title: Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels.
abstract: Autosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL-cholesterol (LDL-C) levels below the 50th percentile for age and gender prior to lipid-lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss-of-function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL-C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholesterolemic phenotype were not found. The common variants p.N902N, c.3842+82T>A, p.D2312D, and p.E4181K in APOB, and c.1863+94A>G in PCSK9 were significantly more prevalent in our cohort compared to the general European population. Interestingly, 40% of our probands carried at least one minor allele for all four common APOB variants compared to 1.5% in the general European population. While we found a low prevalence of rare variants in our cohort, our data suggest that regions in proximity of the analyzed loci, and linked to specific common haplotypes, might harbor additional variants that correct an ADH phenotype.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.forename: Barbara
authors.initials: B
authors.lastname: Sjouke
authors.forename: Kelly
authors.initials: K
authors.lastname: Vis
authors.forename: Janine S E
authors.initials: JS
authors.lastname: de Randamie
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Sigrid W
authors.initials: SW
authors.lastname: Fouchier
mesh_terms: D000328:Adult; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics*; D001055:Apolipoproteins B / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D055815:Young Adult
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases