Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation

Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome. We firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9, and NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4, and LPL). Conducting mendelian randomisation (MR) provided strong evidence of an effect of drug-based genetic scores on coronary artery disease (CAD) risk with the exception of ANGPTL3. We then systematically estimated the effects of each score on 249 metabolic traits…

• NI
  National Institute for Health and Care Research

  Award: MC_UU_00011/1
• BH
  British Heart Foundation

  Awards: MC_UU_00011/1, 18/23/33512, FS/18/23/33512
• UO
  University of Bristol

  Award: MC_UU_00011/1
• MR
  Medical Research Council

  Awards: MC_UU_00011/1, MC_UU_00011/1, MC_UU_00011