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

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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.