Τίτλος:
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
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2020 Elsevier Inc.
Συγγραφείς:
Chroni, A.
Rallidis, L.
Vassou, D.
Gkolfinopoulou, C.
Papakosta, P.
Zervou, M.I.
Goulielmos, G.N.
Kiouri, E.
Pappa, D.
Eliopoulos, E.
Kardassis, D.
Περιοδικό:
Archives of Biochemistry and Biophysics
Εκδότης:
Academic Press Inc.
Λέξεις-κλειδιά:
ABC transporter A1; ABC transporter G1; apolipoprotein A1; apolipoprotein A2; apolipoprotein A4; apolipoprotein E; aryldialkylphosphatase 1; cholesterol ester transfer protein; high density lipoprotein cholesterol; phosphatidylcholine sterol acyltransferase; phospholipid transfer protein; scavenger receptor B; apolipoprotein A; apolipoprotein A-IV; aryldialkylphosphatase; high density lipoprotein; high density lipoprotein cholesterol; PON1 protein, human, adult; alpha helix; Article; clinical article; cohort analysis; computer aided design; controlled study; coronary artery disease; female; genetic heterogeneity; Greece; Greek (citizen); high density lipoprotein cholesterol level; high throughput sequencing; human; human cell; IHH cell line; lipoprotein blood level; lipoprotein metabolism; male; middle aged; priority journal; protein analysis; protein unfolding; single nucleotide polymorphism; structure analysis; thermodynamics; triacylglycerol blood level; triacylglycerol level; chemistry; coronary artery disease; genetics; metabolism; molecular model; single nucleotide polymorphism, Adult; Apolipoproteins A; Aryldialkylphosphatase; Cholesterol, HDL; Cohort Studies; Coronary Artery Disease; Female; Greece; Humans; Lipoproteins, HDL; Male; Middle Aged; Models, Molecular; Polymorphism, Single Nucleotide
DOI:
10.1016/j.abb.2020.108655
