Repurposing lipid-lowering drugs on asthma and lung function: evidence from a genetic association analysis

Abstract

Objective: To explore the correlation between asthma risk and genetic variants affecting the expression or function of lipid-lowering drug targets.

Methods: We conducted Mendelian randomization (MR) analyses using variants in several genes associated with lipid-lowering medication targets: HMGCR (statin target), PCSK9 (alirocumab target), NPC1L1 (ezetimibe target), APOB (mipomersen target), ANGPTL3 (evinacumab target), PPARA (fenofibrate target), and APOC3 (volanesorsen target), as well as LDLR and LPL. Our objective was to investigate the relationship between lipid-lowering drugs and asthma through MR. Finally, we assessed the efficacy and stability of the MR analysis using the MR Egger and inverse variance weighted (IVW) methods.

Results: The elevated triglyceride (TG) levels associated with the APOC3, and LPL targets were found to increase asthma risk. Conversely, higher LDL-C levels driven by LDLR were found to decrease asthma risk. Additionally, LDL-C levels (driven by APOB, NPC1L1 and HMGCR targets) and TG levels (driven by the LPL target) were associated with improved lung function (FEV1/FVC). LDL-C levels driven by PCSK9 were associated with decreased lung function (FEV1/FVC).

Conclusion: In conclusion, our findings suggest a likely causal relationship between asthma and lipid-lowering drugs. Moreover, there is compelling evidence indicating that lipid-lowering therapies could play a crucial role in the future management of asthma.

Keywords: Asthma; Casual association; Lipids; Lowering-lipid therapy; Mendelian randomization.

Fig. 1

Schematic and flowchart progress of lipid-lowering drugs and asthma

Fig. 2

The forest plot for the lipid-lowering target with coronary heart disease (CHD). (CI: confidence interval; OR: odds ratio.)

Fig. 3

The casual effect of different lipid-lowering therapies on asthma risk was detected using the mendelian randomization method and the meta-analysis method was used to pool the MR analysis results of each lowering therapy. (Square: each OR value; Rhomboid: the pooled OR value of fixed effect model; CI: confidence interval; OR: odds ratio)

Fig. 4

The causal effect of different lipid-lowering therapies on FEV1/FVC risk was detected using the mendelian randomization method, and the meta-analysis method was used to pool the mendelian randomization analysis results of each lowering therapy. (Square symbols: each beta value, Rhomboid symbols: the pooled beta value of the fixed-effect model. CI: confidence interval.)