Elsevier

Journal of Clinical Lipidology

Volume 12, Issue 1, January–February 2018, Pages 211-218
Journal of Clinical Lipidology

Original Article
Plasma inducible degrader of the LDLR, soluble low-density lipoprotein receptor, and proprotein convertase subtilisin/kexin type 9 levels as potential biomarkers of familial hypercholesterolemia in children

https://doi.org/10.1016/j.jacl.2017.10.003Get rights and content

Highlights

  • Soluble plasma inducible degrader of the LDLR concentrations are significantly elevated in familial hypercholesterolemia (FH) children.

  • Both proprotein convertase subtilisin/kexin type 9 and inducible degrader of the LDLR plasma concentrations are correlated to low-density lipoprotein (LDL) cholesterol levels.

  • Soluble LDL receptor levels do not discriminate FH children from controls.

  • Plasma biomarkers associated with LDL receptor expression should help identify FH children.

Background

Familial hypercholesterolemia (FH) in children is under-detected. Plasma biomarkers associated with low-density lipoprotein receptor (LDLR) function could help identifying FH children.

Objectives

We aim to assess the clinical value of inducible degrader of the LDLR (IDOL), soluble LDLR (sLDLR), and proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma concentrations in children with FH compared with control children (CCh).

Methods

This was a cross-sectional study performed in a Lipid Unit from a University hospital. The participants were 177 children distributed into FH (n = 77) and CCh (n = 100). Main outcomes were changes in IDOL, sLDLR, and PCSK9 plasma concentrations between children groups; secondary outcomes were the association between IDOL, sLDLR, and PCSK9 and lipid profile determined by 2-dimensional nuclear magnetic resonance.

Results

The IDOL levels were higher in FH compared with CCh (P = .007). The PCSK9 levels were elevated in FH (P < .001). The sLDLR levels had no significant differences between groups. IDOL was significantly positively associated to total and LDL cholesterol and ApoB100 but not to LDL particle number. However, a robust correlation with Lp(a) (P = .001) was observed. PCSK9 had the strongest correlation with LDL-associated parameters including particle number. sLDLR was associated with triglyceride levels (P < .001) and triglyceride-rich particles and inversely to LDL size.

Conclusions

The IDOL and PCSK9 plasma levels are significantly higher in FH children. Interestingly, sLDLR was associated with atherogenic dyslipidemia components. IDOL concentrations show a robust association with Lp(a) levels. To study the role of plasma biomarkers associated with LDLR expression in FH is warranted.

Section snippets

Background

Familial hypercholesterolemia (FH) affects 1 of 250 children. FH is under-detected, particularly in pediatric age.1, 2 Gene defects in LDL receptor (LDLR), apolipoprotein B (ApoB), LDLR adaptor protein 1, and proprotein convertase subtilisin/kexin type 9 (PCSK9) are clinically expressed as an FH phenotype.3 The LDLR is the cornerstone molecule regulating the LDL cholesterol (LDL-C) plasma concentrations.4 LDLR gene mutations, leading to a null or defective receptor, result in a substantial

Study design and patients

This study was a cross-sectional study. One hundred seventy-seven children and adolescents, aged 4 to 18 year, who were participating in the “Early Familial Hypercholesterolemia Detection Program in Children” (DECOPIN) to investigate high cholesterol levels or because they were FH family members, were recruited. Children were distributed into 2 groups: (1) familial hypercholesterolemia (FH; n = 77), if they had a positive genetic study or LDL-C > 150 mg/dL if 1 of the parents had FH and (2)

Subject characteristics

The clinical, biochemical, and genetic characteristics of the 177 children (FH = 77; CCh = 100) are shown in Table 1. The median age of the study participants was 10 years. Age, cholesterol, LDL-C, non-high-density lipoprotein cholesterol (HDL-C) and ApoB100 showed significant differences between the groups. Seventy-three percent of FH children were genetically diagnosed. As expected, LDL (total and subclasses) particle number, as assessed by 2-dimensional nuclear magnetic resonance (2D-1

Discussion

We report data on the IDOL, sLDLR, and PCSK9 plasma concentrations in children with FH and controls. Although in the last years the total PCSK9 plasma levels have been exhaustively studied in different metabolic situations, there is only one publication on sLDLR concentrations in healthy subjects17 and this is the first time that the IDOL plasma concentrations have been reported. A wide concentration range of circulating IDOL levels, including patients with undetectable plasma values, was

Acknowledgments

Authors' contributions: All authors acknowledge that he or she participated sufficiently in work to take public responsibility for its content. All authors of this article have read and approved the final version submitted.

This work was jointly supported by national funding from the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Fundació la Marató de TV3 (ref.20152430), Spanish Atherosclerosis Society (SEA), and FEDER funds. The authors acknowledge

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    The authors have no conflicts of interest relevant to this article to disclose.

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