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Published on: August 28, 2018
Association of PCSK9 Loss-of-Function Variants With Risk of Heart Failure
Linea C Trudsø1,2, Jonas Ghouse1,2, Gustav Ahlberg1,2
1Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Importance:
An animal (mouse) study indicated that deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9) causes cardiac remodeling and heart failure (HF). Cardiac remodeling after PCSK9-inhibitor treatment is a concern for patients and for development of treatment directed against PCSK9.
Objective:
To determine whether genetic variants in the PCSK9 gene are associated with altered cardiac structure, cardiac function, and HF in humans.
Design, Setting, Participants:
This was a nested case-control study within the UK Biobank. Between March 13, 2006, and October 1, 2010, the UK Biobank enrolled 502 480 individuals aged 40 to 69 years. This study focused on a subset of those individuals, who completed cardiac magnetic resonance (CMR) imaging and had available genetic data. Analyses were conducted between November 2, 2021, and October 28, 2022.
Exposures:
Carrier status of predicted loss-of-function (pLoF) PCSK9 variants, R46L missense variant, and a genetic risk score (GRS).
Main Outcomes And Measures:
A total of 11 CMR imaging measurements, generated using a machine learning algorithm, and HF diagnosis.
Results:
In up to 35 135 individuals with CMR images, 18 252 (52%) were female individuals, and mean (SD) age was 55.0 (7.4) years. No significant association between PCSK9 carrier status and CMR indices were found for left ventricular mass (pLoF: β = -1.01; 95% CI, -2.99 to 0.98; P = .32; R46L: β = -0.18; 95% CI, -0.55 to 0.19; P = .35; GRS: β = -0.19; 95% CI, -0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: β = 0.43; 95% CI, -1.32 to 2.18; P = .63; R46L: β = -0.19; 95% CI, -0.52 to 0.14; P = .26; GRS: β = -0.08; 95% CI, -0.35 to 0.20; P = .58) or HF (pLoF: odds ratio [OR], 1.14; 95% CI, 0.56-2.05; P = .69; R46L: OR, 0.99; 95% CI, 0.90-1.10; P = .91; GRS: OR, 1.04; 95% CI, 0.96-1.13; P = .32).
Conclusions And Relevance:
Results of this case-control study suggest that there was no association between PCSK9 genetic variants and altered cardiac structure, cardiac function, or HF in humans.
Insights
Genetic variants in PCSK9 were not associated with cardiac structure, function, or heart failure (HF) in humans. This study suggests PCSK9 genetic variations do not impact cardiac health in the general population.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Human Genetics
Background:
- Mouse studies suggest proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency may lead to cardiac remodeling and heart failure (HF).
- This raises concerns about potential cardiac effects of PCSK9-inhibitor treatments in humans.
Purpose of the Study:
- To investigate the association between genetic variants in the PCSK9 gene and cardiac structure, function, and HF risk in humans.
- To clarify the role of PCSK9 genetic variations in human cardiovascular health.
Main Methods:
- A nested case-control study utilizing UK Biobank data from over 500,000 individuals.
- Focused on a subset with cardiac magnetic resonance (CMR) imaging and genetic data (N=35,135).
- Assessed carrier status for predicted loss-of-function (pLoF) PCSK9 variants, R46L variant, and a PCSK9 genetic risk score (GRS).
Main Results:
- No significant associations were found between PCSK9 genetic variants (pLoF, R46L, GRS) and cardiac structure (left ventricular mass) or function (left ventricular ejection fraction).
- PCSK9 genetic variants were not significantly associated with the risk of heart failure (HF) diagnosis.
- Statistical analysis included detailed CMR measurements and HF diagnoses, with results showing no significant links to PCSK9 variants.
Conclusions:
- This large-scale human study indicates no association between common PCSK9 genetic variants and altered cardiac structure, function, or heart failure.
- The findings suggest that genetic variations in PCSK9 may not be a significant risk factor for cardiac remodeling or HF in the human population.
- These results have implications for understanding the safety profile of PCSK9-targeting therapies.
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