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: 54.42). 04/2006; 354(12):1264-72. DOI: 10.1056/NEJMoa054013
Source: PubMed

ABSTRACT 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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    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.
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    ABSTRACT: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is associated with autosomal dominant hypercholesterolemia (ADH), a state of elevated levels of LDL cholesterol. ADH can result in severe implications like stroke and coronary heart disease. The inhibition of PCSK9 function by therapeutic antibodies that block interaction of PCSK9 with the EGF-A domain of LDL receptor (LDLR) was shown to successfully lower LDL cholesterol levels in clinical studies. Here we present data on the identification, structural and biophysical characterization and in vitro and in vivo pharmacology of a PCSK9 antibody (mAb1). The X-ray structure shows that mAb1 binds the module 1 of the C-terminal domain (CTD) of PCSK9. It blocks access to an area bearing several naturally occurring gain and loss of function mutations. Although the antibody does not inhibit binding of PCSK9 to EGF-A, it partially reverses PCSK9 induced reduction of the LDLR and LDL cholesterol uptake in a cellular assay. mAb1 is also effective in lowering serum levels of LDL cholesterol in cynomolgus monkeys in vivo. Complete loss of PCSK9 is associated with insufficient liver regeneration and increased risk of hepatitis C infections. Blocking of the CTD is sufficient to partially inhibit PCSK9 function. Antibodies binding the CTD of PCSK9 may thus be advantageous in patients that do not tolerate complete inhibition of PCSK9.
    Journal of Molecular Biology 11/2013; 426(4). DOI:10.1016/j.jmb.2013.11.011 · 3.96 Impact Factor
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    ABSTRACT: by defects in the low-density lipoprotein receptor gene and apo lipoprotein B 100 genes, respectively. The clinical phenotype of both diseases is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature coronary heart disease. Objectives. The aim of this study is to perform an association study between different gene sequence variants in low-density lipoprotein and apo lipoprotein B 100 genes to the clinical finding and lipid profile parameters of the study subjects. Material and Methods. A group of 164 familial hypercholesterolemic patients were recruited. The promoter region, exon 2–15 of the low density lipoprotein gene and parts of exon 26 and 29 of apo lipoprotein B 100 gene were screened by Denaturating Gradient High Performance Liquid Chromatography. Results. For the apo lipoprotein B 100 gene, those with apo lipoprotein B 100 gene mutation have a significantly higher frequency of cardiovascular disease (P = 0.045), higher low density lipoprotein cholesterol and total cholesterol: high density lipoprotein cholesterol ratio than those without mutation (P = 0.03 and 0.02, respectively). For the low density lipoprotein gene defect those with frame shift mutation group showed the worst clinical presentation in terms of low density lipoprotein cholesterol level and cardiovascular frequency. Conclusions. There was a statistically significant association between mutations of low density lipoprotein gene and apo lipoprotein B 100 genes and history of cardiovascular disease, younger age of presentation, family history of hyperlipidemia, tendon xanthoma and low density lipoprotein cholesterol level (Adv Clin Exp Med 2013, 22, 1, 00–00).
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