Apolipoprotein isoform E4 does not increase coronary heart disease risk in carriers of low-density lipoprotein receptor mutations.
BACKGROUND
In humans, the E4 allele of the apolipoprotein E gene is associated with increased coronary heart disease risk. Surprisingly, in rodents, apolipoprotein E4 only accelerates the atherosclerotic process when transgenic for the human low-density lipoprotein receptor (LDLR) protein. We therefore investigated whether the LDLR locus interacted with the apolipoprotein E gene genotype on coronary heart disease risk in patients clinically diagnosed with familial hypercholesterolemia with and without LDLR mutation. We investigated whether the presence of an LDLR mutation diminishing LDLR function was protective in E4/E4 carriers.


RESULTS
In a cohort of 2400 patients clinically diagnosed with familial hypercholesterolemia, we found an LDLR gene mutation in 1383 patients, whereas in 1013 patients, such mutation was not present. In 92 patients homozygous for the apolipoprotein E4, the presence of an LDLR mutation conferred lower coronary heart disease risk (hazard ratio, 0.16; 95% CI, 0.05-0.58; P=0.005). Mirroring these results, the apolipoprotein E4/E4 genotype was also associated with lower coronary heart disease risk in patients with familial hypercholesterolemia with an LDLR mutation (hazard ratio, 0.26; hazard ratio, 0.08-0.80; P=0.02).


CONCLUSIONS
LDLR function is key to the detrimental effects of apolipoprotein E4 in humans. Kinetic studies in humans are now required to study the consequences of our observation for prevention of both coronary heart disease and Alzheimer disease.
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jorie
J
Versmissen
Daniëlla M
DM
Oosterveer
Menno
M
Hoekstra
Ruud
R
Out
Jimmy F P
JF
Berbée
Adriana C
AC
Blommesteijn-Touw
Leonie
L
van Vark-van der Zee
Ranitha
R
Vongpromek
Tim
T
Vanmierlo
Joep C
JC
Defesche
Monique
M
Mulder
John J P
JJ
Kastelein
Eric J G
EJ
Sijbrands
D000328:Adult; D000368:Aged; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
D053327:Apolipoprotein E4; D011973:Receptors, LDL