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: 10505838
• 负责人: Olivia Solomon
• 金额: $ 4.31万
• 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/10505838
• 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; Clinical; Clinical Data; Collaborations; Computing Methodologies; Data; Demyelinating Diseases; Disease; Disease Outcome; Early Intervention; Early treatment; East Asian; 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; 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; base; burden of illness; clinical heterogeneity; cohort; disease heterogeneity; disease prognosis; 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.

项目概要 我们研究的目的是确定导致不同风险的祖先相关遗传变异 系统性红斑狼疮 (SLE) 和多发性硬化症 (MS) 在不同人群中的表现 遗传血统。 SLE 是一种具有异质性特征的自身免疫性疾病，其特征是自身抗体 MS 是一种免疫介导的脱髓鞘疾病。我们将调查之间的关联 SLE 和 MS 的遗传血统和临床结果已知在患病率和严重程度方面存在差异 不同种族的 SLE 或 MS 患者。 SLE 的结果将包括发病年龄、自身抗体状态和狼疮 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 约 4,000 例 SLE 和 MS 病例。在目标 1 中，我们将使用来自 UCSF 狼疮遗传学研究的约 2,000 个 SLE 病例， 加州狼疮流行病学研究 (CLUES) 和来自 Kaiser Permanente Northern 的约 2,000 例多发性硬化症病例 加州 (KPNC) MS 研究项目和南加州凯撒医疗机构 (KPSC) MS Sunshine 研究调查全球血统与 SLE 和 MS 的相关结果之间的关联。在目标 2 中， 我们将研究本地血统全基因组以及候选 SLE 和 MS SNP 与 相同的临床结果。在目标 3 中，我们将测试主动烟草和被动烟草之间的关联 吸烟及其各自的结果以及主动和被动之间基因-环境相互作用的测试 吸烟以及全球和当地的血统。通过确定全球和当地的遗传血统是否有助于 SLE 和 MS 的临床异质性和严重程度，或者基因-环境相互作用是否存在差异 对于吸烟等环境暴露，我们也许能够根据疾病风险来定位患者 通过评估混合患者的遗传血统来评估结果。也有可能预测疾病 表现并允许早期干预和改进有针对性的治疗策略，限制严重程度 疾病和改善生活质量。该研究项目和相关培训计划于 与我的赞助商 Lisa Barcellos 博士、共同赞助商 Drs. 的合作。林赛·克里斯韦尔和劳拉·费杰曼，以及 合作者，博士。安德烈斯·卡德纳斯和普莉娅·穆尔贾尼。培养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丰富知识，以及 免疫学以及 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 由一个重视严格科学研究并能够获得许多研究和专业知识的机构 资源。最终，拟议的研究和培训计划中概述的目标的实现将允许 我成为一名多学科的独立研究者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。