Using proteomics to identify the mechanisms underlying the benefits of statins on ischemic heart disease

Ischemic heart disease (IHD) is the single leading cause of mortality globally. Statins are the mainstay for IHD treatment. However, the specific mechanisms underlying statins' benefits on IHD have not been clarified. To examine the mechanisms through proteins, we used two-step Mendelian randomization (MR) approach. First, we examined the associations of genetically mimicked statins with 2923 proteins using genome-wide association of proteins from the UK Biobank Pharma Proteomics Project (UKB-PPP) to identify the proteins affected by statins, and replicated the findings using deCODE. Then we examined the associations of selected proteins with IHD risk using CARDIoGRAMplusC4D using MR, and replicated using FinnGen, and using another set of genetic instruments from deCODE. We selected proteins decreased or increased IHD risk and meanwhile increased or lowered by statins. We further examined the role of the selected protein(s) on common IHD comorbidities, including diabetes, chronic kidney disease (CKD), and kidney function (measured by estimated glomerular filtration rate (eGFR)). Nine proteins were affected by statins, including four proteins (PLA2G7, FGFBP1, ANGPTL1, and PTPRZ1) lowered by statins, and five proteins (EFNA4, COL6A3, ASGR1, PRSS8 and PCOLCE) increased by statins. Among these, PLA2G7 was related to higher risk of IHD after controlling for multiple testing. The associations were robust to different analytic methods and replication using another set of genetic instrument from deCODE, and using another GWAS of IHD from FinnGen. Genetically predicted PLA2G7 had null association with diabetes, CKD, and eGFR. We identified 9 proteins affected by statins, including 7 novel proteins which were not reported previously. PLA2G7 is on the pathway underlying statins' benefits on IHD. The clarification of statins' mechanisms had close relevance to precision medicine, and provided insights to the development of new treatment strategies.