Healthy Individuals Carrying the PCSK9 p.R46L Variant and Familial Hypercholesterolemia Patients Carrying PCSK9 p.D374Y Exhibit Lower Plasma Concentrations of PCSK9

Humphries, Steve E.; Neely, R. D. G.; Whittall, R.; Troutt, Jason S.; Konrad, Robert J.; Scartezini, Mariléia; Li, Ka Wah; Cooper, Jackie A.; Acharya, Jayshree; Neil, Andrew

doi:10.1373/clinchem.2009.129759

Cited by 50 publications

(29 citation statements)

References 33 publications

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“…After only 4 weeks of treatment, PCSK9 levels increased 47% over baseline levels, and this increase was sustained at 8-week, 12-week, and 16-week time points. Similar to what we and others have previously reported ( 7,29,37,38 ), baseline PCSK9 levels were highly correlated with TC and LDL-C levels. We further demonstrated a correlation between baseline PCSK9 and TG levels.…”

Section: Discussionsupporting

confidence: 90%

“…Patients with gain-of-function mutations of PCSK9 present with severe familial hypercholesterolemia and accompanying increased cardiovascular risk (25)(26)(27)(28)(29). In contrast, individuals with loss-of-function mutations in PCSK9, including mutations which prevent the selfcleavage and secretion of the protein, have signifi cantly decreased levels of serum LDL-C and lower cardiovascular risk (30)(31)(32).…”

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confidence: 99%

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High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol

Welder

Zineh

Pacanowski

et al. 2010

Journal of Lipid Research

229

157

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This article is available online at http://www.jlr.org Proprotein convertase subtilisin kexin type 9 (PCSK9) has been recognized as a key regulator of serum low density lipoprotein cholesterol (LDL-C) levels ( 1-7 ). PCSK9 is a protease made and secreted by the liver into the plasma, which then binds to and degrades hepatic LDL receptors (LDLR) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The mechanism by which PCSK9 degrades LDLR is complex. Recent studies suggest that after self-cleavage and secretion, PCSK9 does not have to be enzymatically active to cause degradation of the LDLR ( 19-21 ). Rather, PCSK9 binds to the LDLR and subsequently targets it for lysosomal destruction within the hepatocyte ( 8,(19)(20)(21). This concept of how PCSK9 acts to decrease hepatic LDLR levels is supported by recent fi ndings that disruption of the binding of PCSK9 to the LDLR using anti-PCSK9 antibody results in preserved LDLR and decreased [22][23][24].Several different PCSK9 mutations have been reported in humans. Patients with gain-of-function mutations of PCSK9 present with severe familial hypercholesterolemia and accompanying increased cardiovascular risk (25)(26)(27)(28)(29). In contrast, individuals with loss-of-function mutations in PCSK9, including mutations which prevent the selfcleavage and secretion of the protein, have signifi cantly decreased levels of serum LDL-C and lower cardiovascular risk (30)(31)(32). Approximately 3% of African-Americans are heterozygous for such mutations ( 30 ). Of note, a compound heterozygote for PCSK9 loss-of-function mutations was recently described. The subject, a healthy 32-year-old female, had a serum LDL-C level of 14 mg/dl ( 32 ). A second Abstract Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor (LDLR), causing its subsequent degradation. We fi rst demonstrated that a moderate dose of atorvastatin (40 mg) increases PCSK9 serum levels, suggesting why increasing statin doses may have diminished effi cacy with regard to further LDL-C lowering. Since that initial observation, at least two other groups have reported statin-induced PCSK9 increases. To date, no analysis of the effect of high-dose atorvastatin (80 mg) on PCSK9 over time has been conducted. Therefore, we studied the time course of atorvastatin (80 mg) in human subjects. We measured PCSK9 and lipid levels during a 2-week lead-in baseline period and every 4 weeks thereafter for 16 weeks. We observed that atorvastatin (80 mg) caused a rapid 47% increase in serum PCSK9 at 4 weeks that was sustained throughout 16 weeks of dosing. Importantly, while PCSK9 levels were highly correlated with total cholesterol (TC), LDL-C, and triglyceride (TG) levels at baseline, atorvastatin (80 mg) completely abolished all of these correlations. Together, these results further suggest an explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering. Abbreviations: HDL-...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol

