Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis

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Abstract

Background

It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity.

Methods

Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data.

Results

Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.

Conclusion

This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12944-023-01983-0.

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Most cited references 48

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The MR-Base platform supports systematic causal inference across the human phenome

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Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians

Neil M. Davies, Michael V. Holmes, George Davey Smith (2019)

Mendelian randomisation uses genetic variation as a natural experiment to investigate the causal relations between potentially modifiable risk factors and health outcomes in observational data. As with all epidemiological approaches, findings from Mendelian randomisation studies depend on specific assumptions. We provide explanations of the information typically reported in Mendelian randomisation studies that can be used to assess the plausibility of these assumptions and guidance on how to interpret findings from Mendelian randomisation studies in the context of other sources of evidence

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Author and article information

Contributors

Han Chen: chenhan0688@njmu.edu.cn

Guoxin Zhang: guoxinz@njmu.edu.cn

Journal

Journal ID (nlm-ta): Lipids Health Dis

Journal ID (iso-abbrev): Lipids Health Dis

Title: Lipids in Health and Disease

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-511X

Publication date (Electronic): 12 December 2023

Publication date PMC-release: 12 December 2023

Publication date Collection: 2023

Volume: 22

Electronic Location Identifier: 220

Affiliations

[1 ]Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, ( https://ror.org/04py1g812) 300# Guangzhou Road, Nanjing, 210029 People’s Republic of China

[2 ]Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, ( https://ror.org/04py1g812) Nanjing, People’s Republic of China

[3 ]Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, ( https://ror.org/04py1g812) Nanjing, People’s Republic of China

[4 ]Branch of Health Promotion and Education, Jiangsu Anti-aging Association, Nanjing, People’s Republic of China

Article

Publisher ID: 1983

DOI: 10.1186/s12944-023-01983-0

PMC ID: 10714481

PubMed ID: 38082436

SO-VID: fe927e26-e6c6-4ffd-85d2-97817ce76bb5

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 21 August 2023

Date accepted : 1 December 2023

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ScienceOpen disciplines: Biochemistry

Keywords: drug-target mendelian randomization,cetp,apoc3,ldlr,human longevity

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ScienceOpen disciplines: Biochemistry

Keywords: drug-target mendelian randomization, cetp, apoc3, ldlr, human longevity

Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis

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Abstract

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Supplementary Information

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Most cited references 48

The MR-Base platform supports systematic causal inference across the human phenome

The GTEx Consortium atlas of genetic regulatory effects across human tissues

Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians

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