title: Lipid phenotype and heritage pattern in families with genetic hypercholesterolemia not related to LDLR, APOB, PCSK9, or APOE.
abstract: A substantial proportion of individuals clinically diagnosed as familial hypercholesterolemia (FH) do not carry pathogenic mutations in candidate genes. Whether in them the high cholesterol trait is transmitted monogenically has not been studied.
  
  
  
  We assessed the inheritance pattern, penetrance, and expression of high low-density lipoprotein (LDL)-cholesterol (LDLc) in families with genetic hypercholesterolemia (GH) without known causative mutations (non-FH-GH).
  
  
  
  The study included probands with a clinical diagnosis of FH and their families attending 2 lipid clinics in Spain. Inclusion criteria for probands were LDLc >95th percentile, triglycerides <90th percentile, at least 1 first-degree family member with LDLc >90th percentile, >5 points in the Dutch Lipid Clinic Network criteria score, and absence of mutations in LDLR, APOB, PCSK9 or APOE. Eleven FH families with a LDLR mutation were also examined for comparison.
  
  
  
  We analyzed 49 non-FH-GH probands and 277 first-and second-degree relatives. LDLc was >90th percentile in 37.8% of blood relatives, at concentrations similar to those of probands. LDLc had a normal distribution in non-FH-GH families, in contrast with a bimodal distribution in FH families. When a dominant model was tested, family-based association tests gave much lower heritability values for total cholesterol and LDLc in non-FH-GH (0.39 and 0.32, respectively) than in FH (0.78 and 0.61, respectively).
  
  
  
  Non-FH-GH families have a milder lipid phenotype than genetically defined FH. The heritage pattern of LDLc in non-FH-GH does not fit with a monogenic disorder. Our findings support the concept that most non-FH-GHs are polygenic hypercholesterolemias.
authors.affiliation: Lipid Unit, Department of Internal Medicine, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Jarauta
authors.affiliation: Lipid Unit, Department of Internal Medicine, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: María Rosario
authors.initials: MR
authors.lastname: Pérez-Ruiz
authors.affiliation: Lipid Unit, Department of Internal Medicine, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Sofia
authors.initials: S
authors.lastname: Pérez-Calahorra
authors.affiliation: Lipid Unit, Department of Internal Medicine, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Mateo-Gallego
authors.affiliation: Lipid Unit, Department of Internal Medicine, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cenarro
authors.affiliation: Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clínic, Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cofán
authors.affiliation: Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clínic, Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.affiliation: Lipid Unit, Department of Internal Medicine, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza, Zaragoza, Spain. Electronic address: civeira@unizar.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.affiliation: Departamento de Anatomía, Embriología y Genetica Animal, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Tejedor
mesh_terms: D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000032:analysis; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis* / Q000235:genetics; D017270:Lipoprotein(a) / Q000097:blood; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D017270:Lipoprotein(a); D011973:Receptors, LDL; D014280:Triglycerides; D002097:C-Reactive Protein; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Familial hypercholesterolemia; Family study; Heritability; Hypercholesterolemia; Segregation