Identification and characterization of a rare variant in apolipoprotein A-IV, p.(V336M), and evaluation of HDL functionality in a Greek cohort with extreme HDL cholesterol levels.

Abstract

High-Density Lipoprotein cholesterol (HDL-C) levels do not correlate well with Coronary Artery Disease (CAD) risk, while HDL functionality affects atherogenesis and is a better prognostic marker for CAD. Often, the extreme HDL-C levels have a multigenic origin. Here, we searched for single-nucleotide polymorphisms (SNPs) in ten genes of HDL metabolism in a Greek cohort with very low (<10th percentile, n = 13) or very high (>90th percentile, n = 21) HDL-C. We also evaluated the association between HDL-C levels, HDL functionality (anti-oxidant capacity) and CAD in the subjects of this cohort. Individuals with low HDL-C levels had higher triglyceride levels, lower apoA-I levels, decreased HDL anti-oxidant capacity and higher incidence of CAD compared with individuals with control or high HDL-C levels. With next generation sequencing we identified 18 exonic SNPs in 6 genes of HDL metabolism and for selected amino acid changes we performed computer-aided structural analysis and modeling. A previously uncharacterized rare apolipoprotein A-IV variant, apoA-IV [V336M], present in a subject with low HDL-C (14 mg/dL) and CAD, was expressed in recombinant form and structurally and functionally characterized. ApoA-IV [V336M] had similar α-helical content to WT apoA-IV but displayed a small thermodynamic stabilization by chemical unfolding analysis. ApoA-IV [V336M] was able to associate with phospholipids but presented reduced kinetics compared to WT apoA-IV. Overall, we identified a rare apoA-IV variant in a subject with low HDL levels and CAD with altered biophysical and phospholipid binding properties and showed that subjects with very low HDL-C presented with HDL dysfunction and higher incidence of CAD in a Greek cohort.

• Authors: Angeliki Chroni, Loukianos Rallidis, Despoina Vassou, Christina Gkolfinopoulou, Paraskevi Papakosta, Maria I Zervou, George N Goulielmos, Estela Kiouri, Danae Pappa, Elias Eliopoulos, Dimitris Kardassis
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 696 Pg. 108655 (12 15 2020) ISSN: 1096-0384 [Electronic] United States
• PMID: 33130088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Apolipoproteins A
• Cholesterol, HDL
• Lipoproteins, HDL
• apolipoprotein A-IV
• Aryldialkylphosphatase
• PON1 protein, human

Topics

• Adult
• Apolipoproteins A (chemistry, genetics)
• Aryldialkylphosphatase (metabolism)
• Cholesterol, HDL (metabolism)
• Cohort Studies
• Coronary Artery Disease (genetics, metabolism)
• Female
• Greece
• Humans
• Lipoproteins, HDL (metabolism)
• Male
• Middle Aged
• Models, Molecular
• Polymorphism, Single Nucleotide