Genetic and Phenotypic Analysis of Multiple Sclerosis in Hispanics

西班牙裔多发性硬化症的遗传和表型分析

基本信息

批准号：
9490457
负责人：
Jacob L McCauley
金额：
$ 62.01万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9490457
关键词：
Address Adoption Affect Alleles Axon Caucasians Central Nervous System Diseases Chronic Clinical Complex Data Analyses Data Set Deterioration Development Disease Disease Outcome Disease susceptibility Environmental Exposure Etiology European Family member Follow-Up Studies Generations Genes Genetic Genetic Predisposition to Disease Genetic Variation Genetic study Genome Scan Genomics Genotype Gliosis HLA-DRB1 Hispanics Impairment Individual Inflammation International Light Longevity Meta-Analysis Methodology Morbidity - disease rate Multiple Sclerosis Myelin Nerve Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Pathology Patients Phenotype Population Populations at Risk Predisposition Prevalence Quality of life Reporting Research Risk Role Scanning Siblings Susceptibility Gene Technology Testing Time Twin Studies Underrepresented Populations United States Variant admixture mapping clinical heterogeneity cohort cost disability experience gene discovery genetic analysis genetic association genetic variant genome wide association study genome-wide improved neuroimmunologic disease novel racial and ethnic risk variant treatment response

项目摘要

PROJECT SUMMARY This application proposes to address the critical need to include underrepresented populations in genomic research, with the purpose of enhancing our understanding of the genetic and phenotypic landscape of multiple sclerosis in the Hispanic population. Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease of the central nervous system affecting more than 400,000 individuals in the United States. MS is characterized by chronic inflammation, myelin loss, gliosis, and varying degrees of axonal pathology which impair saltatory conduction along axons that is necessary for normal functioning of nerve impulses. MS has an undetermined etiology and results in episodic or progressive neurological dysfunction. Although life span is modestly shortened, most patients experience increasing disability and consequent deterioration in quality of life. MS thus carries a significant morbidity that takes an immeasurable toll on the patients and their family members. The involvement of genetic factors in MS has long been appreciated. However, the clinical heterogeneity and complex etiology of MS have been confounding factors for genetic studies. While the first confirmed MS genetic association (with the HLA-DRB1*1501 allele) was identified in the early 1970's, further gene discoveries were limited until late 2007. At that time, we demonstrated that a common non-synonymous functional SNP in the IL7RA gene was associated with an increased risk of MS. This result was confirmed in the first genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC). These breakthroughs, along with both statistical and technological advances, have led to the identification and confirmed association of >190 genetic variants for MS susceptibility. Despite these advances, we have only uncovered a relatively small proportion of the genetic influences in MS. Much is yet to be understood regarding the role of these and other genes in MS. We must explore how these known genetic factors influence not only disease susceptibility, but disease outcomes, therapeutics, and responses to environmental exposures. While current research findings are unraveling the genetic underpinnings of individuals with Northern European genetic ancestry, large genetic studies of MS in Hispanics have yet to be realized. Moreover, the generalization of current findings to individuals of different genetic ancestry is a significant and unanswered question, especially in light of the reported differences in prevalence, clinical course, and progression of MS across various ancestral populations. We hypothesize that observed phenotypic differences between racial/ethnic populations are influenced by population-specific genetic factors. Our proposal seeks to broaden our understanding of the genetic etiology of multiple sclerosis, with a specific focus on performing the first battery of comprehensive analyses to elucidate the genetic and phenotypic manifestations of MS in the diverse Hispanic population, an understudied group that represents a rapidly growing percentage of the US population. To achieve this, we propose three specific aims: 1) Characterize established MS risk loci within a Hispanic patient cohort; 2) Perform genome-wide scans to identify novel genetic loci for MS susceptibility; 3) Explore genotype-phenotype correlations across racial/ethnic populations.

项目概要该应用旨在解决将代表性不足的人群纳入基因组中的迫切需求研究，旨在增强我们对多种遗传和表型景观的理解西班牙裔人口中的硬化症。多发性硬化症 (MS) 是一种使人衰弱的神经免疫学和中枢神经系统的神经退行性疾病影响了美国超过 400,000 人国家。 MS 的特点是慢性炎症、髓磷脂缺失、神经胶质增生和不同程度的轴突损伤。损害沿轴突的跳跃传导的病理学，这是神经正常功能所必需的冲动。 MS 的病因尚未确定，可导致阵发性或进行性神经功能障碍。尽管寿命略有缩短，但大多数患者的残疾和随之而来的残疾越来越严重生活质量恶化。因此，多发性硬化症具有显着的发病率，给患者造成不可估量的损失。患者及其家人。遗传因素与多发性硬化症的关系早已被人们认识到。然而，MS 的临床异质性和复杂的病因一直是遗传因素的混杂因素。研究。虽然第一个确认的 MS 遗传关联（与 HLA-DRB1*1501 等位基因）是在 1970 年代初，进一步的基因发现受到限制，直到 2007 年末。当时，我们证明了一个共同的基因 IL7RA 基因中的非同义功能性 SNP 与 MS 风险增加相关。这个结果国际多重基因组关联研究（GWAS）证实了这一点硬化症遗传学联盟 (IMSGC)。这些突破以及统计和技术方面的突破进展已导致超过 190 个遗传变异与 MS 易感性的关联的鉴定和证实。尽管取得了这些进展，我们只发现了 MS 中相对较小部分的遗传影响。关于这些基因和其他基因在多发性硬化症中的作用还有很多待了解。我们必须探索这些已知的遗传因素不仅影响疾病的易感性，还影响疾病的结果、治疗方法和对环境暴露的反应。虽然目前的研究结果正在揭示遗传基础对于具有北欧遗传血统的个体，西班牙裔多发性硬化症的大规模遗传学研究尚未开展意识到了。此外，将当前的研究结果推广到不同遗传祖先的个体是一个这是一个重要且尚未解答的问题，特别是考虑到所报告的患病率、临床病程、以及 MS 在不同祖先人群中的进展。我们假设观察到的表型种族/族裔人群之间的差异受到人群特定遗传因素的影响。我们的建议旨在扩大我们对多发性硬化症遗传病因学的理解，特别关注进行第一组综合分析以阐明遗传和表型表现多发性硬化症在不同西班牙裔人群中的比例，这是一个未被充分研究的群体，其比例正在快速增长的美国人口。为了实现这一目标，我们提出了三个具体目标：1) 描述已建立的多发性硬化症风险位点的特征在西班牙裔患者队列中； 2) 进行全基因组扫描以确定 MS 的新遗传位点易感性； 3) 探索跨种族/族裔群体的基因型-表型相关性。