APOB and CCL17 as Mediators in the Protective Effect of SGLT2 Inhibition against Myocardial Infarction: Insights from Proteome-wide Mendelian Randomization

Lili Shi; Gen Li; Ningxin Hou; Ling Tu; Jun Li; Jinlan Luo; Shuiqing Hu

doi:10.1016/j.ejphar.2024.176619

APOB and CCL17 as Mediators in the Protective Effect of SGLT2 Inhibition against Myocardial Infarction: Insights from Proteome-wide Mendelian Randomization

Eur J Pharmacol. 2024 Apr 26:176619. doi: 10.1016/j.ejphar.2024.176619. Online ahead of print.

Authors

Lili Shi¹, Gen Li², Ningxin Hou², Ling Tu¹, Jun Li², Jinlan Luo³, Shuiqing Hu⁴

Affiliations

¹ Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China.
² Department of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
³ Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China. Electronic address: jinlanluo@hust.edu.cn.
⁴ Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China; Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: hushuiqing@hust.edu.cn.

PMID: 38679119
DOI: 10.1016/j.ejphar.2024.176619

Abstract

Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer a novel therapeutic avenue for myocardial infarction (MI). However, the exact nature of this relationship and the underlying mechanisms are not fully understood.

Methods: Utilizing a two-sample Mendelian Randomization (MR) analysis, we elucidated the causal effects stemming from the inhibition of SGLT2 on MI. Then, The pool of 4907 circulating proteins within the plasma proteome were utilized to explore the mediators of SGLT2 inhibitors on MI. Protein-protein network and enrichment analysis were conducted to clarify the potential mechanism. Finally, employing MR analysis and meta-analysis techniques, we systematically assessed the causal associations between SGLT2 inhibition and coronary heart diseases (CHD).

Results: SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of MI (odds ratio [OR] = 0.462, [95% CI 0.222, 0.958], P = 0.038). Among 4907 circulating proteins, we identified APOB and CCL17 which were related to both SGLT2 inhibition and MI. Mediation analysis showed evidence of the indirect effect of SGLT2 inhibition on MI through APOB (β= -0.557, 95%CI [-1.098, -0.155]) with a mediated proportion of 72%, and CCL17 (β= -0.176, 95%CI [-0.332, -0.056]) with a mediated proportion of 17%. The meta-analysis result showed that SGLT2 inhibition was associated with a lower risk of CHD.

Conclusion: Based on proteome-wide mendelian randomization, APOB and CCL17 were seen as mediators in the protective effect of SGLT2 inhibition against myocardial infarction.

Keywords: Circulating protein; Mendelian randomization; Myocardial infarction; Sodium-glucose cotransporter 2 inhibition.