The role of natural selection in SLE risk among African-Americans

自然选择在非裔美国人 SLE 风险中的作用

• 批准号: 8805337
• 负责人: Paula Sofia Ramos
• 金额: $ 12.91万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-12 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805337
• 关键词: Admixture; Affect; Africa; African; African American; Alleles; Amino Acids; Area; Autoimmune Diseases; Autoimmunity; Binding Sites; Bioinformatics; Biological; Caucasians; Cell Line; Chromatin; Clinical Research; Complex; DNA Methylation; Data; Data Set; Detection; Development; Diagnosis; Disease; Disease susceptibility; Environment; Etiology; European; Evolution; Extramural Activities; Fibrosis; Frequencies; Future; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomic Segment; Genomics; Goals; Haplotypes; High Prevalence; Human; Human Genome; Immune response; Incidence; Inflammation; Island; Knowledge; Lead; Length; Lupus; Medical; Medicine; Mentorship; Messenger RNA; MicroRNAs; Natural History; Natural Selections; Nature; Outcome; Population; Population Genetics; Predisposition; Prevalence; Public Health; Quantitative Trait Loci; Research; Research Infrastructure; Research Personnel; Research Training; Resources; Rheumatism; Rheumatology; Risk; Role; Sampling; Scanning; Sea; Sequence Analysis; Severities; Severity of illness; Shapes; Sierra Leone; Signal Transduction; Source; South Carolina; Structure; Systemic Lupus Erythematosus; Testing; Training; Universities; Variant; base; career; computerized tools; database of Genotypes and Phenotypes; disorder risk; gene discovery; genome-wide; health disparity; histone modification; improved; indexing; innovation; insight; monocyte; multidisciplinary; pressure; programs; public health relevance; risk variant; sample fixation; skills; statistics; success; targeted treatment; therapy development; trait; transcription factor; translational study

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a severe autoimmune disorder that disproportionately affects African Americans (AA). Despite tremendous progress in elucidating its genetic etiology, research has been mainly limited to Caucasians, and little progress has been made in the identification of the specific disease-predisposing functional variations. Since the genome structure of a population is influenced by environmental pressures, and immune responses are particularly sensitive to the environment, it is possible that, throughout evolution, population-specific positive natural selection has led to a increased frequency of alleles that also predispose to autoimmune diseases like SLE. The goal of this project is to discover functional SLE risk variants in AAs while improving our understanding of the genetic basis of SLE that is due to natural selection. In order to accomplish this, Dr. Ramos will (1) identify regions of the genome that have been the target of recent positive natural selection in AA using two complementary population genetics statistics, (2) identify regions that are both predisposing to SLE and under selection, and (3) compute thorough functional annotation of the adaptive SLE risk variants to identify adaptive functional variation associated with SLE. Dr. Ramos is a human geneticist in the Division of Rheumatology at the Medical University of South Carolina (MUSC). Her long-term career goal is to become an independent translational researcher in the genetics of autoimmunity. To facilitate her transition into an independent investigator, she seeks to further her skills and broaden the multidisciplinary nature of her research by training in population and evolutionary genetics, and bioinformatics and computational tools for the analysis of high-dimensional large-scale datasets. The environment for the success of Dr. Ramos is provided by (1) a mentorship team with the mentorship track record and varied expertise needed to support her project, (2) the availability of samples from unique African American and African populations and the established infrastructure to continue and expand studies on these populations, (3) support from the endowed Smart State Center in Inflammation and Fibrosis, the Multidisciplinary Clinical Research Center (MCRC) for Rheumatic Diseases in African Americans, and the growing Center Genomic Medicine, and (4) the Department of Medicine's robust mentorship program. The identification of functional adaptive alleles that contribute to SLE risk in AA will contributeto an understanding of the role of positive natural selection in shaping SLE risk and vastly improve knowledge about the etiology of SLE in AA. These results will provide critical preliminary data supporting extramural applications to conduct focused analysis of sequence data, functional studies, expand to other populations and to other autoimmune diseases. The training will enable Dr. Ramos to achieve her long-term objective of becoming an independent investigator leading multidisciplinary teams conducting innovative genomic research in autoimmune disease.

 描述（由申请人提供）：系统性红斑狼疮 (SLE) 是一种严重的自身免疫性疾病，对非裔美国人 (AA) 的影响尤为严重，尽管在阐明其遗传病因方面取得了巨大进展，但研究主要限于白种人，且进展甚微。由于群体的基因组结构受到环境压力的影响，并且免疫反应对环境特别敏感，因此有可能，在整个进化过程中，特定人群的积极自然选择导致等位基因频率增加，这些等位基因也易患 SLE 等自身免疫性疾病。该项目的目标是发现 AA 中的功能性 SLE 风险变异，同时增进我们对 SLE 遗传基础的理解。为了实现这一目标，拉莫斯博士将 (1) 使用两个互补的群体遗传学统计数据来识别最近在 AA 中成为积极自然选择目标的基因组区域，(2) 识别出两者都有倾向Ramos 博士是南卡罗来纳医科大学 (MUSC) 风湿病学系的人类遗传学家。她的长期职业目标是成为一名自身免疫遗传学的独立转化研究员，为了促进她向独立研究者的转变，她寻求通过人口和疾病方面的培训来提高她的技能并扩大她的研究的多学科性质。进化的用于分析高维大规模数据集的遗传学、生物信息学和计算工具 Ramos 博士的成功环境是由 (1) 一个导师团队提供的，该团队拥有支持她的项目所需的导师记录和各种专业知识。 ，（2）来自独特的非裔美国人和非洲人群的样本的可用性以及继续和扩大对这些人群的研究的现有基础设施，（3）来自捐赠的智能州炎症和纤维化中心、多学科临床研究中心（MCRC）的支持) )非洲裔美国人风湿病和不断发展的基因组医学中心，以及 (4) 医学部强大的指导计划，确定导致 AA 中 SLE 风险的功能适应性等位基因将有助于理解积极自然的作用。这些结果将提供支持外部应用的关键初步数据，以进行序列数据的集中分析、功能研究，并扩展到其他人群和其他自身免疫性疾病。该培训将使拉莫斯博士能够实现她的长期目标，即成为一名独立研究者，领导多学科团队进行自身免疫性疾病的创新基因组研究。