Apolipoprotein Isoform E4 Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations

Jorie Versmissen, Daniella M. Oosterveer, Menno Hoekstra, Ruud Out, Jimmy F. P. Berbee, Adriana C. Blommesteijn-Touw, Leonie van Vark-van der Zee, Ranitha Vongpromek, Tim Vanmierlo, Joep C. Defesche, Monique Mulder, John J. P. Kastelein, Eric J. G. Sijbrands*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)

Abstract

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. Methods and 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. (Circ Cardiovasc Genet. 2011;4:655-660.)
Original languageEnglish
Pages (from-to)655-U366
JournalCirculation : Cardiovascular Genetics
Volume4
Issue number6
DOIs
Publication statusPublished - Dec 2011

Keywords

  • apolipoprotein E
  • coronary heart disease
  • familial hypercholesterolemia

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