Assessing the efficacy and safety of angiotensinogen inhibition using human genetics

Abstract

Background Novel angiotensinogen (AGT) inhibitors are in early clinical development for treatment of hypertension. Evidence that this therapeutic approach will safely reduce risk of cardiovascular outcomes in humans is limited. We leveraged genetic data from more than one million individuals to characterise the effects of AGT inhibition. Methods We identified a genetic instrument for AGT inhibition from systolic blood pressure (SBP) genome-wide association study data, and investigated its relationship with AGT gene expression and circulating AGT protein concentration. We examined the instrument's association with cardiovascular and renal outcomes, and compared the effect of the instrument with that of genetic instruments for other renin-angiotensin system (RAS) components and the causal effect of SBP overall. We performed phenome-wide association analyses to identify unanticipated effects of AGT inhibition. Results The AGT instrument (rs2478539; 0.49 mmHg lower SBP per G-allele) was strongly associated with hypertension, and showed evidence of colocalisation with AGT mRNA expression across various tissues. Scaled to a 10 mmHg lower SBP, the AGT instrument was associated with a 41% lower risk of major cardiovascular events, a composite of myocardial infarction, coronary revascularisation and stroke (111,549 cases; odds ratio 0.59, 95% confidence interval, 0.47 ‒ 0.74; P = 3.1 × 10-6). There was little evidence of heterogeneity between the AGT vascular estimates when compared to equivalent estimates from other RAS targets and the effect of SBP lowering more broadly, and no strong evidence of potential target-mediated adverse effects. Conclusion Our findings suggest that inhibition of AGT safely reduces risk of major vascular events. These results support ongoing clinical development programmes for AGT inhibitors.