Genetically proxied inhibition of angiotensinogen synthesis is associated with lower cardiovascular risk

Background and AimsAngiotensinogen synthesis inhibitors have shown promising blood pressure-lowering effects in early-stage trials, but their impact on cardiovascular outcomes remains unknown. We investigated associations between genetic variants mimicking angiotensinogen synthesis inhibition and cardiovascular phenotypes. MethodsWe developed a genetic proxy for hepatic angiotensinogen synthesis downregulation comprising AGT variants that lower liver AGT expression (N=1,183) and circulating angiotensinogen levels (N=47,745), selected to mimic the effects of RNA-based angiotensinogen-targeting therapies. Using drug-target Mendelian randomization, we assessed effects on coronary artery disease (210,842 cases, 1,167,328 controls), stroke (110,182 cases, 1,503,898 controls) and heart failure (207,306 cases, 2,151,210 controls), along with vascular endophenotypes and safety outcomes. ResultsMirroring pharmacological angiotensinogen synthesis inhibitors in trials, the AGT genetic instrument was associated with lower systolic (SBP, -0.60 [-0.71;-0.48] mmHg) and diastolic blood pressure (DBP, -0.40 [-0.46;-0.33] mmHg), and higher renin and potassium levels. Genetically proxied angiotensinogen synthesis inhibition was associated with lower odds of coronary artery disease (OR per mmHg SBP reduction: 0.954 [0.937-0.972]), stroke (OR: 0.949 [0.928-0.970]) and heart failure (OR: 0.972 [0.957-0.987]) with effect sizes proportional to the SBP-lowering effects of genetic proxies for other renin-angiotensin-aldosterone system drug classes. We found additional associations with lower burden of atherosclerosis, cerebral small vessel disease, and adverse cardiac remodeling on imaging endophenotypes. Aside from hyperkalemia, we detected no links to major safety concerns, including impaired kidney function. ConclusionsGenetic downregulation of angiotensinogen synthesis is associated with lower cardiovascular disease burden without concerning safety signals, supporting the potential of angiotensinogen inhibitors to reduce cardiovascular risk. Structured graphical abstractO_ST_ABSKey QuestionC_ST_ABSIs there human genetic evidence suggesting that inhibition of hepatic angiotensinogen synthesis can reduce long-term cardiovascular risk? Key FindingGenetically proxied angiotensinogen synthesis inhibition is associated with lower risk of coronary artery disease, stroke and heart failure, as well as favorable effects on cardiac and cerebrovascular pathologies, without raising major safety concerns. Effect estimates were comparable in magnitude to those observed for genetic proxies of approved RAAS-blocking therapies. Take-home MessageHuman genetic evidence supports the hypothesis that angiotensinogen synthesis inhibition may reduce both cardiovascular event risk and chronic subclinical vascular disease burden, providing a strong rationale for prioritizing angiotensinogen inhibitors in cardio- and cerebrovascular outcome trials. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/26347887v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@264dd8org.highwire.dtl.DTLVardef@c0c6f6org.highwire.dtl.DTLVardef@46752dorg.highwire.dtl.DTLVardef@1b71c12_HPS_FORMAT_FIGEXP M_FIG Genetically proxied angiotensinogen synthesis inhibition and cardiovascular risk reduction. Graphical overview of the study design. Created in https://www.biorender.com/ AGT: angiotensinogen, pQTL: protein quantitative trait loci, eQTL: expressive quantitative trait loci, LD: linkage disequilibrium, MR: Mendelian Randomization, SBP: systolic blood pressure, DBP: diastolic blood pressure, UKBB: UK Biobank, CAD: coronary artery disease, RAAS: renin-angiotensin-aldosterone system, CVD: cardiovascular disease, ICH: intracerebral hemorrhage, SAH: subarachnoid hemorrhage, cIMT: carotid intima-media thickness, cSVD: cerebral small vessel disease, HF: heart failure, HFrEF: heart failure with reduced ejection fraction, HFpEF: heart failure with preserved ejection fraction, MRI: magnetic resonance imaging, eGFR: estimated glomerular filtration rate, UACR: urinary albumin-to-creatinine ratio, MVP: Million Veteran Program C_FIG