Background PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds low-density lipoprotein receptor, preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis. The PCSK9-rs562556 variant has been reported as a gain-of-function mutation. The aim of this study was to determine whether the PCSK9-low-density lipoprotein receptor-rs562556 axis is associated with carotid artery plaques between 2 visits separated by almost 20 years in a longitudinal population cohort. Methods and Results The STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort is a longitudinal familial cohort from the Lorraine region of France. Participants attending 2 visits (visit 1 and visit 4) separated by 18.5 years (mean) were included (n=997). Carotid artery plaques were determined with standardized vascular echography. The mean age of the adult population at visit 1 was 42±5 years. At visit 4, 203 (20.4%) participants had arterial plaques. Participants who developed arterial plaques were older (42.7±5.4 versus 41.7±4.7 years), more often male (60% versus 49%), smokers (29% versus 18%), with diabetes mellitus (6% versus 3%), and higher cholesterol levels (low-density lipoprotein cholesterol, 1.6±0.4 versus 1.5±0.3 g/L) (all P<0.05). The independent factors associated with arterial plaques were age, smoking, and low-density lipoprotein cholesterol. Higher PCSK9 levels were associated with arterial plaques on top of the clinical model (odds ratio, 2.14; 95% CI,= 1.28-3.58); the missense mutation coding the single-nucleotide polymorphism rs562556 was associated with both higher PCSK9 concentration and incident carotid arterial plaques. Conclusions Higher PCSK9 concentration was associated with the development of arterial plaques almost 20 years in advance in a healthy middle-aged population. Mutations of the single-nucleotide polymorphism rs562556 associated with both PCSK9 levels and arterial plaques reinforce the potential causality of our findings. PCSK9 inhibitors could be useful for primary cardiovascular prevention.
Keywords: LDL receptor; PCSK9; STANISLAS cohort; arterial plaques; cholesterol; rs562556 mutations.