title: Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting.
abstract: OBJECTIVE
  The purpose of this study was to determine the frequency of mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB) genes in consecutive patients with a clinical diagnosis of familial combined hyperlipidemia (FCH) in a nonresearch setting.
  
  
  BACKGROUND
  The lipid phenotype frequently overlaps in familial hypercholesterolemia (FH) and FCH. Detection of causative mutations in LDLR or APOB provides an unequivocal diagnosis of FH, but such genetic testing has not been systematically performed in FCH.
  
  
  METHODS
  We used Lipochip (Progenika, Derio, Spain), a microarray that includes 203 causative mutations in LDLR and 4 APOB defects, to investigate 143 unrelated FCH patients.
  
  
  RESULTS
  Mutations of LDLR were found in 28 patients (overall prevalence, 19.6%). No APOB defects were found. Compared with patients who had a normal LDLR gene, patients with mutations had lower waist circumference (p = 0.02); significantly (p < 0.005) higher total cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apoB; nonsignificantly (p = 0.063) lower triglycerides; and a lower frequency of diabetes mellitus (22% vs. 0%, respectively; p = 0.002). Total cholesterol and apoB levels showed the best receiver-operator characteristics curves in the prediction of LDLR mutations, with areas under the curve (95% CI: of 0.750 (95% confidence interval [CI]: 0.647 to 0.853) and 0.744 (95% CI: 0.636 to 0.851), respectively. Total cholesterol of 335 mg/dl and apoB of 185 mg/dl were the best thresholds for diagnosis of LDLR mutations.
  
  
  CONCLUSIONS
  Screening for LDLR defects is advisable for patients with a clinical diagnosis of FCH showing high total cholesterol or apoB levels. Diagnostic criteria for FH should not exclude patients whose personal and familial lipid values appear to fit the clinical criteria of FCH.
authors.affiliation: Unidad de Lípidos and Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. civeira@unizar.es
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Jarauta
authors.forename: Ana
authors.initials: A
authors.lastname: Cenarro
authors.forename: Angel L
authors.initials: AL
authors.lastname: García-Otín
authors.forename: Diego
authors.initials: D
authors.lastname: Tejedor
authors.forename: Daniel
authors.initials: D
authors.lastname: Zambón
authors.forename: Miguel
authors.initials: M
authors.lastname: Mallen
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.forename: Miguel
authors.initials: M
authors.lastname: Pocoví
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000175:diagnosis* / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D015995:Prevalence; D011336:Probability; D012372:ROC Curve; D011973:Receptors, LDL / Q000235:genetics*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D013030:Spain / Q000453:epidemiology; D018709:Statistics, Nonparametric
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL