title: The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene.
abstract: Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low-density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9). Familial hypercholesterolemia (FH) caused by mutation in the LDLR gene is the most frequent form of ADH. The incidence of FH is particularly high in the Lebanese population presumably as a result of a founder effect. In this study we characterize the spectrum of the mutations causing FH in Lebanon: we confirm the very high frequency of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH Lebanese probands recruited and identify other less frequent mutations in the LDLR. Finally, we show that the p.Leu21dup, an in frame insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9, known to be associated with lower LDL-cholesterol levels in general populations, is also associated with a reduction of LDL-cholesterol levels in FH patients sharing the p.C681X mutation in the LDLR. Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL-cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia.
authors.affiliation: Inserm, U781, Paris, France. marianne.abi-fadel@inserm.fr
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
authors.forename: Sélim
authors.initials: S
authors.lastname: Jambart
authors.forename: Georges
authors.initials: G
authors.lastname: Halaby
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Gannagé-Yared
authors.forename: Antoine
authors.initials: A
authors.lastname: Sarkis
authors.forename: Ghada
authors.initials: G
authors.lastname: Beaino
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
authors.forename: Nabiha
authors.initials: N
authors.lastname: Salem
authors.forename: Sandra
authors.initials: S
authors.lastname: Corbani
authors.forename: Hermine
authors.initials: H
authors.lastname: Aydénian
authors.forename: Claudine
authors.initials: C
authors.lastname: Junien
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau