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ABCG5/G8 gene is associated with hypercholesterolemias without mutation in candidate genes and non-cholesterol sterols

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 (5?-cholestanol, ?-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 5?-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.

 Fuente: Journal of Clinical Lipidology Volume 11, Issue 6, November-December 2017, Pages 1432-1440.e4

Editorial: Elsevier

 Año de publicación: 2017

Nº de páginas: 31

Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.jacl.2017.09.005

ISSN: 1933-2874,1876-4789

Autores/as

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

POCOVI, MIGUEL

CENARRO, ANA

CIVEIRA, FERNANDO