Human genetic support for hepatic AGT silencing for cardiovascular risk reduction

In our new preprint, we develop a genetic proxy for hepatic AGT synthesis inhibition, enabling human genetic validation of a promising emerging antihypertensive target.

𝐁𝐚𝐜𝐤𝐠𝐫𝐨𝐮𝐧𝐝:
AGT (angiotensinogen) is a key component of the renin-angiotensin-aldosterone system (RAAS) that is successfully targeted by multiple antihypertensive therapies. It is produced in the liver by hepatocytes, making it a promising target for GalNAc-delivered RNA therapeutics.

Both an ASO and an siRNA have shown promising blood pressure-lowering effects in phase 2 studies, but phase 3 cardiovascular outcome trials are still pending (e.g. KARDIA-3 results not expected before 2030).

𝐖𝐡𝐚𝐭 𝐰𝐞 𝐝𝐢𝐝:
1️⃣ We constructed a genetic proxy of hepatic inhibition of AGT synthesis using 46 variants in the AGT locus that influence its liver expression and/or its circulating protein levels.

2️⃣ This genetic proxy recapitulated the expected effects of pharmacological inhibition of AGT synthesis in clinical trials: decreases in systolic and diastolic blood pressure, as well as increases in renin levels (compensatory) and serum potassium.

3️⃣ Testing associations with major clinical cardiovascular outcomes, we found genetically proxied downregulation of AGT synthesis to be associated with lower odds of coronary artery disease, stroke, and heart failure.

4️⃣ Per unit decrease in systolic blood pressure, these effects are comparable to those observed for genetic proxies of other RAAS targets currently used in clinical practice.

5️⃣ We observed consistent widespread effects across secondary endpoints including ischemic and hemorrhagic stroke subtypes, and biomarkers of subclinical atherosclerosis, cerebral small vessel disease, and adverse cardiac remodeling.

6️⃣ Key (on-target) safety signals aligned well with expectations (e.g. hyperkalemia), with no evidence for increased risk of kidney injury, liver damage, or other major adverse outcomes.

7️⃣ A phenome-wide analysis supports a predominantly cardiovascular benefit profile without additional safety concerns.

Great work led by lab members Panagiotis Zangas, Murad Omarov, and Lanyue Zhang.

https://www.medrxiv.org/content/10.64898/2026.03.08.26347887v1