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Association between genetically proxied lipid-lowering drug targets, lipid traits, and amyotrophic lateral sclerosis: a mendelian randomization study

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Abstract

Background

The use of circulating lipid traits as biomarkers to predict the risk of amyotrophic lateral sclerosis (ALS) is currently controversial, and the evidence-based medical evidence for the use of lipid-lowering agents, especially statins, on ALS risk remains insufficient. Our aim was to apply a Mendelian randomization (MR) approach to assess the causal impact of lipid-lowering agents and circulating lipid traits on ALS risk.

Materials and methods

Our study included primary and secondary analyses, in which the risk associations of lipid-lowering gene inhibitors, lipid traits, and ALS were assessed by the inverse variance weighting method as the primary approach. The robustness of the results was assessed using LDSC assessment, conventional MR sensitivity analysis, and used Mediating MR to explore potential mechanisms of occurrence. In the secondary analysis, the association of lipid-lowering genes with ALS was validated using the Summary data-based Mendelian Randomization (SMR) method.

Results

Our results showed strong evidence between genetic proxies for Apolipoprotein B (ApoB) inhibitor (OR = 0.76, 95% CI = 0.68 − 0.86; P = 5.58 × 10−6) and reduced risk of ALS. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (OR = 1.06, 95% CI = 0. 85–1.33) was not found to increase ALS risk. SMR results suggested that ApoB expression was associated with increased ALS risk, and colocalization analysis did not support a significant common genetic variation between ApoB and ALS. Mediator MR analysis suggested a possible mediating role for interleukin-6 and low-density lipoprotein cholesterol (LDL-C). While elevated LDL-C was significantly associated with increased risk of ALS among lipid traits, total cholesterol (TC) and ApoB were weakly associated with ALS. LDSC results suggested a potential genetic correlation between these lipid traits and ALS.

Conclusions

Using ApoB inhibitor can lower the risk of ALS, statins do not trigger ALS, and LDL-C, TC, and ApoB levels can predict the risk of ALS.

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Data availability

Circulating lipid traits are available at http://csg.sph.umich.edu/willer/public/lipids2013/ (Used to obtain HDL-C, LDL-C, TC and TG). https://www.ebi.ac.uk/gwas/publications/27005778 (Used to obtain ApoB and ApoA1). Aggregated data for ALS and IL-6 are available from the GWAS Catalog: https://www.ebi.ac.uk/gwas/publications/29566793; https://www.ebi.ac.uk/gwas/publications/27989323. CAD: http://www.cardiogramplusc4d.org/data-downloads/. eQTL data for lipid-lowering drug targets gene were obtained from the GTEx V8 (https://gtexportal.org/) and eQTLGen (https://www.eqtlgen.org/) Consortium.

Abbreviations

MR:

Mendelian Randomization

SMR:

Summary data-based Mendelian Randomization

HMGCR:

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

NPC1L1:

Niemann–Pick C1-Like 1

PCSK9:

Proprotein convertase subtilisin/kexin type 9

CETP:

Cholesteryl Ester Transfer Protein

LDL-C:

Low-density lipoprotein cholesterol

HDL-C:

High-density lipoprotein cholesterol

TC:

Total cholesterol

TG:

Triglycerides

ApoB:

Apolipoprotein B

ApoA1:

Apolipoprotein A1

ALS:

Amyotrophic lateral sclerosis

CAD:

Coronary artery disease

IL-6:

Interleukin-6

IV:

Instrumental variable

OR:

Odds ratio

CI:

Confidence interval

IVW:

Inverse variance weighting method

GLGC:

Global Lipid Genetics Consortium

GWAS:

Genome-wide association study

NCBI:

National Center for Biotechnology Information

CARDIoGRAM:

Coronary ARtery DIsease Genome wide Replication and Meta-analysis

LD:

Linkage disequilibrium

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Acknowledgements

The authors thank all the participants and researchers who contributed and collected data.

Funding

This research was supported by the National Natural Science Foundation of China (No. 81860826).

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Authors and Affiliations

  1. Graduate School, Jiangxi University of Traditional Chinese Medicine, Yangming Road, Nanchang, Jiangxi, China

    Zhaoqi Yan, Yifeng Xu & Keke Li

  2. Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, 445 Bayi Dadao, Nanchang, Jiangxi, China

    Liangji Liu

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Contributions

YZQ is the principal manuscript writer, designed the study, and wrote the manuscript. XYF and LKK contributed to the data analysis and data interpretation. LLJ contributed to the revision of the manuscript. All the authors contributed to the article and approved the submitted version.

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Correspondence to Liangji Liu.

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Yan, Z., Xu, Y., Li, K. et al. Association between genetically proxied lipid-lowering drug targets, lipid traits, and amyotrophic lateral sclerosis: a mendelian randomization study. Acta Neurol Belg 124, 485–494 (2024). https://doi.org/10.1007/s13760-023-02393-w

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