TY - JOUR
T1 - Association of PCSK9 Loss-of-Function Variants With Risk of Heart Failure
AU - Trudso, Linea C. C.
AU - Ghouse, Jonas
AU - Ahlberg, Gustav
AU - Bundgaard, Henning
AU - Olesen, Morten S. S.
PY - 2023
Y1 - 2023
N2 - 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 35135 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: beta = -1.01; 95% CI, -2.99 to 0.98; P = .32; R46L: beta = -0.18; 95% CI, -0.55 to 0.19; P = .35; GRS: beta = -0.19; 95% CI, -0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: beta = 0.43; 95% CI, -1.32 to 2.18; P = .63; R46L: beta = -0.19; 95% CI, -0.52 to 0.14; P = .26; GRS: beta = -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.
AB - 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 35135 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: beta = -1.01; 95% CI, -2.99 to 0.98; P = .32; R46L: beta = -0.18; 95% CI, -0.55 to 0.19; P = .35; GRS: beta = -0.19; 95% CI, -0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: beta = 0.43; 95% CI, -1.32 to 2.18; P = .63; R46L: beta = -0.19; 95% CI, -0.52 to 0.14; P = .26; GRS: beta = -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.
KW - HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
KW - DENSITY-LIPOPROTEIN CHOLESTEROL
KW - ECTOPIC FAT ACCUMULATION
KW - GENETIC-VARIANTS
KW - INHIBITOR ALIROCUMAB
KW - MONOCLONAL-ANTIBODY
KW - EXPERIMENTAL-MODELS
KW - PCSK9
KW - EFFICACY
KW - SAFETY
U2 - 10.1001/jamacardio.2022.4798
DO - 10.1001/jamacardio.2022.4798
M3 - Journal article
C2 - 36542369
VL - 8
SP - 159
EP - 166
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 2
ER -