Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes.
Circ Genom Precis Med
; 11(5): e001992, 2018 05.
Article
in En
| MEDLINE
| ID: mdl-29748315
ABSTRACT
BACKGROUND:
Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes.METHODS:
We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290).RESULTS:
Several independent variants at the PCSK9 gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L; P=1.94×10-17). We discovered 4 independent PCSK9 SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201; P=7.01×10-9) and 7 suggestive hits (P<1×10-6). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness.CONCLUSIONS:
Variants at the PCSK9 gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the PCSK9 gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts. CLINICAL TRIAL REGISTRATION URL http//www.clinicaltrials.gov. Unique Identifier NCT00497887.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Atherosclerosis
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Proprotein Convertase 9
Type of study:
Clinical_trials
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Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Limits:
Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Circ Genom Precis Med
Year:
2018
Document type:
Article