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: 8214252
• 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/8214252
• 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. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a common cause of severe neurological disability resulting from the interruption of myelinated tracts in the central nervous system. MS is second only to trauma as a cause of neurologic disability in young adults, affecting approximately 2 million people worldwide and more than 400,000 individuals in the US. Remarkably, the incidence of MS seems to have increased considerably over the last century, and this increase may have occurred primarily in women. The socioeconomic consequences of this long-lasting disease are staggering as 75- 85% of patients are eventually unemployed and at high risk for social isolation. Conservative estimates indicate that this chronic illness results in healthcare costs exceeding $200 billion annually in the United States alone. Thus, MS is the second most costly neurological disorder after Alzheimer's disease. Despite important advances in therapeutics, none of the currently available disease-modifying drugs convincingly alter the long-term prognosis of the disease. Clinical manifestations are extremely diverse, but very little is known about the underlying cause of this variability. It can vary from a benign illness to a rapidly evolving and incapacitating disease. Onset may be abrupt or insidious, and early symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. Most patients ultimately experience progressive disability and twenty-five years after onset approximately 80% of affected individuals will require assistance with ambulation. Thus over the long-term, MS is most often a severe disease requiring profound lifestyle adjustments to the affected and their families. We aim to identify the genes and the gene-specific variants that code for products involved in MS susceptibility. To achieve our goals, we will collect blood samples to extract DNA from a large number of individuals recruited from populations at high, intermediate and low MS risk. By analyzing their genetic makeup, we will be able to understand the rules of MS heritability. We anticipate that there may be several genes involved in MS risk. These genes may work independently or together, and affect susceptibility in concert with environmental factors. Particular combinations of inherited genetic variants may also determine when symptoms develop, or how the disease progresses. Their identification will help to define the basic etiology of MS, improve risk assessment, and influence therapeutics.

描述（由申请人提供）：多发性硬化（MS）是一种常见且严重的CNS疾病，其特征在于髓鞘丢失、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，但其发病机制中存在明确的（尽管是部分的）遗传贡献。尽管长期以来一直在努力，但对MS遗传学的了解仍然不完整。我们的总体目标是通过对非裔美国人的遗传学研究来促进对MS发病机制的理解。该人群独特的遗传结构，以及非裔美国人和欧洲人之间MS风险（和表型）的差异，为获得对疾病易感性和病因学的有价值见解提供了独特的机会。该提案建立在最近获得的大量数据的基础上，这些数据导致了罕见基因组变异导致疾病风险的假设。它包括三个主要的研究目标，桥梁基因组筛选与功能研究：在具体目标1中，我们将生成和分析高覆盖率的序列信息（调控区，外显子和外显子侧翼区）的基因与代表性的非裔美国人MS和控制基因组的关联的强有力证据。根据该数据集，将在验证队列中对约500种变异进行基因分型，以全面描述等位基因异质性并发现人群特异性相关罕见变异。在具体目标2中，我们建议以40倍分辨率对多代、多病例家族的基因组进行测序，并搜索血统相同（IBD）的DNA片段，目的是鉴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，我们还将使用高覆盖率的RNAseq，全面分析受影响和未受影响的家族成员的CD 4+、CD 8+和B细胞的MS转录组。最后，EVI 5（ch.1p22.1）是一个经过充分验证的易感基因，在非裔美国人中显示出最强的MHC外关联。在具体目标3中，我们的目标是确定EVI 5中的等位基因差异如何有助于改变免疫突触的形成，从而有助于MS易感性。这里描述的一个大的和良好表征的样品集的可用性，再加上高性能的实验室技术的帮助下，提供了一个很好的机会，以确定和表征MS相关基因。这些信息可以转化为临床上有用的遗传生物标志物，并揭示新的治疗靶点。 公共卫生相关性：多发性硬化症（MS）是由中枢神经系统中有髓鞘束中断引起的严重神经功能障碍的常见原因。MS是仅次于创伤的年轻人神经功能障碍的第二大原因，影响全球约200万人，美国超过40万人。值得注意的是，MS的发病率似乎在上个世纪显著增加，并且这种增加可能主要发生在女性中。这种长期存在的疾病的社会经济后果是惊人的，因为75- 85%的患者最终失业，并处于社会孤立的高风险之中。保守估计表明，仅在美国，这种慢性疾病每年导致的医疗保健费用就超过2000亿美元。因此，MS是仅次于阿尔茨海默病的第二大最昂贵的神经系统疾病。尽管在治疗方面取得了重要进展，但目前可用的疾病修饰药物中没有一种令人信服地改变疾病的长期预后。临床表现是非常多样的，但很少有人知道这种变异性的根本原因。它可以从一种良性疾病变化到一种快速发展和致残的疾病。发病可能是突然的或潜伏的，早期症状可能很严重或看起来很微不足道，患者可能数月或数年不寻求医疗照顾。大多数患者最终经历进行性残疾，并且在发病后25年，大约80%的受影响个体将需要辅助治疗。因此，从长远来看，MS通常是一种严重的疾病，需要对受影响者及其家人进行深刻的生活方式调整。我们的目标是确定基因和基因特异性变异的编码产品参与MS易感性。为了实现我们的目标，我们将收集血液样本，从高、中和低MS风险人群中招募的大量个体中提取DNA。通过分析他们的基因组成，我们将能够了解MS遗传性的规则。我们预计可能有几个基因参与MS风险。这些基因可以独立或共同发挥作用，并与环境因素一起影响易感性。遗传性遗传变异的特定组合也可能决定症状何时出现或疾病如何进展。他们的鉴定将有助于确定MS的基本病因，改善风险评估，并影响治疗。