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

项目摘要 我们研究的目的是确定与祖先相关的遗传变异， 系统性红斑狼疮（SLE）和多发性硬化（MS）在不同的受试者中的表现 遗传祖先系统性红斑狼疮（SLE）是一种以自身抗体为特征的异质性自身免疫性疾病 MS是一种免疫介导的脱髓鞘疾病。我们将调查 SLE和MS的遗传血统和临床结局，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的结局将包括发病年龄、自身抗体状态和狼疮 肾炎MS的结局将包括发病年龄、认知障碍和MS严重程度评分。我们将研究 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例SLE病例， 加州狼疮流行病学研究（CLUES）和来自Kaiser Permanente北方的约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 研究全球血统与SLE和MS关注结果的相关性。在目标2中， 我们将研究地方祖先全基因组和候选SLE和MS SNPs与SLE和MS的关联。 相同的临床结果。在目标3中，我们将测试主动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吸烟之间的基因-环境相互作用的测试 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 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 对于环境暴露，如吸烟，我们可能能够根据疾病风险来定位患者， 结果通过评估混合患者的遗传祖先。也有可能预测疾病 临床表现，并允许早期干预和改善有针对性的治疗策略，限制严重程度 疾病和改善生活质量。该研究项目和相关的培训计划是在 与我的赞助商，丽莎贝洛斯博士，共同赞助商，林赛克里斯韦尔博士和劳拉Fejerman， Andres Cardenas博士和Priya Moorjani博士。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强大知识，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， 由一个重视严谨科学研究的机构，并有机会获得许多研究和专业知识， 资源最终，拟议的研究和实现培训计划中概述的目标将使 我成为一个多学科的，独立的研究者，并促进我过渡到博士后 职位和早期调查员教师或研究职位。

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.