Title: Identification of drug targets for cardio-metabolic diseases through integration of proteome and trajectories of intermediates
Funder: The Academy of Medical Sciences

Abstract: Proteins are a major source of drug targets. Previously, I have used Mendelian randomization (MR, a genetic epidemiology method to infer causality) to identify proteins that reduce human disease risk. However, the causal intermediates linking proteins with diseases are still unclear. My hypothesis is that proteins changing the trajectories of the intended intermediates (e.g. blood pressure (BP) change over time) are more likely to be effective drug targets and have less adverse effects. In this project, I aim to understand the causal chain linking 5,135 plasma proteins (N=20,300), BP and Blood glucose (BGlu) change over ten years (N=79,836), and cardio-metabolic diseases (e.g. cardiovascular diseases and diabetes; N=898,130) in a MR framework. This work will attempt to answer four key questions: 1.What genetic variants are associated with plasma proteins? 2.What are the genetic variants associated with BP and BGlu changes? 3.How do BP and BGlu changes mediate the association between protein and cardio-metabolic diseases? 4.How do the MR findings compare with historical clinical trial evidence? Four objectives address these questions: 1.Meta-analysis of genome wide association studies (GWAS) of plasma proteins 2.GWAS of trajectories of BP and BGlu 3.Network MR linking proteins, trajectories of BP and BGlu, and cardio-metabolic diseases. 4.Integration of causal evidence of MR and drug trials Findings of this project will directly inform prioritisation of tractable drug targets for cardio-metabolic disease treatment. Results and analysis pipelines will be made openly available via platforms I developed/co-developed, e.g. MR-RCT, MR-Base and EpiGraphDB.

Lay abstract: Human proteins, as molecules in the body, are major sources of therapeutic drugs. My recent proteomics paper has identified hundreds of proteins that reduce the risk of a wide range of diseases and prioritised novel drugs. Now we need to understand whether intermediate traits (e.g. blood pressure and blood glucose (BP/BGlu) change over time) are on the causal pathway linking the proteins with diseases (e.g. cardio-metabolic diseases). Understanding these pathways will enable the development of more effective and safer drugs. The problem: On the pathways from proteins to cardio-metabolic diseases, the intermediate traits play key roles in linking the two. The hypothesis is that anti-hypertensive and anti-diabetic drugs reduce cardio-metabolic disease risk via changing BP/BGlu over time, but such hypothesis is still unproven. We can use genetic data to mimic this biological process and predict causal links. But the challenges now are 1) genetic studies of proteomics are in their infancy. Most proteins lack good data to conduct genetic analyses; 2) little genetic study of BP/BGlu change over time exists. The solution: In this award, I will combine protein data from three recent studies (N=20,300), and investigate genomic regions that influence BP/BGlu change over time from two large-scale biobanks (N=79,836). With these new results, I will estimate the causal links among proteins, BP/BGlu change over time and cardio-metabolic diseases (N=898,130). The impact: This work will give important insights into proteins that influence BP/BGlu change over time. This will support the design and development of new drugs for cardio-metabolic disease treatments.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE