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Genetic and Metabolic Determinants of Plasma PCSK9 Levels

Donald W. Reynolds Cardiovascular Clinical Research Center, Departments of Internal Medicine (S.G.L., J.C.C., J.D.H., H.H.H.) and Molecular Genetics (T.A.L., J.D.H., H.H.H.), and the Howard Hughes Medical Institute (H.H.H.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046

Address all correspondence and requests for reprints to: Helen H. Hobbs, Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9046. E-mail: helen.hobbs{at}utsouthwestern.edu.

Context: PCSK9 is a secreted protein that influences plasma levels of low-density lipoprotein cholesterol (LDL-C) and susceptibility to coronary heart disease. PCSK9 is present in human plasma, but the factors that contribute to differences in plasma concentrations of PCSK9 and how they impact on the levels of lipoproteins have not been well-characterized.

Objective: The aim of the study was to measure PCSK9 levels in a large, ethnically diverse population (n = 3138) utilizing a sensitive and specific sandwich ELISA.

Design: We conducted an observational study in the Dallas Heart Study, a multiethnic, probability-based sample of Dallas County.

Results: Plasma levels of PCSK9 varied over approximately 100-fold range (33–2988 ng/ml; median, 487 ng/ml). Levels were significantly higher in women (517 ng/ml) than in men (450 ng/ml), and in postmenopausal women compared to premenopausal women (P < 0.0001), irrespective of estrogen status. Plasma levels of PCSK9 correlated with plasma levels of LDL-C (r = 0.24) but explained less than 8% of the variation in LDL-C levels (r² = 0.073). Other factors that correlated with PCSK9 levels included plasma levels of triglycerides, insulin, and glucose. Individuals with loss-of-function mutations in PCSK9 and reduced plasma levels of LDL-C also had significantly lower plasma levels of PCSK9 after adjusting for age, gender, and LDL-C levels (P < 0.0001).

Conclusion: Multiple metabolic and genetic factors contribute to variation in plasma levels of PCSK9 in the general population. Although levels of PCSK9 correlate with plasma levels of LDL-C, they account for only a small proportion of the variation in the levels of this lipoprotein.

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