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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:580.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Femoral Atherosclerosis In Heterozygous Familial Hypercholesterolemia

Influence Of The Genetic Defect

Mireia Junyent; Rosa Gilabert; Daniel Zambón; Miguel Pocoví; Miguel Mallén; Montserrat Cofán; Isabel Núñez; Fernando Civeira; Diego Tejedor; Emilio Ros

From the Unitat de Lípids, Servei d’Endocrinologia i Nutrició (M.J., D.Z., M.C., E.R.) and Secció d’Ecografia, Centre de Diagnòstic per l’Imatge (R.G., I.N.), Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona and Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Spain; Departamento de Bioquímica, Biología Molecular y Celular (M.P., M.M.), Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain; Hospital Universitario Miguel Servet (F.C.), Zaragoza, Spain; and Progenika Biopharma S.A. (D.T.), Derio, Spain.

Correspondence to Dr Emilio Ros, Unitat de Lípids, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. E-mail eros{at}clinic.ub.es

Objective— The purpose of this study was to assess femoral atherosclerosis by ultrasound in patients with molecularly defined heterozygous familial hypercholesterolemia (FH) in comparison with matched control subjects and in relation to mutational class in the LDL receptor and apolipoprotein B (APOB) genes.

Methods and Results— Femoral intima-media thickness (IMT) and plaque were evaluated in 146 FH patients carrying null alleles (n=48), defective-receptor alleles (n=62), undetermined-function alleles (n=25), or APOB defects (n=11) and in 193 healthy subjects. Twenty-three patients had coronary heart disease (CHD). The frequency of both tendon xanthomas and CHD was 2-fold higher and average LDL cholesterol was 30 mg/dL higher in null-allele genotype compared with receptor-defective mutations. All femoral measurements were increased in FH patients versus controls (P<0.001), and null-allele mutations showed higher age-, sex-, and LDL cholesterol-adjusted maximum IMT than receptor-defective or APOB defects (P for trend, 0.001). By multivariate analysis, independent associations of mean IMT, a measure of early atherosclerosis, were age, LDL cholesterol, sex, and systolic blood pressure. Age, null-allele genotype, sex, and smoking explained 42% of the variability of maximum IMT, a measure of advanced atherosclerosis.

Conclusions— FH patients have increased femoral IMT in relation to mutational class. The findings support the usefulness of genetic testing in FH beyond securing the diagnosis.

Femoral intima-media thickness (IMT) was assessed in 146 patients with molecularly defined familial hypercholesterolemia (FH) and 193 controls. IMT was increased in FH patients versus controls. Compared with receptor-defective or APOB defects, receptor-negative genotype showed higher IMT, independently of LDL cholesterol. Genetic testing is useful in FH beyond securing diagnosis.

Key Words: familial hypercholesterolemia • femoral atherosclerosis • intima-media thickness • atheroma plaque • low-density lipoprotein receptor mutations • apolipoprotein B mutations

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