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（应用程序提供）：全身性红斑狼疮（SLE）是一种严重的自身免疫性疾病，对非裔美国人（AA）的影响不成比例。尽管在阐明其遗传病因方面取得了巨大进展，但研究主要仅限于高加索人，在鉴定特定疾病的功能变化方面几乎没有取得进展。由于人口的基因组结构受环境压力的影响，免疫调查剂对环境特别敏感，因此，在整个进化过程中，特定于人群的阳性自然选择可能导致等位基因的频率增加，而这些等位基因的频率也增加了，这种频率也易于自身免疫性疾病，例如SLE。该项目的目的是在AAS中发现功能性SLE风险变体，同时提高我们对自然选择造成的SLE遗传基础的理解。为了实现这一目标，Ramos博士（1）使用两个完整的人群遗传学统计数据，确定已成为AA近期自然选择的目标区域，（2）确定既倾向于SLE和选择的区域，以及（3）计算适应性SLE的彻底功能性的SLEINT，以确定与适应性差异相关的适应性SLEINT。 Ramos博士是南卡罗来纳州医科大学（MUSC）风湿病学系的人类遗传学家。她的长期职业目标是成为自身免疫遗传学的独立翻译研究员。为了促进自己向独立研究者的过渡，她试图通过人口和进化遗传学的培训以及生物信息学和计算工具来进一步扩大自己的技能，并扩大其研究的多学科性质，以分析高维大型数据集。 （1）一个心态跟踪和支持她的项目所需的专业知识的心态团队提供了Ramos博士成功的环境；在非洲裔美国人和不断发展的中心基因组医学中，以及（4）医学系强大的心态计划。在AA中导致SLE风险的功能自适应等位基因的鉴定将有助于理解积极自然选择在塑造SLE风险中的作用，并大大提高AA中SLE病因的知识。这些结果将提供关键的初步数据，支持壁外应用，以对序列数据，功能研究，扩展到其他人群以及其他自身免疫性疾病进行重点分析。该培训将使拉莫斯博士能够实现她的长期目标，成为一支独立的研究人员领导的多学科团队，从事自身免疫性疾病的创新基因组研究。