS pathogenesis by means of genetic research in African Americans. The distinct genetic architecture of this population, together with the differences in MS risk (and phenotypes) between African Americans and Europeans, provide a unique opportunity to gain valuable insights into disease susceptibility and etiology. This proposal builds on a large body of recently acquired data leading to the hypothesis that rare genomic variants contribute to disease risk. It includes three main research goals that bridge genomic screens with functional research: In Specific Aim 1 we will generate and analyze high-coverage sequence information (regulatory regions, exons, and exon-flanking regions) for genes with strong evidence of association in representative African American MS and control genomes. From this dataset, approximately 500 variants will be genotyped in a validation cohort for the full description of allelic heterogeneity and the discovery of population-specific associated rare variants. In Specific Aim 2 we propose to sequence the genome of a multi-generational, multi-case family at 40x resolution and search for DNA segments identical by descent (IBD) with the goal of identifying rare allelic variants linked to disease expression in this particular family. In addition, we will use high coverage RNAseq to comprehensive analyze the MS transcriptome of CD4+, CD8+ and B cells in affected and unaffected family members. Finally, EVI5 (ch.1p22.1) is a well-validated susceptibility gene, and showed the strongest association outside the MHC in African Americans. In Specific Aim 3 our goal is to determine how allelic differences in EVI5 contribute to altered formation of the immunological synapse, thus contributing to MS susceptibility. The availability of a large and well characterized sample-set as described here, coupled with the aid of high-powered laboratory technologies, provide an outstanding opportunity to identify and characterize MS-related genes. This information may translate into clinically useful genetic biomarkers and reveal novel targets for therapy.

描述（由申请人提供）：多发性硬化症（MS）是一种常见且严重的中枢神经系统疾病，其特征是髓磷脂丧失，慢性炎症，轴突和少突胶质细胞病理学以及进行性神经功能障碍。虽然MS的确切原因尚不清楚，但仍有一个明确的（尽管部分）对其发病机理产生了部分遗传贡献。尽管长期努力，但对MS遗传学的了解仍然不完整。我们的总体目标是通过非裔美国人的遗传研究来为对MS发病机理的理解做出贡献。该人群的独特遗传结构，以及非裔美国人和欧洲人之间MS风险（和表型）的差异，提供了一个独特的机会，以获得对疾病易感性和病因的宝贵见解。该提案建立在大量最近获得的数据的基础上，导致假设罕见的基因组变异有助于疾病风险。它包括三个主要的研究目标，可以通过功能研究启用基因组筛查：在特定目标1中，我们将对具有强大的非裔美国人MS和控制基因组相关的基因生成和分析高覆盖序列信息（调节区域，外显子和外显子涌向区域）。从该数据集中，将在验证队列中对大约500种变体进行基因分型，以完整描述等位基因异质性和发现特定人群相关的稀有变体。在特定的目标2中，我们建议以40倍分辨率对多代，多代酶家族的基因组进行测序，并搜索通过下降（IBD）相同的DNA片段，目的是确定与该特定家族中疾病表达相关的罕见等位基因变异。此外，我们将使用高覆盖率RNASEQ全面分析受影响和未受影响的家庭成员中CD4+，CD8+和B细胞的MS转录组。最后，EVI5（Ch.1p22.1）是一个验证良好的敏感性基因，在非裔美国人中显示了MHC以外的最强关联。在特定目标3中，我们的目标是确定EVI5中的等位基因差异如何促进免疫突触的形成改变，从而有助于MS易感性。如下所述，较大且特征良好的样品集的可用性，并借助高功率实验室技术，为识别和表征与MS相关的基因提供了绝佳的机会。该信息可能会转化为临床上有用的遗传生物标志物，并揭示治疗的新靶标。