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

• Published in: Journal of clinical lipidology Vol. 11; no. 6; pp. 1432 - 1440.e4
• Main Authors: Lamiquiz-Moneo, Itziar, Baila-Rueda, Lucía, Bea, Ana M., Mateo-Gallego, Rocío, Pérez-Calahorra, Sofía, Marco-Benedí, Victoria, Martín-Navarro, Antonio, Ros, Emilio, Cofán, Montserrat, Rodríguez-Rey, José Carlos, Pocovi, Miguel, Cenarro, Ana, Civeira, Fernando
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2017
• Subjects: ABCG5/G8; Adolescent; Adult; Aged; ATP Binding Cassette Transporter, Sub-Family G, Member 5 - genetics; Cholestanol - blood; Cholesterol absorption; Cholesterol, LDL - blood; Cholesterol, LDL - genetics; Female; Genetic Association Studies; Genetic hypercholesterolemia; Genetic Predisposition to Disease; Humans; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - pathology; Lipoproteins - genetics; Male; Middle Aged; Mutation; Noncholesterol sterols; Sterols - blood; Young Adult; Genetic hypercholesterolemia; Noncholesterol sterols; Cholesterol absorption; ABCG5/G8
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2017.09.005

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. 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. 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. 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. 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. •Phytosterols as markers of intestinal cholesterol absorption are elevated in familial hypercholesterolemia (FH).•The present study demonstrates an increase in ABCG5/G8 mutations in FH.•Subjects with mutations in ABCG5/G8 have increased plasma phytosterols.•We show for the first time that ABCG5/G8 is involved in the etiopathogenesis of FH.