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

全球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: 10315167
• 负责人: Olivia Solomon
• 金额: $ 4.2万
• 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/10315167
• 关键词: Achievement; Affect; African American; Age; Age of Onset; Amerindian; Asians; Autoantibodies; Autoimmune Diseases; Biostatistical Methods; California; Cause of Death; Central Nervous System Diseases; Clinical; Clinical Data; Collaborations; Computing Methodologies; Data; Demyelinating Diseases; Disease; Disease Outcome; Early Intervention; Early treatment; Environmental Exposure; Environmental Risk Factor; Epidemiologic Methods; European; Faculty; Genetic; Genetic Risk; Genetic study; Genome; Genotype; Goals; Immune; Immunology; Impaired cognition; Individual; Institution; Knowledge; Lead; Lupus; Lupus Nephritis; Mediating; Modification; Multiple Sclerosis; Not Hispanic or Latino; Other Genetics; Outcome; Passive Smoking; Patients; 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; base; burden of illness; clinical heterogeneity; cohort; disease heterogeneity; disorder risk; epidemiology study; gene environment interaction; 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

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.

项目摘要 我们研究的目的是确定与祖先相关的遗传变异，从而导致差异风险 全身性红斑狼疮（SLE）和多发性硬化症（MS）的表现 遗传祖先。 SLE是一种自身免疫性疾病，具有自身抗体特征的异质特征 形成和MS是一种免疫介导的脱髓鞘疾病。我们将调查 已知在遗传血统和SLE和MS的临床结局在患病率和严重程度上有所不同 SLE或MS患者的不同种族。 SLE的结果将包括发病时代，自动抗体状态和狼疮 肾炎。 MS的结果将包括发病年龄，认知障碍和MS严重程度评分。我们将学习 〜4,000 SLE和MS案件。在AIM 1中，我们将使用UCSF狼疮遗传学研究和 加利福尼亚狼疮流行病学研究（线索）和约2,000毫秒的病例来自Kaiser Permanente Northern 加利福尼亚（KPNC）MS研究计划和Kaiser Permanente南加州（KPSC）MS Sunshine 研究全球血统的关联以及SLE和MS感兴趣的结果。在AIM 2中， 我们将调查局部祖先基因组以及候选SLE和MS SNP与 相同的临床结果。在AIM 3中，我们将测试主动烟草和被动烟草之间的关联 吸烟和各自的结果以及活性和被动之间的基因环境相互作用的测试 吸烟以及全球和地方血统。通过确定全球和地方遗传血统是否有助于 SLE和MS的临床异质性和严重程度，或者如果基因 - 环境相互作用差异 随着环境暴露（例如吸烟），我们可能能够根据疾病的风险来针对患者 通过评估混合患者的遗传血统来结局。也可以预测疾病 表现并允许早期干预并改善目标治疗策略限制了严重程度 疾病和改善生活质量。该研究项目和相关的培训计划是在 与我的赞助商丽莎·巴塞洛斯（Lisa Barcellos）博士合作，共同发起人，博士。 Lindsey Criswell和Laura Fejerman，以及 合作者，博士。 Andres Cardenas和Priya Moorjani。培训计划强调科学生产力 并建立关于流行病学，生物统计和计算方法的知识，以及 免疫学和SLE和MS自身免疫性疾病过程。作为加州大学伯克利分校的学生，我得到了很好的支持 通过一个重视严格科学研究并获得许多研究和专业的机构 资源。最终，培训计划中概述的目标的拟议研究和实现将允许 我成为一名多学科的独立研究者，并促进我过渡到博士后 职位和早期评估教职员工或研究职位。