Common and Low-Frequency Genetic Variants in the <i>PCSK9</i> Locus Influence Circulating <i>PCSK9</i> Levels

<jats:sec> <jats:title>Objective —</jats:title> <jats:p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that influences plasma low-density lipoprotein concentration and susceptibility to coronary heart disease. Circulating PCSK9 levels show considerable interindividual differences, but the factors responsible for this variation are largely unknown.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> We analyzed circulating PCSK9 levels in 4 cohorts of healthy, middle-aged Swedes (n=5722) and found that PCSK9 levels varied over ≈50-fold range, showed a positive relationship with plasma low-density lipoprotein–cholesterol concentration, and were associated with plasma triglyceride, fibrinogen, insulin, and glucose concentrations. A genome-wide association study conducted in 2 cohorts (n=1215) failed to uncover common genetic variants robustly associated with variation in circulating PCSK9 level. As expected, the minor allele of the <jats:italic>PCSK9</jats:italic> R46L variant was in all cohorts associated with reduced PCSK9 levels and decreased plasma low-density lipoprotein–cholesterol concentrations, but no relationship was observed with the plasma triglyceride concentration. Further mapping of the <jats:italic>PCSK9</jats:italic> locus revealed a common polymorphism (rs2479415, minor allele frequency 43.9%), located ≈6 kb upstream from <jats:italic>PCSK9</jats:italic> , which is independently associated with increased circulating PCSK9 levels. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion—</jats:title> <jats:p> Common and low-frequency genetic variants in the <jats:italic>PCSK9</jats:italic> locus influence the pronounced interindividual variation in circulating PCSK9 levels in healthy, middle-aged white (predominantly Swedish) subjects. </jats:p> </jats:sec>