ABCG5/G8 gene is associated with hypercholesterolemias without mutation in candidate genes and noncholesterol sterols

J Clin Lipidol. 2017 Nov-Dec;11(6):1432-1440.e4. doi: 10.1016/j.jacl.2017.09.005. Epub 2017 Oct 4.

Abstract

Context: Approximately 20% to 40% of clinically defined familial hypercholesterolemia (FH) cases do not show a causative mutation in candidate genes (mutation-negative FH), and some of them may have a polygenic origin.

Objective: The aim of this work was to study the prevalence of ABCG5/G8 genetic variants in mutation-negative FH, as defects in these genes relate to intestinal hyperabsorption of cholesterol and thus ABCG5/G8 variants could explain in part the mechanism of hypercholesterolemia.

Design, setting, and patients: We sequenced the ABCG5/G8 genes in 214 mutation-negative FH and 97 controls. Surrogate markers of cholesterol absorption (5α-cholestanol, β-sitosterol, campesterol, stigmasterol, and sitostanol) were quantified by high-performance liquid chromatography-tandem mass spectrometry in both studied groups.

Results: We found 8 mutation-negative FH patients (3.73%) with a pathogenic mutation in ABCG5/G8 genes. We observed significantly higher concentration of surrogate markers of cholesterol absorption in mutation-negative FH than in controls. In addition, we found significantly higher concentrations of cholesterol absorption markers in mutation-negative FH with ABCG5/G8 defects than in mutation-negative, ABCG5/G8-negative FH. A gene score reflecting the number of common single nucleotide variants associated with hypercholesterolemia was significantly higher in cases than in controls (P = .032). Subjects with a gene score above the mean had significantly higher 5α-cholestanol and stigmasterol than those with a lower gene score.

Conclusions: Mutation-negative FH subjects accumulate an excess of rare and common gene variations in ABCG5/G8 genes. This variation is associated with increased intestinal absorption of cholesterol, as determined by surrogate makers, suggesting that these loci contribute to hypercholesterolemia by enhancing intestinal cholesterol absorption.

Keywords: ABCG5/G8; Cholesterol absorption; Genetic hypercholesterolemia; Noncholesterol sterols.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 5 / genetics*
  • Adolescent
  • Adult
  • Aged
  • Cholestanol / blood
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / genetics*
  • Hyperlipoproteinemia Type II / pathology
  • Lipoproteins / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Sterols / blood
  • Young Adult

Substances

  • ABCG5 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • Cholesterol, LDL
  • Lipoproteins
  • Sterols
  • Cholestanol