title: Cosegregation of serum cholesterol with cholesterol intestinal absorption markers in families with primary hypercholesterolemia without mutations in LDLR, APOB, PCSK9 and APOE genes.
abstract: OBJECTIVE
  The genetic cause and pathogenic mechanism of approximately 20-40% of autosomal dominant hypercholesterolemias (ADH) are unknown. Increased cholesterol intestinal absorption has been associated to ADH. If this variation contributes to their pathogenesis is unknown.
  
  
  RESULTS
  We studied cholesterol absorption (phytosterols and cholestanol serum concentrations) and cholesterol synthesis (desmosterol serum concentration) in 20 families with ADH without causal mutations in LDLR, APOB, PCSK9 or APOE genes (non-FH ADH) selected from 54 non-FH ADH probands with (non-cholesterol sterol concentrations above 75th percentile) and without (under 75th percentile) hyperabsorption. The concentrations of cholestanol, sitosterol, campesterol and stigmasterol were higher in affected than in non-affected subjects (p = 0.003, <0.001.<0.001, 0.002, respectively). There was a strong cosegregation of hyperabsorption with high LDL cholesterol within hyperabsorber families with odds ratio 6.80 (confidence interval 1.656-27.9), p = 0.008. In hyperabsorber families, 60.5% of subjects were hyperabsorbers and 76% of them had high LDL cholesterol versus 38.3% and 63% in non-hyperabsorber families, respectively.
  
  
  CONCLUSIONS
  Most hypercholesterolemic family members with a hyperabsorber proband are hyperabsorbers. These absorption markers are significantly and positively associated with LDL cholesterol, and predispose to high LDL cholesterol in family members. Our data suggest that complex interindividual variation in cholesterol absorption is involved in many non-FH ADH.
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain. Electronic address: lubailarueda@gmail.com.
authors.forename: Lucía
authors.initials: L
authors.lastname: Baila-Rueda
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
authors.forename: María Rosario
authors.initials: MR
authors.lastname: Pérez-Ruiz
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Jarauta
authors.affiliation: Universidad de Zaragoza, Departamento de Anatomía, Embriología y Genética Animal, 50009, Zaragoza, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Tejedor
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Mateo-Gallego
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
authors.forename: Iztiar
authors.initials: I
authors.lastname: Lamiquiz-Moneo
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: de Castro-Orós
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cenarro
authors.affiliation: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
mesh_terms: D000328:Adult; D053299:Apolipoprotein B-100 / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C569471:APOB protein, human; C000612345:ApoE protein, human; D053299:Apolipoprotein B-100; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Cholesterol absorption; Familial cosegregation; Genetic hypercholesterolemias; Phytosterols