Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis

Figure 1. Associations of LPL (red), ANGPTL4 (blue), and ANGPTL3 (green) genotype with lipoprotein lipids and fatty acids. The associations were scaled so that each genotype is associated with 1-SD (∼0.55 mmol/L) lower concentration of triglycerides. The associations were meta-analysed across six population cohorts, up to 61 240 participants. P(diff) denotes the P-value for the comparison of the metabolic associations of ANGPTL3 (or ANGPTL4) with those of the LPL genotype. Closed symbols: P < 0.0002; open symbols: P ≥ 0.0002. C, cholesterol; DHA, Docosahexaenoic acid; FA, fatty acids; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; TG, triglycerides; VLDL, very-low-density lipoprotein.

Figure 2. Associations of LPL (red), ANGPTL4 (blue), and ANGPTL3 (green) genotypes with the lipoprotein lipid compositions. Analyses details are as in Figure 1. TG% refers to the triglyceride concentration relative to total lipids within a single lipoprotein particle. Similar definition applied to C%. Closed symbols: P < 0.0002; open symbols: P ≥ 0.0002.

Figure 3. Associations of LPL (red), ANGPTL4 (blue), and ANGPTL3 (green) genotypes with non-lipid measures. Analyses details are as in Figure 1. Closed symbols: P < 0.0002; open symbols: P ≥ 0.0002.

Figure 4. The effects of LPL, ANGTPL4, ANGPLT3 genotypes on GlycA (left) and CPR (right) compared with the effects of triglycerides on these markers. Associations of the variants and GRSs with GlycA were analysed in the present study, whilst associations with CRP were meta-analysed from CHARGE and UKBB. Details on the triglyceride and LDL cholesterol GRS are given in Supplementary material online, Figures S7 and S8. Closed symbols: P < 0.01 (corrected for multiple testing 0.05/5). Open symbols: P ≥ 0.01.

Figure 5. Associations of LPL (red), ANGPTL4 (blue), and ANGPTL3 (green) genotypes with (A) risk factors and (B) cardiometabolic endpoints. The detailed information on the source data (consortia or UK Biobank) used here is summarized in Supplementary material online, Table S3. For fasting insulin, as the instrument SNP was not available, proxy SNPs were used (rs3850634 for ANGPTL3 and rs11991231 for LPL, R 2 > 0.85 with the instrument SNP). However, no proxy with R 2 > 0.85 was found for ANGPTL4 rs116843064 and thus the result is missing from the figure. BMI, body mass index; WHRadjBMI, Waist-to-hip ratio adjusted for BMI. Closed symbols: P < 0.0002; open symbols: P ≥ 0.0002.