Global and Local Genetic Ancestry Impacts on Differential Outcome of Systemic Lupus Erythematosus and Multiple Sclerosis

整体和局部遗传血统对系统性红斑狼疮和多发性硬化症不同结果的影响

• 批准号: 10668484
• 负责人: Olivia Solomon
• 金额: $ 4.49万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668484
• 关键词: Achievement; Affect; African American; Age; Age of Onset; Amerindian; Asian ancestry; Autoantibodies; Autoimmune Diseases; Biostatistical Methods; California; Cause of Death; Central Nervous System Diseases; Classification; Clinical; Clinical Data; Collaborations; Computing Methodologies; Data; Demyelinating Diseases; Diagnosis; Disease; Disease Outcome; Disparity; Early Intervention; Early treatment; East Asian; Environmental Exposure; Environmental Risk Factor; Epidemiologic Methods; Etiology; European; Faculty; Genetic; Genetic Risk; Genetic study; Genome; Genotype; Goals; Immune; Immunology; Impaired cognition; Individual; Institution; Knowledge; Lupus; Lupus Nephritis; Mediating; Mental Depression; Modification; Multiple Sclerosis; Not Hispanic or Latino; Other Genetics; Outcome; Passive Smoking; Patients; Persons; Population; Positioning Attribute; Postdoctoral Fellow; Prevalence; Process; Productivity; Prognosis; Quality of life; Race; Reporting; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Assessment; Risk Factors; Role; San Francisco; Severities; Severity of illness; Single Nucleotide Polymorphism; Smoking; Students; Study Subject; Systemic Lupus Erythematosus; Testing; Tobacco smoking behavior; Training; Underrepresented Populations; Universities; Variant; Work; burden of illness; candidate selection; clinical heterogeneity; cohort; disease heterogeneity; disease prognosis; disorder risk; epidemiology study; gene environment interaction; genetic risk factor; genetic variant; genome-wide; health disparity; improved; interest; machine learning algorithm; multi-ethnic; multidisciplinary; multiple sclerosis patient; nervous system disorder; programs; smoking exposure; social; targeted treatment; treatment strategy; whole genome; young adult; young woman

PROJECT SUMMARY The objective of our study is to identify ancestry related genetic variants contributing to differential risk of manifestations of both systemic lupus erythematosus (SLE) and multiple sclerosis (MS) in subjects of different genetic ancestries. SLE is an autoimmune disease with heterogenous features characterized by autoantibody formation and MS is an immune-mediated, demyelinating disorder. We will investigate the association between genetic ancestry and clinical outcomes of SLE and MS that are known to differ in prevalence and severity between SLE or MS patients of different races. Outcomes for SLE will include age of onset, autoantibody status, and lupus nephritis. Outcomes for MS will include age of onset, cognitive impairment, and MS severity score. We will study ~4,000 SLE and MS cases. In Aim 1, we will use ~2,000 SLE cases from the UCSF Lupus Genetics Study and California Lupus Epidemiology Study (CLUES) and ~2,000 MS cases from the Kaiser Permanente Northern California (KPNC) MS Research Program and Kaiser Permanente Southern California (KPSC) MS Sunshine Study to investigate the association of global ancestry and the outcomes of interest for SLE and MS. In Aim 2, we will investigate the association of local ancestry genome-wide and of candidate SLE and MS SNPs with the same clinical outcomes. In Aim 3, we will test for the association between both active and passive tobacco smoking and respective outcomes as well as test for gene-environment interaction between active and passive smoking and global and local ancestry. By establishing whether global and local genetic ancestry contribute to clinical heterogeneity and severity of SLE and MS, or if there are differences in gene-environment interaction with environmental exposures such as smoking, we might be able to target patients based on risk of disease outcomes by evaluating genetic ancestry of admixed patients. It might also be possible to predict disease manifestations and allow for early intervention and improved targeted treatment strategies limiting severity of disease and improving quality of life. This research project and associated training plan were developed in collaboration with my sponsor, Dr. Lisa Barcellos, co-sponsors, Drs. Lindsey Criswell and Laura Fejerman, and collaborators, Drs. Andres Cardenas and Priya Moorjani. The training plan emphasizes scientific productivity and building a strong knowledge of epidemiologic, biostatistical, and computational methods, as well as immunology and SLE and MS autoimmune disease processes. As a student at UC Berkeley, I am well supported by an institution that values rigorous scientific research and have access to many research and professional resources. Ultimately, the proposed research and achievement of the goals outlined in the training plan will allow me to become a multidisciplinary, independent investigator and facilitate my transition into a post-doctoral position and early-investigator faculty or research position.

项目总结 我们研究的目的是找出与血统相关的基因变异，这些变异会导致不同的风险。 系统性红斑狼疮(SLE)和多发性硬化症(MS)在不同疾病人群中的表现 基因祖先。系统性红斑狼疮是一种自身免疫性疾病，具有自身抗体的异质性特征。 形成和多发性硬化症是一种免疫调节的脱髓鞘疾病。我们将调查两者之间的联系 已知SLE和MS患病率和严重程度不同的SLE和MS的遗传祖先和临床结果 不同种族的SLE或MS患者。SLE的预后将包括发病年龄、自身抗体状态和狼疮。 肾炎。多发性硬化症的结果将包括发病年龄、认知障碍和多发性硬化症严重程度评分。我们会研究 约4000例系统性红斑狼疮和多发性硬化症。在目标1中，我们将使用来自加州大学旧金山分校狼疮遗传学研究的约2,000例SLE病例和 加州狼疮流行病学研究(线索)和来自北方Kaiser Permanente的约2,000例MS病例 加州(KPNC)MS研究计划和凯撒永久南加州(KPSC)MS阳光 研究目的2是调查全球血统与系统性红斑狼疮和多发性硬化症相关结果的相关性， 我们将调查当地祖先全基因组和候选SLE和MS SNPs与 同样的临床结果。在目标3中，我们将测试主动烟草和被动烟草之间的关联 吸烟与各自的结局以及基因-环境交互作用在主动和被动之间的检验 吸烟和全球和本地血统。通过确定全球和当地的遗传祖先是否有助于 系统性红斑狼疮和多发性硬化症的临床异质性和严重程度，或者基因-环境交互作用是否存在差异 对于吸烟等环境暴露，我们可能能够根据疾病风险来定位患者。 通过评估混血患者的遗传血统来评估结果。预测疾病也是可能的 并允许早期干预和改进的针对性治疗策略，以限制其严重程度 疾病和生活质量的提高。这项研究项目和相关的培训计划是在#年制定的 与我的赞助人，丽莎·巴塞洛斯博士，共同赞助人，林赛·克里斯韦尔博士和劳拉·费泽曼博士，以及 合作者安德烈斯·卡德纳斯博士和普里亚·穆尔贾尼。培训计划强调科学生产力 并建立流行病学、生物统计学和计算方法的深厚知识，以及 免疫学与系统性红斑狼疮和多发性硬化症自身免疫性疾病的进程。作为加州大学伯克利分校的一名学生，我得到了很好的支持 由一家重视严谨科学研究并能够接触到许多研究和专业人员的机构 资源。最终，拟议的研究和实现培训计划中概述的目标将使 我要成为一名多学科的独立研究员，并促进我向博士后的过渡 职位和早期研究员教职或研究职位。