Emerging antihypertensive therapies and cardiovascular, kidney, and metabolic outcomes: a Mendelian randomization study

Figure 1. Study design. AGTi, angiotensinogen inhibitor; ERA, endothelin receptor antagonist; sGCs, soluble guanylate cyclase stimulator; PDE5i, phosphodiesterase type 5 inhibitor; SBP, systolic blood pressure; GWAS, genome-wide association study; SNP, single nucleotide polymorphism; eQTL, expression quantitative loci; MR, Mendelian randomization; SMR, summary-based Mendelian randomization; CKM, cardiovascular kidney and metabolic; IVW, inverse-variance weighted; GWAS, genome-wide association studies; (*) indicates a blood pressure GWAS meta-analysis.12

Figure 2. MR estimates for the effect of genetically reduced BP through antihypertensive drug target perturbation on outcomes. Data were represented as OR with 95% CI of the outcome per 10 mmHg decrease in SBP. AGTi, angiotensinogen inhibitor; ERAs, endothelin receptor antagonists; PDE5i, phosphodiesterase type 5 inhibitors; sGCs; soluble guanylate cyclase stimulators; AF, atrial fibrillation; CAD, coronary artery disease; MI myocardial infarction; HF, heart failure; T2D, type 2 diabetes; CKD, chronic kidney disease.

Figure 3. SMR results. The x-axis represents the β estimates from SMR analysis, and the y-axis represents the −log10(PSMR). The circle signifies the corresponding gene that encodes the protein targeted by the antihypertensive drug class (PDE5A gene – PDE5 inhibitors, GUCY1A3 gene – sGC stimulators, AGT gene – AGT inhibitors). βSMR were estimates from SMR analysis per 1 unit increase in the expression of the genes in a particular tissue. βSMR < 0 suggests that an increase in gene expression levels in a particular tissue was associated with a decreased disease risk, and vice versa. The upper horizontal dashed line represents the −log10 of the Bonferroni-corrected P-value (0.0003), corresponding to −log10(pSMR) = 3.523, while the lower horizontal dashed line indicates the −log10 of the nominal P-value (0.05), equivalent to −log10(pSMR) = 1.301. The asterisk indicates HEIDI P> 0.01; AAo, artery aorta; Atib, artery tibial; BCH, brain cerebellar hemisphere; BC, brain cerebellum; Thy, thyroid; HAA, heart atrial appendage; AGTi, angiotensinogen inhibitor; PDE5i, phosphodiesterase type 5 inhibitors; sGCs; soluble guanylate cyclase stimulators.

Figure 4. Results from MR, SMR, and colocalization analyses. From left to right, the first graph shows MR results for PDE5 inhibitors (PDE5i) and sGC stimulators (sGCs) with associated outcomes. The second graph shows SMR results for PDE5A and GUCY1A3 and outcomes. The third graph shows the PP (%) for the scenario of distinct causal variants (H3) and of shared causal variant (H4) for the two traits—gene expression level and outcome risk. AAo, artery aorta; Atib, artery tibial; Thy, thyroid. CAD, coronary artery disease; MI, myocardial infarction; CKD, chronic kidney disease; T2D, type 2 diabetes.