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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    • "In their seminal paper, Abifadel and colleagues demonstrated that a PCSK9 gain-of-function (GOF) mutation is the third most common cause of autosomal dominant hypercholesterolemia (ADH), a genetic disease associated with premature atherosclerosis (Abifadel et al., 2003). Thereafter, wholelife lower concentrations of plasma LDL-cholesterol (LDL-C) and protection against cardiovascular diseases were associated with PCSK9 loss-of-function (LOF) mutations (Cohen et al., 2006). "
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    ABSTRACT: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to familial hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine-sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake, whereas cells originally derived from an individual with FHBL (HLC-R104C/V114A) displayed a strong decrease in PCSK9 secretion (-89.7%; P<0.001) and had a 106% increase (P=0.0104) of LDL uptake. Pravastatin treatment significantly enhanced LDL receptor (LDLR) and PCSK9 mRNA gene expression, as well as PCSK9 secretion and LDL uptake in both control and S127R HLCs. Pravastatin treatment of multiple clones led to an average increase of LDL uptake of 2.19±0.77-fold in HLC-S127R compared to 1.38±0.49 fold in control HLCs (P<0.01), in line with the good response to statin treatment of individuals carrying the S127R mutation (mean LDL cholesterol reduction=60.4%, n=5). In conclusion, urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function.
    Disease Models and Mechanisms 11/2015; DOI:10.1242/dmm.022277 · 4.97 Impact Factor
    • "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; 33(43). DOI:10.1016/j.vaccine.2015.09.044 · 3.62 Impact Factor
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    • "Among the PCSK9 loss-of-function variants, R46L is the most prevalent and affects nearly 1/50 individuals [31] [32] [33]. This mutation is associated with decreased PCSK9 levels, LDL-C concentrations and CAD risk [29] [31] in non-FH subjects. A recent study by Saavedra et al. [34] showed that HeFH carrying the R46L had lower LDL-C levels and a reduced CVD risk compared with non-carriers. "
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    ABSTRACT: Objective: To assess the relationship between LDLR genotype and the plasma levels of PCSK9, LDL-C, and lipoprotein (a) (Lp(a)) in a large cohort of genetically defined FH heterozygotes (HeFH). Methods: A total of 292 HeFH carrying one of the nine French-Canadian mutations in the LDLR gene were recruited. The cohort included 226 carriers of a negative-receptor (NR) mutation and 66 carriers of a defective-receptor (DR) LDLR gene mutation. Fifty-six control subjects, who were matched with the HeFH subjects based on gender and body mass index, were also recruited. Results: PCSK9 levels were higher in the HeFH group than in the control group (317.9±107.1ng/mL vs. 203.3±59.8ng/mL; P<0.0001). The strength of the association between PCSK9 and LDL-C levels was similar among controls (r=0.37; P=0.005) and HeFH (r=0.31; P<0.0001). Furthermore, a multiple linear regression analysis revealed that the positive correlation between PCSK9 and LDL-C levels remained significant after adjusting for LDLR genotype in the HeFH group. Conclusion: These results suggested that the contribution of PCSK9 levels to the phenotypic severity in FH heterozygotes is independent of LDLR genotype.
    Metabolism: clinical and experimental 09/2015; 64(11). DOI:10.1016/j.metabol.2015.08.007 · 3.89 Impact Factor
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