ASGR1 inhibitors, inflammation, and heart failure: A Mendelian randomization analysis

Abstract This study investigates the causal relationship between Asialoglycoprotein receptor 1 (ASGR1) inhibitors, inflammation, and heart failure (HF). Leveraging data from the Global Lipids Genetics Consortium (2021) and the UK Biobank, we identified instrumental variables for ASGR1 and validated these genetic instruments using coronary heart disease (CHD) patients as positive controls. We employed Instrumental variable weighted (IVW) and Summary‐data‐based Mendelian Randomization (SMR) methods to assess the association of ASGR1 with HF and its associated risk factors, comparing efficacy with PCSK9 and LDLR. Mediation analysis of inflammatory biomarkers was conducted using a two‐step Mendelian randomization approach, with sensitivity analyses performed using conventional MR methods. IVW analysis demonstrates a significant positive correlation between ASGR1 expression and HF, myocardial infarction, non‐ischemic cardiomyopathy, and calcific aortic valvular stenosis. Patients with HF comorbid with CHD showed an increased likelihood of benefit. ASGR1 exhibited a stronger effect on HF compared to PCSK9. Similar conclusions were drawn from SMR analysis. Additionally, LDLR shows no causal relationship with HF but appears negatively correlated with non‐ischemic cardiomyopathy. Among the 91 inflammatory proteins studied, Leukemia inhibitory factor receptor (LIF‐R) and Urokinase‐type plasminogen activator (uPA) were found to mediate the effects of ASGR1 on HF. Sensitivity analyses indicate no evidence of pleiotropy in reported results. This study supports a causal association between ASGR1 inhibitors and HF, providing genetic evidence for the anti‐inflammatory role of ASGR1 inhibitors in reducing HF risk. LIF‐R and uPA, identified as potential mediators, introduce a novel therapeutic pathway for HF management.