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CLINICAL RESEARCH: LIPID DISORDER

Frequency of Low-Density Lipoprotein Receptor Gene Mutations in Patients With a Clinical Diagnosis of Familial Combined Hyperlipidemia in a Clinical Setting

Fernando Civeira, MD, PhD^_*,_*, Estibaliz Jarauta, MD^_*, Ana Cenarro, PhD^_*, Angel L. García-Otín, PhD^_*, Diego Tejedor, PhD, Daniel Zambón, MD, PhD, Miguel Mallen, BSc, Emilio Ros, MD, PhD and Miguel Pocoví, PhD

^_* Unidad de Lípidos and Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (I+CS), Zaragoza, Spain
Progenika Biopharma S.A., Derio, Spain
Unitat de Lípids, Servei d'Endocrinologia I Nutrició, Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clínic, and Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain
Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain

Manuscript received January 9, 2008; revised manuscript received May 6, 2008, accepted June 2, 2008.

^_* Reprint requests and correspondence: Dr. Fernando Civeira, Hospital Universitario Miguel Servet, Avda. Isabel La Católica 1-3, Zaragoza 50009, Spain (Email: civeira{at}unizar.es).

Objectives: 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.

Key Words: familial combined hyperlipidemia • familial hypercholesterolemia • LDLR mutations

Abbreviations and Acronyms   Apo = apolipoprotein   CI = confidence interval   FCH = familial combined hyperlipidemia   FH = familial hypercholesterolemia   LDL = low-density lipoprotein   LDLR = low-density lipoprotein receptor gene   ROC = receiver-operator characteristic

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