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

该项目分为三个阶段，每个阶段都为学生提供不同但互补的研究技能：在第一阶段（2017年9月至2019年3月），学生将识别影响慢性肾脏疾病（CKD）中改变的循环因子水平的人类遗传变异，并与不良心脏事件相关。这些循环因子包括EPO和MR-proADM，它们是hif信号的中介，hif信号是GSK药物达普罗司他的关键通路靶点。然而，这些因素在不良心脏事件中的因果作用尚不确定。该学生将对新数据进行全基因组研究，并对现有数据进行meta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mrp - proadm数据。我们还将推进TMPRSS6基因的第三阶段已知变体，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。已经确定的变体包括与循环MR-proADM水平相关的三个基因中的变体，以及与循环EPO水平相关的EPO基因附近的变体。在第二阶段（2019年4月至2020年3月），学生将与GSK主管合作，使用电子医疗记录在英国生物银行中得出不良心脏事件的测量方法。由于在项目过程中，50万英国生物银行参与者的年龄将在51岁至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年心血管疾病病例将达到2万例，其中包括5000例中风。在第三阶段（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EPO、MR-proADM和血红蛋白（因TMPRSS6基因变异而升高）较高循环水平对心脏不良事件的因果作用。学生将使用在第一阶段确定的基因变异作为“工具”来测试这些特征与不良心脏结果之间的因果关系。高血压和高血压将是次要结局，因为高血压与心血管疾病有关，CKD患者的高血压发病率更高。基因变异作为暴露特征的明确代理——这里是EPO， MR-proADM或血红蛋白——用于检测与结果特征的关联——这里是MACE，高血压和高血压。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，没有两个研究小组将以完全相同的方式解决同一个研究问题，学生将被安排在一个领先的、经验丰富的研究团队中。

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.