The contribution of PCSK9 levels to the phenotypic severity of familial hypercholesterolemia is independent of LDL receptor genotype

Drouin‐Chartier, Jean‐Philippe; Tremblay, André; Hogue, Jean-Charles; Ooi, Teik Chye; Lamarche, Benoı̂t; Couture, Patrick

doi:10.1016/j.metabol.2015.08.007

Cited by 11 publications

(9 citation statements)

References 39 publications

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“…Hence, the exploration of prognostic predicator for FH patients may be of great interest. Notably, PCSK9 level has been consistently reported to be significantly higher in patients with FH comparing with normocholesterolemic participants and higher circulating PCSK9 level might contribute to a worse hypercholesterolemic phenotype in FH patients independent of LDLR genotype [33, 34]. For example, Drouin-Chartier et al has reported that mean PCSK9 levels were significantly higher in the HeFH group than in the control group (317.9 vs. 203.3 ng/mL) [33].…”

Section: Discussionmentioning

confidence: 99%

Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy

et al. 2019

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BackgroundProprotein convertase subtilisin/kexin 9 (PCSK9) has been proposed as a novel target for coronary artery disease (CAD). Familial hypercholesterolemia (FH) is characterized by high prevalence of CAD and major cardiovascular events (MACEs). However, no data is available on the association between PCSK9 levels and MACEs in FH patients with standard lipid lowering therapy.MethodsA total of 338 consecutive heterozygous FH (Dutch Lipid Clinic Network score ≥ 6) was enrolled and followed up for the occurrence of MACEs. Multidetector CT and coronary angiography were performed to determine coronary artery calcification score (CACS) and Gensini score (GS). Multivariable Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma PCSK9 concentrations were determined by enzyme immunoassay.ResultsPCSK9 was independently and positively associated CACS and GS at baseline. During a mean follow-up of 3 years, 33 (9.8%) events occurred. Patients with MACEs had higher median PCSK9 compared with those without (332.47 vs. 311.89 ng/mL, p = 0.038). Kaplan–Meier analysis revealed that patients with higher PCSK9 presented lower event-free survival (p = 0.0017). PCSK9 was statistically correlated with MACEs after adjusting for confounding factors, with the HR per SD being 1.86 (1.31–2.65) and 3.70 (1.16–11.82) for the highest tertile compared with the lowest tertile. Adding PCSK9 to Cox prediction model led to a statistical improvement in net reclassification and integrated discrimination.ConclusionElevated levels of PCSK9 were positively associated with the development of CAD and future cardiovascular events, suggesting that measurement of PCSK9 concentration might be useful for cardiovascular risk stratification. Further studies are needed to confirm our results.

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Section: Discussionmentioning

confidence: 99%

Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy

et al. 2019

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“…For instance, plasma PCSK9 levels positively correlate with LDL-C; for LDL-C levels typically seen in homozygous FH (ie, LDL-C > 13.0 mmol/L, as seen in the index cases reported here), baseline plasma PCSK9 levels are 2-to 3-fold higher than normolipidemic controls. [24][25][26] Also, statins upregulate PCSK9 expression; the PCSK9 promoter contains a sterol regulator element site and is co-expressed with LDLR after nuclear translocalization of the sterol regulator element binding protein-2 in response to low intracellular cholesterol. 27 Index case A remained on rosuvastatin 40 mg daily while plasma was taken for PCSK9 determination.…”

Section: Discussionmentioning

confidence: 99%

Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia

Iacocca

Wang

Sarkar

et al. 2018

Canadian Journal of Cardiology

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“…We previously reported a significant association between total apoB concentrations and PCSK9 levels ( r = 0.31) in HeFH subjects [23]. Our power analysis indicated that the probability to detect a true change in plasma apoB-48 of 0.31 units per unit change in PCSK9 levels with 118 HeFH subjects at a two-sided 0.05 significance level was 91%.…”

Section: Methodsmentioning

confidence: 70%

“…Concomitantly, PCSK9 stimulates chylomicron secretion in intestinal cells [20–22]. Studies from our group and others reported higher levels of PCSK9 in FH subjects [23, 24]. However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized.…”

Section: Introductionmentioning

confidence: 99%

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels

Drouin‐Chartier¹,

Hogue

Tremblay³

et al. 2017

Lipids Health Dis

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BackgroundPrevious studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B-48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized. The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH).MethodsA total of 118 HeFH, 6 HoFH, and 117 controls were included in the study. Plasma PCSK9 and apoB-48 concentrations were measured in the fasting state.ResultsPlasma PCSK9 and apoB-48 levels were higher in FH subjects compared with controls (PCSK9: HoFH: 642.6 ± 246.9 vs. HeFH: 324.9 ± 119.8 vs. controls: 194.5 ± 65.9 ng/mL, P < 0.0001; apoB-48: HoFH: 14.71 ± 4.36 vs. HeFH: 6.55 ± 4.24 vs. controls: 3.03 ± 2.07 μg/mL; P < 0.0001). There were no correlations between apoB-48 and PCSK9 plasma levels in both controls (ρ = 0.06, P = 0.5) and HeFH subjects (ρ = 0.07, P = 0.4). Multiple linear regression analysis showed that the FH status was the only independent factor associated with apoB-48 levels, contributing to 28.7% of the variance (P < 0.0001).ConclusionsThese data indicate that the elevation in plasma apoB-48 levels associated with FH is independent of PCSK9 levels.Trial registration NCT02225340.

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The contribution of PCSK9 levels to the phenotypic severity of familial hypercholesterolemia is independent of LDL receptor genotype

Cited by 11 publications

References 39 publications

Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy

Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy

Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels

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