Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia.
OBJECTIVE
Defects in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a highly atherogenic condition. The effect of different LDLR mutations on coronary heart disease (CHD) risk is insufficiently defined. We assessed carotid intima-media thickness (IMT), a surrogate marker of CHD, in relation to LDLR mutational class in FH.


METHODS
In 436 Spanish FH patients (223 men and 213 women, age 44+/-14 years) with known LDLR mutations, alleles were classified by standard criteria as null (n=269), defective (n=162), or undetermined (n=5). LDLR defects were detected using a microarray (Lipochip) designed to uncover prevalent mutations in Spain and gene sequencing when no mutations were detected. Carotid IMT and plaque were assessed in FH patients and 268 healthy subjects.


RESULTS
All carotid measurements were increased in FH patients versus controls (p<0.05), irrespective of genotype. After adjustment for gender and age, patients with null alleles compared with defective alleles had similar mean and maximum common carotid artery (CCA) IMT, but higher maximum IMT at any carotid segment, with median values (95% confidence interval) of 1.25 mm (1.19-1.31) and 1.11 mm (1.05-1.18), respectively. Multivariate analysis showed that null alleles were independently associated with maximum CCA-IMT (beta=0.09, p=0.033) with an impact similar to that of gender (beta=0.10, p=0.035).


CONCLUSIONS
FH patients show advanced carotid atherosclerosis in relation to LDLR mutational class. The findings support the utility of genetic testing in FH beyond providing a secure diagnosis.
Junyent
Mireia
M
Unitat de Lípids, Servei d'Endocrinologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Villarroel 160, 08036 Barcelona, Spain.
Gilabert
Rosa
R
Jarauta
Estíbaliz
E
Núñez
Isabel
I
Cofán
Montserrat
M
Civeira
Fernando
F
Pocoví
Miguel
M
Mallén
Miguel
M
Zambón
Daniel
D
Almagro
Fátima
F
Vega
Juan
J
Tejedor
Diego
D
Ros
Emilio
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002339:Carotid Arteries / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics*; D016022:Case-Control Studies; D003327:Coronary Disease / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D011973:Receptors, LDL