Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia

J Clin Lipidol. 2023 Sep-Oct;17(5):643-658. doi: 10.1016/j.jacl.2023.07.003. Epub 2023 Jul 27.

Abstract

Background: The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in dyslipidemia may go beyond its immediate effects on low-density lipoprotein receptor (LDL-R) activity.

Objective: This study aimed to assess PCSK9-derived alterations of high-density lipoprotein (HDL) physiology, which bear a potential to contribute to cardiovascular risk profile.

Methods: HDL was isolated from 33 patients with familial autosomal dominant hypercholesterolemia (FH), including those carrying PCSK9 gain-of-function (GOF) genetic variants (FH-PCSK9, n = 11), together with two groups of dyslipidemic patients employed as controls and carrying genetic variants in the LDL-R not treated (ntFH-LDLR, n = 11) and treated (tFH-LDLR, n = 11) with statins, and 11 normolipidemic controls. Biological evaluations paralleled by proteomic, lipidomic and glycomic analyses were applied to characterize functional and compositional properties of HDL.

Results: Multiple deficiencies in the HDL function were identified in the FH-PCSK9 group relative to dyslipidemic FH-LDLR patients and normolipidemic controls, which involved reduced antioxidative, antiapoptotic, anti-thrombotic and anti-inflammatory activities. By contrast, cellular cholesterol efflux capacity of HDL was unchanged. In addition, multiple alterations of the proteomic, lipidomic and glycomic composition of HDL were found in the FH-PCSK9 group. Remarkably, HDLs from FH-PCSK9 patients were systematically enriched in several lysophospholipids as well as in A2G2S2 (GP13) glycan and apolipoprotein A-IV. Based on network analysis of functional and compositional data, a novel mosaic structure-function model of HDL biology involving FH was developed.

Conclusion: Several metrics of anti-atherogenic HDL functionality are altered in FH-PCSK9 patients paralleled by distinct compositional alterations. These data provide a first-ever overview of the impact of GOF PCSK9 genetic variants on structure-function relationships in HDL.

Keywords: Computational biology; Familial hypercholesterolemia; Gain-of-function mutation; High-density lipoproteins; Low-density lipoprotein receptor; Proprotein convertase subtilisin kexin type 9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Hyperlipoproteinemia Type II* / genetics
  • Lipoproteins, HDL / genetics
  • Mutation
  • Proprotein Convertase 9* / genetics
  • Proteomics
  • Receptors, LDL / genetics
  • Structure-Activity Relationship

Substances

  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Lipoproteins, HDL
  • Receptors, LDL