| Title: | PCSK9 genetic variants, carotid atherosclerosis and vascular remodelling |
| Journal: | Open Heart |
| Published: | 1 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41073127/ |
| DOI: | https://doi.org/10.1136/openhrt-2025-003348 |
| URL: | https://openheart.bmj.com/content/12/2/e003348.full.pdf |
Publication 16654
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Abstract
BACKGROUND: Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial regulator of cholesterol metabolism. Loss-of-function variants in PCSK9 are associated with lower levels of circulating low-density lipoprotein cholesterol (LDL-C) and reduced cardiovascular disease (CVD) risk, while gain-of-function variants correlate with elevated LDL-C concentrations and increased CVD risk. This study investigated whether genetically determined LDL-C levels, proxied by four PCSK9 genetic variants, influence common carotid artery atherosclerosis.</p>
METHODS: The analysis included 3040 European participants (mean age 64.2±5.4 years; 45.8% men) at high cardiovascular risk from the IMPROVE Study, alongside 49 088 individuals of white British ancestry (mean age 55.2±7.6 years; 47.9% men) from the UK Biobank (UKB). Ultrasonographic measurements of common carotid intima-media thickness (CC-IMTmean, CC-IMTmax, CC-IMTmean-max) were obtained. Four lipid-level affecting genetic variants in the PCSK9 locus were selected for analysis, both individually and in a standardised Lipid-Lowering Allelic Score (LLAS), to assess their effects on LDL-C and PCSK9 levels in the IMPROVE cohort and on ultrasonographic measures in both IMPROVE and UKB.</p>
RESULTS: In the IMPROVE cohort, PCSK9 variants (rs11206510, rs2479409, rs11591147, rs11583680) exhibited expected effect directions, although not all statistically significant, on LDL-C and PCSK9 levels. The LLAS was negatively correlated with CC-IMTmean, CC-IMTmax and CC-IMTmean-max among women in IMPROVE, and among men and overall in UKB (all p<0.05). Effect sizes were comparable between cohorts.</p>
CONCLUSIONS: Genetic variants in the PCSK9 locus influence LDL-C levels and CC-IMT, in keeping with proven benefits of PCSK9 inhibitors on atherosclerotic cardiovascular events.</p>
15 Keywords
- Aged
- Biomarkers
- Carotid Artery Diseases
- Carotid Intima-Media Thickness
- Cholesterol, LDL
- Female
- Genetic Predisposition to Disease
- Genetic Variation
- Humans
- Male
- Middle Aged
- Proprotein Convertase 9
- Risk Factors
- United Kingdom
- Vascular Remodeling
25 Authors
- Daniela Coggi
- Joey Ward
- Chiara Macchi
- Bruna Gigante
- Mauro Amato
- Donald M Lyall
- Beatrice Frigerio
- Alessio Ravani
- Daniela Sansaro
- Nicola Ferri
- Maria Giovanna Lupo
- Massimiliano Ruscica
- Fabrizio Veglia
- Nicolo Capra
- Antonio Gallo
- Matteo Pirro
- Kai Savonen
- Douwe J Mulder
- Roberta Baetta
- Elena Tremoli
- Jill P. Pell
- Paul Welsh
- Naveed Sattar
- Damiano Baldassarre
- Rona J Strawbridge
1 Application
| Application ID | Title |
|---|---|
| 71392 | Investigating complex relationships between genetics, exposures, biomarkers, endophenotypes and cardiometabolic, inflammatory, immune and brain-related health outcomes |
Enabling scientific discoveries that improve human health