title: Children with hypercholesterolemia of unknown cause: Value of genetic risk scores.
abstract: Familial hypercholesterolemia (FH) is caused by mutations in LDLR, APOB, or PCSK9, and in a previous study, we identified a causative mutation in these FH genes in 95% (255 of 269) of children with the FH phenotype. It has been hypothesized that a polygenic form of hypercholesterolemia is present in FH patients in whom no mutation is identified in the 3 FH genes.
  
  
  
  To address whether a polygenic form of hypercholesterolemia, defined as high-weighted effect of low-density lipoprotein cholesterol (LDL-C) raising SNPs expressed as the genetic risk score (GRS), is present in the remaining 14 children.
  
  
  
  On reassessment of the molecular diagnosis and clinical phenotype, 8 FH kindreds met the criteria for hypercholesterolemia of unknown cause and were included in this study. We calculated a weighted GRS comprising 10 established LDL-C-associated SNPs and the APOE genotype in these index cases and evaluated whether the index cases were characterized by an increased GRS compared to 26 first-degree relatives. Phenotypically affected and unaffected individuals could not be distinguished based on any of the risk scores.
  
  
  
  In this and our previous study, we show that a causal mutation in LDLR, APOB, and PCSK9 can be identified in almost all children with a definite clinical diagnosis of FH. In the small group of patients without a mutation, we did not observe a higher GRS compared with unaffected relatives, which suggests that the FH phenotype is not caused by the aggregate of LDL-C increasing SNPs. Our data imply that application of the GRS is not instrumental as a diagnostic tool to individually define clinically diagnosed FH patients with polygenic hypercholesterolemia in our study population.
authors: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: b.sjouke@amc.uva.nl.
authors: Barbara
authors: B
authors: Sjouke
authors: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Michael W T
authors: MWT
authors: Tanck
authors: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Sigrid W
authors: SW
authors: Fouchier
authors: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Joep C
authors: JC
authors: Defesche
authors: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Barbara A
authors: BA
authors: Hutten
authors: Department of Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Albert
authors: A
authors: Wiegman
authors: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: John J P
authors: JJP
authors: Kastelein
authors: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: G Kees
authors: GK
authors: Hovingh
mesh_terms: D000293:Adolescent; D001055:Apolipoproteins B / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9 / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D018570:Risk Assessment
chemical_list: D001055:Apolipoproteins B; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Familial hypercholesterolemia; Genetic risk scores; Polygenic hypercholesterolemia