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. 2009 Jul;94(7):2537-43.
doi: 10.1210/jc.2009-0141. Epub 2009 Apr 7.

Genetic and metabolic determinants of plasma PCSK9 levels

Susan G Lakoski  1 , Thomas A Lagace, Jonathan C Cohen, Jay D Horton, Helen H Hobbs
Affiliations

Genetic and metabolic determinants of plasma PCSK9 levels

Susan G Lakoski et al. J Clin Endocrinol Metab. 2009 Jul.

Abstract

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 (r(2) = 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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Figures

Figure 1
Figure 1
The distribution of fasting plasma concentrations of PCSK9 in the Dallas Heart Study (n = 3138) excluding individuals on statins (97 women and 117 men) in all subjects (A), in men only (B; n = 1392), and in women only (C; n = 1746). Levels of PCSK9 were measured using a sandwich ELISA in plasma samples obtained after an overnight fast, as described in Subjects and Methods. Significant differences were observed between men and women after adjustment for age, ethnicity, BMI, diabetes, and plasma levels of LDL-C, HDL-C, and triglycerides (P < 0.0001).
Figure 2
Figure 2
Effect of menopause status and estrogen usage in women (A) and effect of age in men (B) on median fasting plasma concentrations of PCSK9 in the Dallas Heart Study. The median level is denoted by a horizontal line. The gray boxes denote the 75th and 25th percentiles; the whiskers represent the 95th and 5th percentiles. A, Premenopausal women had significantly higher plasma levels of PCSK9 than did postmenopausal women (P = 0.001). Estrogen treatment did not significantly affect significant fasting PCSK9 levels in postmenopausal women. B, No difference in plasma levels of PCSK9 was apparent between men over age 50 yr and men younger than 50 yr. Subjects on statins were not included in the analysis.
Figure 3
Figure 3
Plasma concentrations of LDL-C (mean ± se; top) and PCSK9 (median; bottom) in relationship to APOE genotypes in the Dallas Heart Study. The APOE genotypes were determined using a TaqMan assay with custom-made probes. The APOE112 and APOE158 single nucleotide polymorphisms were combined to create the APOE genotypes. The mean plasma levels of LDL-C were significantly different between the APOE genotypes using one-way ANOVA (P < 0.0001). PCSK9 levels were not significantly different among APOE genotypes (P = 0.10) in the Dallas Heart Study. The P values reflect a model adjusted for age, ethnicity, gender, and BMI. Subjects on statins were not included in the analysis.
Figure 4
Figure 4
The distribution of plasma PCSK9 levels in African-Americans who were heterozygous for a nonsense mutation in PCSK9 (Y142X or C679X) (A); European-Americans heterozygous or homozygous for PCSK9:R46L (B); and median plasma levels of PCSK9 in African-Americans and European-Americans with various sequence variations in PCSK9 (C). A, African-American individuals heterozygous for a nonsense mutation had significantly lower median PCSK9 concentrations compared with those without the mutation after adjusting for age and sex (P < 0.0001) and after adjusting for LDL-C (P < 0.0001). B, In European-Americans, individuals heterozygous for R46L had significantly lower plasma PCSK9 in age and sex-adjusted models (P = 0.0004) and after adjusting for plasma LDL-C levels (P = 0.004). C, Relationship between nonsynonymous variants in PCSK9 and plasma levels of LDL-C in African-Americans (All, n = 1607) (left) and European-Americans (All, n = 909) (right) in the Dallas Heart Study. Individuals heterozygous for nonsynonymous variants not associated with changes in LDL-C were included in the analysis (PCSK9: G670E, A53V, V474I). Subjects taking statins were excluded.*, P < 0.05.
Figure 5
Figure 5
Effect of statins on plasma concentrations of PCSK9 in men (left) and women (right) in the Dallas Heart Study. Statin use was determined by interview and medication reconciliation.
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