Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease

Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
New England Journal of Medicine (Impact Factor: 55.87). 04/2006; 354(12):1264-72. DOI: 10.1056/NEJMoa054013
Source: PubMed


A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.
We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.
Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).
These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.

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    • "Gain of function mutations in PCSK9 are associated with autosomal dominant hypercholesterolemia, a disease that is characterized by increased LDL-C levels (>300 mg/dL) and a corresponding increased risk of CVD [6]. In contrast, humans with loss-of-function PCSK9 mutations are hypocholesterolemic (15–25% decrease in LDL-C) and have approximately half the incidence of CVD, most likely because of a life-long reduction of LDL-C [7]. Strikingly, individuals with compound heterozygote loss-of-function mutations, have exceptionally low serum LDL-C (<20 mg/dL) and appear healthy despite having no detectible circulating PCSK9 [8]. "
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    ABSTRACT: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the low-density lipoprotein receptor (LDL-R). Mutations that cause increased activity of PCSK9 are associated with hypercholesterolemia, atherosclerosis and early cardiovascular disease (CVD), whereas individuals with loss-of-function mutations in PCSK9 are apparently healthy but are hypocholesterolemic and have a dramatically decreased risk of CVD. In this study, we generated virus-like particle (VLP)-based vaccines targeting PCSK9. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides. A vaccine targeting PCSK9 may, therefore, be an attractive alternative to monoclonal antibody-based therapies.
    Vaccine 09/2015; DOI:10.1016/j.vaccine.2015.09.044 · 3.62 Impact Factor
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    • "In addition to its effect on LDL-r, PCSK9 modulates cholesterol transport and metabolism, as well as production of apolipoprotein B-containing lipoproteins in intestinal cells [4]. Persons with loss-of-function mutations in the PCSK9 gene have low LDL-C concentrations [5] and a substantially lower cardiovascular risk [6] [7]. In contrast, persons with gain-of-function mutations of the PCSK9 gene develop familial hypercholesterolemia (FH) which is associated with an increased prevalence of premature cardiovascular diseases [8] [9]. "
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    ABSTRACT: PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) increases LDL cholesterol (LDL-C) levels by stimulating the degradation of Low Density Lipoprotein receptors (LDL-r). This protein is now of high interest because antibodies which inhibit its effect on LDL-r are being developed. A severe hypercholesterolemia and / or an elevation of lipoprotein(a) can be treated with lipoprotein apheresis (LA) in high-risk patients. We measured serum PCSK9 levels in patients eligible for the extracorporeal treatment: in 40 patients (Cohort I) who were treated with different systems before and after apheresis sessions and in the intervals between sessions. 10 patients (Cohort II) who were eligible but did not start LA yet served as controls. Patients' baseline serum PCSK9 levels were elevated relative to healthy volunteers and LA sessions acutely reduced the mean PCSK9 concentrations by 51%. Comparison of the effectiveness of the different LA methods demonstrated the DSA and HELP were more effective than the DALI system. After 24 h PCSK9 levels had returned to baseline compared to 8 days for the LDL-C concentrations to return to its pre-apheresis levels. In Cohort II baseline PCSK9 levels were similar to those in Cohort I. The acute reductions of PCSK9 by apheresis may be beneficial with respect to increasing the effectiveness of lipid-lowering drugs and with respect to an anti-atherosclerotic effect. In the future, antagonists to PCSK9 will probably be combined with or possibly replace LA in patients with a very high cardiovascular risk. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis. Supplements 05/2015; 18. DOI:10.1016/j.atherosclerosissup.2015.02.028 · 2.29 Impact Factor
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    • "The B2 allele of the functional CETP Taq 1B (B1/B2) polymorphism (rs708272) is associated with an increase in HDL-C levels [11] [20] [21]. The X allele of the PCSK9 C679X polymorphism (rs28362286) is a loss of function mutation associated with reductions in LDL-C levels [13] [14] [22]. "
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    ABSTRACT: Dyslipidaemia can lead to the development of atherosclerosis and cardiovascular disease (CVD), however its prevalence has been shown to differ between ethnic groups in South Africa (SA). Therefore the aim of this study was to investigate ethnic differences in the association between serum lipid levels and polymorphisms within genes involved in lipid metabolism in black and white SA women. In a convenient sample of 234 white and 209 black SA women of Xhosa ancestry, body composition (DXA) and fasting serum lipids were measured. Participants were genotyped for the cholesteryl ester transfer protein (CETP, rs708272, B1/B2), lipoprotein lipase (LPL, rs328, S/X), hepatic lipase (LIPC, rs1800588, C/T) and proprotein convertase subtilisin/kexin type 9 (PCSK9, rs28362286, C/X) polymorphisms. Compared to white women, black women had lower concentrations of serum total cholesterol (TC, P < 0.001), low density lipoprotein cholesterol (LDL-C, P < 0.001), high density lipoprotein cholesterol (HDL-C, P < 0.001) and triglycerides (TG, P < 0.001). There were significant differences in the genotype and allele frequency distributions between black and white women for the LPL S/X (P < 0.001), PCSK9 C679X (P = 0.002) and LIPC 514C/T (P < 0.001) polymorphisms. In black women only, there were genotype effects on serum lipid levels. Specifically, women with the LPL SX genotype had lower TC and LDL-C and higher HDL-C concentrations than those with the SS genotype and women with the CETP B2 allele had lower LDL-C concentrations than those with the B1B1 genotype. Polymorphisms within the LPL and CETP genes were associated with a more protective lipid profile in black, but not white SA women. This supports the hypothesis that the more favorable lipid profile of black compared to white SA women is associated with polymorphisms in lipid metabolism genes, specifically the LPL and CETP genes. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Atherosclerosis 03/2015; 240(2):311-317. DOI:10.1016/j.atherosclerosis.2015.03.027 · 3.99 Impact Factor
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