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Low‐density lipoprotein cholesterol and lifespan: A Mendelian randomization study

Daghlas, I; Gill, D (2021) Low‐density lipoprotein cholesterol and lifespan: A Mendelian randomization study. Br J Clin Pharmacol, 87 (10). pp. 3916-3924. ISSN 1365-2125 https://doi.org/10.1111/bcp.14811
SGUL Authors: Gill, Dipender Preet Singh

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Abstract

Aims It is unknown whether long‐term low‐density lipoprotein cholesterol (LDL‐c) lowering increases lifespan and longevity in a general population not selected for elevated cardiovascular risk. The present study aimed to investigate the overall and gene‐specific effect of circulating LDL‐c levels on lifespan and longevity in a general population. Methods Leveraging data from the Global Lipids Genetics Consortium (n = 173 082), we identified genetic variants to proxy LDL‐c levels generally, and also through perturbation of particular drug targets (HMGCR, NPC1L1 and PCSK9). We investigated their association with lifespan (n = 1 012 240) using Mendelian randomization, and replicated results using the outcome of longevity to the 90th vs. 60th percentile age (11 262 cases/25 483 controls). Results A 1‐standard deviation increase in genetically proxied LDL‐c was associated with 1.2 years lower lifespan (95% confidence interval [CI] −1.55, −0.87; P = 3.83 × 10−12). Findings were consistent in statistical sensitivity analyses, and when considering the outcome of longevity (odds ratio for survival to the 90th vs 60th percentile age 0.72, 95% CI 0.64, 0.81, P = 7.83 × 10−8). Gene‐specific Mendelian randomization analyses showed a significant effect of LDL‐c modification through PCSK9 on lifespan (−0.99 years, 95% CI −1.43, 0.55, P = 6.80 × 10−6); however, estimates for HMGCR and NPC1L1 were underpowered. Conclusions This genetic evidence supports that higher LDL‐c levels reduce lifespan and longevity. In a general population that is not selected for increased cardiovascular risk, there is likely to be a net lifespan benefit of LDL‐c lowering therapies, particularly for PCSK9 inhibitors, although randomized controlled trials are necessary before modification of clinical practice.

Item Type: Article
Additional Information: This is the peer reviewed version of the following article: Daghlas, I, Gill, D. Low-density lipoprotein cholesterol and lifespan: A Mendelian randomization study. Brit Jnl Clinical Pharma. 2021; 87( 10): 3916– 3924, which has been published in final form at https://doi.org/10.1111/bcp.14811. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Keywords: HMGCR, LDL-c, Mendelian randomization, NPC1L1, PCSK9, lifespan, Pharmacology & Pharmacy, 1115 Pharmacology and Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Br J Clin Pharmacol
ISSN: 1365-2125
Language: eng
Dates:
DateEvent
23 September 2021Published
4 April 2021Published Online
26 February 2021Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
RE/18/4/34215British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
CL-2020-16-001National Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
PubMed ID: 33704808
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113046
Publisher's version: https://doi.org/10.1111/bcp.14811

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