@article{10902/12351,
year = {2017},
url = {http://hdl.handle.net/10902/12351},
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.},
organization = {This study was supported by grants from the Spanish Ministry of Economy and Competitiveness PI15/01983, PI13/02507, PI12/01321, CIBERCV, CIBEROBN, and Cuenca Villoro Foundation. These projects are co-financed by Instituto de Salud Carlos III and the European Regional Development Fund (ERDF) of the European Union “A way to make Europe.”},
publisher = {Elsevier},
publisher = {Journal of Clinical Lipidology

 Volume 11, Issue 6, November-December 2017, Pages 1432-1440.e4},
title = {ABCG5/G8 gene is associated with hypercholesterolemias without mutation in 
candidate genes and non-cholesterol sterols},
author = {Lamiquiz Moneo, Itziar and Baila Rueda, Lucía and Bea, Ana M. and Mateo Gallego, Rocío and Pérez Calahorra, Sofía and Marco Benedí, Victoria and Martín Navarro, Antonio and Ros, Emilio and Cofán, Montserrat and Rodríguez Rey, José Carlos and Pocovi, Miguel and Cenarro, Ana and Civeira, Fernando},
}