Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect.
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.


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 approximately 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.
Junyent
Mireia
M
Unitat de Lípids, Servei d'Endocrinologia i Nutrició, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain.
Gilabert
Rosa
R
Zambón
Daniel
D
Pocoví
Miguel
M
Mallén
Miguel
M
Cofán
Montserrat
M
Núñez
Isabel
I
Civeira
Fernando
F
Tejedor
Diego
D
Ros
Emilio
E
D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D005260:Female; D005263:Femoral Artery; D005500:Follow-Up Studies; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011336:Probability; D012016:Reference Values; D017678:Sex Distribution; D017539:Tunica Intima / Q000473:pathology; D018608:Ultrasonography, Doppler
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL