Investigating Effects of Plasma Apolipoprotein E on Ischemic Heart Disease Using Mendelian Randomization Study

Background: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). Methods: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. Results: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. Conclusions: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.