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SGLT2 inhibition, plasma proteins, and heart failure: a proteome-wide Mendelian Randomization and colocalization
Jinlan Luo1,2, Lili Shi1,2, Jingrui Liu2,3
1Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces heart failure (HF) risk. This study found that plasma leucine rich repeat transmembrane protein 2 (LRRTM2) mediates this protective effect, offering new therapeutic insights.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Heart Failure (HF) remains a significant global health concern.
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly used for HF management.
- The precise mechanisms underlying SGLT2 inhibition's benefits in HF are not fully elucidated.
Purpose of the Study:
- To investigate the causal relationship between SGLT2 inhibition and HF.
- To identify circulating proteins that mediate the effects of SGLT2 inhibition on HF.
- To explore potential therapeutic targets for HF prevention and treatment.
Main Methods:
- A two-sample, two-step Mendelian Randomization (MR) analysis was employed.
- Genetic variants associated with SGLT2 inhibition, 4,907 circulating proteins (from deCODE), and HF (from HERMES consortium) were utilized.
- Mediation and colocalization analyses were performed to assess causal pathways.
Main Results:
- SGLT2 inhibition was causally associated with a reduced risk of HF (OR = 0.44, P = 0.003).
- Leucine rich repeat transmembrane protein 2 (LRRTM2) was identified as a protein linked to both SGLT2 inhibition and HF.
- LRRTM2 mediated 24.6% of the effect of SGLT2 inhibition on HF (P = 0.02).
Conclusions:
- SGLT2 inhibition exerts a protective effect against heart failure.
- Plasma LRRTM2 is a potential mediator of SGLT2 inhibition's benefits in HF.
- Targeting LRRTM2 may represent a novel therapeutic strategy for managing heart failure.
Objective:
To investigate the causal contributions of Sodium-glucose cotransporter 2 (SGLT2) inhibition on Heart Failure (HF) and identify the circulating proteins that mediate SGLT2 inhibition's effects on HF.
Methods:
Applying a two-sample, two-step Mendelian Randomization (MR) analysis, we aimed to estimate: (1) the causal impact of SGLT2 inhibition on HF; (2) the causal correlation of SGLT2 inhibition on 4,907 circulating proteins; (3) the causal association of SGLT2 inhibition-driven plasma proteins on HF. Genetic variants linked to SGLT2 inhibition derived from the previous studies. The 4,907 circulating proteins were derived from the deCODE study. Genetic links to HF were obtained through the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium.
Results:
SGLT2 inhibition demonstrated a lower risk of HF (odds ratio [OR] = 0.44, 95% CI [0.26, 0.76], P = 0.003). Among 4,907 circulating proteins, we identified leucine rich repeat transmembrane protein 2 (LRRTM2), which was related to both SGLT2 inhibition and HF. Mediation analysis revealed that the impact of SGLT2 inhibition on HF operates indirectly through LRRTM2 [β = -0.20, 95% CI (-0.39, -0.06), P = 0.02] with a mediation proportion of 24.6%. Colocalization analysis provided support for the connections between LRRTM2 and HF.
Conclusion:
The study indicated a causative link between SGLT2 inhibition and HF, with plasma LRRTM2 potentially serving as a mediator.
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