Welder

Zineh

Pacanowski

et al. 2010

Journal of Lipid Research

229

157

View full text Add to dashboard Cite

show abstract

“…All of these SAAPs belong to gene LDLR and rank top 140 among 13736 SAAPs (less than 1.00%). These results are just in accordance with some previously published research works [28][29][30], which point out that FH results from defective lowdensity lipoprotein receptor (LDLR) activity, mainly due to LDLR gene defects.…”

Section: F Case Studiessupporting

confidence: 92%

Extraction of Sequence Conservation Features for the Prioritization of Candidate Single Amino Acid Polymorphisms

Gan

Zhang

et al. 2011

IJIEEB

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Abstract-Although remarkable success has been achieved by genome-wide association (GWA) studies over the past few years, genetic variants discovered in GWA studies can typically account for only a small fraction of heritability of most common diseases. As such, the identification of multiple rare variants that are associated with complex diseases has been receiving more and more attentions. However, most of the recently developed statistical approaches for detecting association of rare variants with diseases require the selection of functional variants before the successive analysis, making an effective bioinformatics method for filtering out non-relevant rare variants indispensible. In this paper, we focus on a specific type of genetic variants called single amino acid polymorphisms (SAAPs). We propose to prioritize candidate SAAPs for a specific disease according to their association scores that are calculated using a guilt-by-association model with a set of features derived from protein sequences. We validate the proposed approach in a systematic way and demonstrate that the proposed model is powerful in distinguishing disease-associated SAAPs for the specific disease of interest.

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“…Other studies have documented variable changes in plasma PCSK9 for carriers of PCSK9 loss-offunction and gain-of-function variants compared with control individuals (noncarriers of a particular PCSK9 variant) (34,36,37 ). In fact, circulating PCSK9 may differentially affect plasma LDLC concentrations, depending on whether an individual carries a PCSK9 variant that alters its LDLR-degrading activity and depending on the mode of action of that particular PCSK9 mutation and/or variant.…”

Section: Discussionmentioning

confidence: 99%

“…It binds 10 times better to the liver LDLR than PCSK9-WT, thereby decreasing the plasma PCSK9 concentrations in D374Y carriers compared with noncarriers and augmenting LDLR degradation (38 ). On the other hand, plasma PCSK9 concentrations are also reduced in carriers of the loss-of-function PCSK9-R46L variant, which is associated with reduced LDLC concentrations (24,36,37 ), although the reason for this observation is less clear. Our studies with HEK293 cell cultures showed no change in the rate of PCSK9-R46L secretion (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Novel Loss-of-Function PCSK9 Variant Is Associated with Low Plasma LDL Cholesterol in a French-Canadian Family and with Impaired Processing and Secretion in Cell Culture

et al. 2011

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BACKGROUND: PCSK9 (proprotein convertase subtilisin/kexin type 9) is a polymorphic gene whose protein product regulates plasma LDL cholesterol (LDLC) concentrations by shuttling liver LDL receptors (LDLRs) for degradation. PCSK9 variants that cause a gain or loss of PCSK9 function are associated with hyper-or hypocholesterolemia, which increases or reduces the risk of cardiovascular disease, respectively. We studied the clinical and molecular characteristics of a novel PCSK9 loss-of-function sequence variant in a white French-Canadian family.

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Healthy Individuals Carrying the PCSK9 p.R46L Variant and Familial Hypercholesterolemia Patients Carrying PCSK9 p.D374Y Exhibit Lower Plasma Concentrations of PCSK9

Cited by 50 publications

References 33 publications

High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol

High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol

Extraction of Sequence Conservation Features for the Prioritization of Candidate Single Amino Acid Polymorphisms

Novel Loss-of-Function PCSK9 Variant Is Associated with Low Plasma LDL Cholesterol in a French-Canadian Family and with Impaired Processing and Secretion in Cell Culture

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