doi:10.1016/j.jacl.2017.09.005engLamiquiz-Moneo, I.Baila-Rueda, L.Bea, A.M.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.ABCG5/G8 gene is associated with hypercholesterolemias without mutation in candidate genes and noncholesterol sterolsART-2017-103589Context 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.2017http://zaguan.unizar.es/record/7537210.1016/j.jacl.2017.09.005http://zaguan.unizar.es/record/75372oai:zaguan.unizar.es:75372Journal of Clinical Lipidology 11, 6 (2017), 1432-1440.e4by-nc-ndhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccess