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

Lamiquiz-Moneo, I. (Universidad de Zaragoza) ; Baila-Rueda, L. ; Bea, A.M. (Universidad de Zaragoza) ; Mateo-Gallego, R. ; Pérez-Calahorra, S. ; Marco-Benedí, V. ; Martín-Navarro, A. ; Ros, E. ; Cofán, M. ; Rodríguez-Rey, J.C. ; Pocovi, M. ; Cenarro, A. ; Civeira, F. (Universidad de Zaragoza)

Resumen: 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 (5a-cholestanol, ß-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 5a-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.

Idioma: Inglés

DOI: 10.1016/j.jacl.2017.09.005

Año: 2017

Publicado en: Journal of Clinical Lipidology 11, 6 (2017), 1432-1440.e4
ISSN: 1933-2874

Factor impacto JCR: 3.58 (2017)

Categ. JCR: PHARMACOLOGY & PHARMACY rank: 61 / 260 = 0.235 (2017) - Q1 - T1

Factor impacto SCIMAGO: 1.654 - Cardiology and Cardiovascular Medicine (Q1) - Nutrition and Dietetics (Q1) - Internal Medicine (Q1) - Endocrinology, Diabetes and Metabolism (Q1)

Tipo y forma: Article (PostPrint)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)