Barbara Sjouke1, Michael W T Tanck2, Sigrid W Fouchier3, Joep C Defesche4, Barbara A Hutten2, Albert Wiegman5, John J P Kastelein6, G Kees Hovingh6. 1. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: b.sjouke@amc.uva.nl. 2. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 3. 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. 4. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 5. Department of Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 6. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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 FHpatients in whom no mutation is identified in the 3 FH genes. OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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 FHpatients with polygenic hypercholesterolemia in our study population.