PCSK9R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease

Benn, Marianne; Nordestgaard, Børge G.; Grande, Peer; Schnohr, Peter; Tybjærg‐Hansen, Anne

doi:10.1016/j.jacc.2010.02.044

Cited by 282 publications

(192 citation statements)

References 25 publications

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“…PCSK9 is secreted by the liver and acts as an endogenous inhibitor of the LDL receptor (LDLR). PCSK9 loss-of-function (LOF) mutations contribute to low levels of plasma LDL-cholesterol and protection against cardiovascular diseases [1,2]. For instance, the PCSK9 LOF low-frequent variant p.R46L (rs11591147; minor allele frequency in the HapMap-CEU (Centre d'Etude du Polymorphisme [Utah residents with northern and western European ancestry] population: 2.8%) has been shown to increase the number of cell surface LDLRs in hepatocytes in vitro [3], leading to a mean reduction in LDL-cholesterol of 9% to 16% in p.R46L carriers.…”

Section: Introductionmentioning

confidence: 99%

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

et al. 2015

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Aims/hypothesis Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol homeostasis. PCSK9 inhibitors are being actively developed to lower LDL-cholesterol levels. However, there are conflicting data regarding the consequences of Pcsk9 deficiency on glucose homeostasis in mouse models. Here, we analysed in humans the association between the PCSK9 p.R46L loss-of-function (LOF) variant and (1) glucose homeostasis variables; (2) type 2 diabetes status; and (3) the risk of 9 year incident type 2 diabetes in a prospective study. Methods PCSK9 p.R46L was genotyped in 4630 French participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study and in 1342 French participants with type 2 diabetes. The association between p.R46L and metabolic traits or type 2 diabetes risk was assessed through linear or logistic regression models adjusted for age, sex and BMI. The association between p.R46L and incident type 2 diabetes was assessed using a Cox regression model adjusted for sex, age and BMI at baseline. Results Significant associations (p<10 −6 ) were found between p.R46L and lower total cholesterol (−0.394 mmol/l), LDL-cholesterol (−0.393 mmol/l) and apolipoprotein B concentrations (−0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin, HbA 1c , HOMA-B, HOMA-IR) or type 2 diabetes risk. Furthermore, no significant association between p.R46L variant and risk of incident type 2 diabetes was observed in DESIR. Conclusions/interpretation The PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in Electronic supplementary material The online version of this article

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Section: Introductionmentioning

confidence: 99%

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

et al. 2015

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“…Dieser Zusammenhang für die R46L-"Loss-of-function"-Mutation wurde durch eine umfangreiche Metaanalyse an 66.698 Probanden eindrucksvoll bestätigt. Eine Reduktion des LDL-C in der Gruppe der R46L-Mutations-Träger um 12 % ging auch in dieser Auswertung mit einer signifikanten Reduktion des KHK-Risikos um 28 % einher [18].…”

Section: Entdeckung Von Pcsk9unclassified

PCSK9 − „missing link“ der familiären Hypercholesterinämie

Thiery

Burkhardt

2016

Herz

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“…Mutations in this gene are associated with hypocholesterolemia and hypercholesterolemia through LOF [49][50][51] and GOF . Importantly, these mutations may be chronic hyperglycemia 45) .…”

Section: Pcsk9 and The Presence/severity Of Cadmentioning

confidence: 99%

“…For example, PCSK9 exhibits beneficial effects on liver regeneration after a hepatic insult; thus, caution should be exercised when using a PCSK9 inhibitor in patients suffering from hepatitis or liver cirrhosis 23,38) . In addition, PCSK9 plays an important role sustaining the normal pancreatic islet function; thus, combined PCSK9 inhibitor/statin therapy may cause large increases in LDLR expression and increase lipid accumulation in pancreatic cells to involved in CAD risk 49,51,53,54) and contribute to the severity of coronary artery atherosclerosis 55) . For example, the Atherosclerosis Risk in Communities study demonstrated that carriers of the PCSK9 LOF variants R46L and Y142X or C679X were respectively associated with a 15% (28%) reduction in mean LDL-C levels and a 47% (88%) reduction in cardiovascular risk dur ing a 15-year follow-up 51) .…”

Section: Pcsk9 and The Presence/severity Of Cadmentioning

confidence: 99%

PCSK9: A key factor modulating atherosclerosis

2015

JAT

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Coronary artery disease (CAD) due to obstructive atherosclerosis is a leading cause of death and has been recognized as a worldwide health threat. Measures to decrease low-density lipoprotein cholesterol (LDL-C) levels are the cornerstone in the management of patients with atherosclerotic cardiovascular disease, particularly those with CAD, for over two decades. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly recognized protein, plays a key role in cholesterol homeostasis by enhancing degradation of hepatic LDL receptor (LDLR). Interestingly, PCSK9 is also involved in the inflammatory process. Plasma PCSK9 and lipid or nonlipid cardiovascular risk factors are correlated, and the associations between PCSK9 with cardiovascular health and disease make this protein worthy of attention for the treatment of hyperlipidemia and atherosclerosis. Here, we provide an overview of the physiological role of PCSK9, which contributes to atherosclerosis, and provide data on PCSK9 as a novel pharmacological target. Clinical evidence shows that PCSK9 inhibition is as promising as statins as a target to treat CAD. The efficacy of these drugs may potentially enable effective CAD prophylaxis for more patients.

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PCSK9R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease

Cited by 282 publications

References 25 publications

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

PCSK9 − „missing link“ der familiären Hypercholesterinämie

PCSK9: A key factor modulating atherosclerosis

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