The role of common genetic variants for predicting the modulation of cardiovascular outcomes

常见遗传变异在预测心血管结局调节中的作用

• 批准号: 1930042
• 金额: --
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1930042
• 关键词: role; common; genetic; variants; predicting

There are three stages to the project, each providing the student with a different but complementary set of research skills:In stage 1 (Sept 2017-March 2019) the student will identify human genetic variants that influence circulating levels of factors that are altered in chronic kidney disease (CKD) and are associated with adverse cardiac events. These circulating factors include EPO and MR-proADM as intermediaries of HIF-signaling, the key pathway target of GSK's agent daprodustat. However, the causal role of these factors in adverse cardiac events is uncertain. The student will perform genome wide studies of new data and perform meta analyses with existing data, including EPO data from 6200 individuals from 3 studies - InCHIANTI (N=1200), PREVEND (N=2506) and HealthABC (N=2488) and MR-proADM data from 8914 individuals from two published studies - PREVEND (6674) and Atherogene (2240). We will also take forward into stage 3 known variants in the TMPRSS6 gene, that are associated with Haemoglobin, and the protein product of which is associated with the relevant pathway - HIF signaling. Variants already identified include those in three genes associated with circulating MR-proADM levels and a variant near the EPO gene associated with circulating EPO levels.In stage 2 (April 2019-March 2020) the student will work with GSK supervisors to derive measures of adverse cardiac events in the UK Biobank using electronic medical records. Because the 500,000 UK Biobank participants will be aged 51 to 85 during the course of the project, and the electronic health records are being updated every 6 months, the student will have access to one of the most powerful population based cohort studies of incident disease in real time. Conservative estimates of incident cardiovascular disease cases by 2020 are 20,000, including 5000 strokes.In stage 3 (April 2020-October 2021) the student will use the genetic approach of Mendelian Randomization to test the causal role of higher circulating levels of EPO, MR-proADM and Haemoglobin (as raised by TMPRSS6 gene variants ) on adverse cardiac events. The student will use the genetic variants identified in stage 1 as "instruments" to test the causal relationship between these traits and adverse cardiac outcomes. Hypertension and higher blood pressure will be secondary outcomes, since hypertension is associated with cardio-vascular disease and patients with CKD have a higher incidence of hypertension. The genetic variants act as an unconfounded proxy for the exposure trait - here EPO, MR-proADM or Haemoglobin - to be tested for association with the outcome traits - here MACE, Hypertension and higher blood pressure. The risk of the project is that other people have access to the UK Biobank data. However, no two research groups will be addressing the same research question in exactly the same way and the student will be well placed in a leading, highly experienced research team.

该项目分为三个阶段，每个阶段为学生提供一套不同但互补的研究技能：在第 1 阶段（2017 年 9 月至 2019 年 3 月），学生将识别影响慢性肾病 (CKD) 中改变的因子循环水平的人类遗传变异，这些变异与不良心脏事件相关。这些循环因子包括作为 HIF 信号传导中介的 EPO 和 MR-proADM，HIF 信号传导是 GSK 药物 daprodustat 的关键途径靶点。然而，这些因素在不良心脏事件中的因果作用尚不确定。学生将对新数据进行全基因组研究，并对现有数据进行荟萃分析，包括来自 3 项研究（InCHIANTI (N=1200)、PREVEND (N=2506) 和 HealthABC (N=2488)）的 6200 名个体的 EPO 数据，以及来自两项已发表研究（PREVEND (6674) 和 Atherogene (2240)）的 8914 名个体的 MR-proADM 数据。我们还将进入第三阶段 TMPRSS6 基因的已知变体，这些变体与血红蛋白相关，其蛋白质产物与相关途径 - HIF 信号传导相关。已经确定的变异包括与循环 MR-proADM 水平相关的三个基因中的变异，以及与循环 EPO 水平相关的 EPO 基因附近的变异。在第二阶段（2019 年 4 月至 2020 年 3 月），学生将与葛兰素史克主管合作，利用电子病历得出英国生物库中不良心脏事件的测量结果。由于 500,000 名英国生物银行参与者在项目期间年龄将在 51 至 85 岁之间，并且电子健康记录每 6 个月更新一次，因此学生将能够实时访问最强大的基于人群的突发疾病队列研究之一。保守估计，到 2020 年，心血管疾病事件病例数为 20,000 例，其中包括 5000 例中风。在第 3 阶段（2020 年 4 月至 2021 年 10 月），学生将使用孟德尔随机化的遗传方法来测试较高循环水平的 EPO、MR-proADM 和血红蛋白（由 TMPRSS6 基因变异引起）对不良心脏事件的因果作用。学生将使用第一阶段中确定的遗传变异作为“工具”来测试这些特征与不良心脏结果之间的因果关系。高血压和血压升高将是次要结局，因为高血压与心血管疾病相关，而 CKD 患者的高血压发病率较高。遗传变异作为暴露特征（这里是 EPO、MR-proADM 或血红蛋白）的无混杂代理，将被测试与结果特征（这里是 MACE、高血压和高血压）的关联。该项目的风险在于其他人可以访问英国生物银行的数据。然而，没有两个研究小组会以完全相同的方式解决相同的研究问题，学生将在一个领先的、经验丰富的研究团队中处于有利地位。