Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia

Huijgen, Roeland; Fouchier, Sigrid W.; Denoun, Michael; Hutten, Barbara A.; Vissers, Maud N.; Lambert, Gilles; Kastelein, John J.P.

doi:10.1194/jlr.p023994

Cited by 59 publications

(41 citation statements)

References 26 publications

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“…PCSK9 levels correlated inversely with LDL cholesterol levels in FH patients. 22 PCSK9 inhibitors are being tested in phase III trials 23 now, and are expected to be highly effective in FH patients. 24,25 Our definition of extreme groups might have been too restrictive, as it constitutes a very small proportion of the FH sample (500 out of 17 000).…”

Section: Discussionmentioning

confidence: 99%

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

et al. 2014

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Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (Po1 Â 10 À4 ). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

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Section: Discussionmentioning

confidence: 99%

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

et al. 2014

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“…Circulating PCSK9 levels were extremely elevated in ARH at 526±31 ng/mL. 11,12 We first assessed cell-surface LDLR expression in lymphocytes isolated from control individuals and ARH patients by flow cytometry. After mevastatin treatment, ∆ mean fluorescence intensity (MFI) levels of cell surface LDLR expression reached a maximum of 635±56 arbitrary unit (AU) in control lymphocytes.…”

Section: Resultsmentioning

confidence: 99%

Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report

Thedrez

Sjouke

Passard

et al. 2016

ATVB

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Objective— Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Approach and Results— Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. Conclusions— PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.

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“…Expression of LDLRs on the cell surface is regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9). Recently, Huijgen et al (2012) reported that plasma levels of PCSK9 were associated with LDL cholesterol levels in patients with familial hypercholesterolemia. In addition, overexpression of PCSK9 induced negative modulation of LDLR expression and decreased plasma LDL clearance, also promoting atherosclerosis (Herbert, 2010).…”

Section: Ldl Receptormentioning

confidence: 99%

Genetically Modified Animal Models for Lipoprotein Research

Shiomi¹,

Koike²,

Ishida³

2012

Lipoproteins - Role in Health and Diseases

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Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia

Cited by 59 publications

References 26 publications

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report

Genetically Modified Animal Models for Lipoprotein Research

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