LDL receptor function ‘key’ to the detrimental effects of APOE4 gene
MedWire News: The e4 allele of the apolipoprotein E gene (APOE) does not increase the risk for coronary heart disease (CHD) in carriers of low-density lipoprotein receptor gene (LDLR) mutations, say researchers.
Previous studies have shown that the e4 allele of APOE is associated with increased CHD risk in humans, explain Eric Sijbrands (Erasmus University Medical Center, Rotterdam, the Netherlands) and team. However, in rodents, APOE4 only accelerates the atherosclerotic process when transgenic for the human LDLR protein.
The team therefore investigated whether the LDLR locus interacts with the APOE genotype on CHD risk in patients clinically diagnosed with familial hypercholesterolemia (FH), with and without an LDLR mutation. Reporting in the journal Circulation: Cardiovascular Genetics, the researchers say that among 2400 FH patients, 1383 had a mutation in LDLR and 92 were homozygous for APOE4. A total of 603 CHD events were observed, of which 547 were in APOE3/E3, E3/E4, and E4/E4 individuals.
Sijbrands and co-investigators found that the prevalence of CHD was lowest in the APOE4/E4 genotyped patients, but only significantly so in the group with an LDLR mutation, at 6.1% versus 25.1% for APOE4/E4 and E3/E3 individuals, respectively.
Within the entire cohort, the presence of an LDLR mutation was not significantly associated with CHD. However, in APOE4/E4 genotyped patients a strong protective effect of an LDLR mutation was observed (hazard ratio [HR]=0.16).
Similarly, in the entire cohort, the APOE4/E4 genotype was not significantly related to CHD. However, when the researchers performed separate analyses for patients with and without the LDLR mutation they found that a protective effect was restricted to APOE4 homozygotes who had an LDLR mutation (HR=0.26).
Commenting on their findings, the authors say: "Our data reveal a protective role for LDLR mutations in FH subjects carrying the APOE4/E4 genotype; in fact, this genotype seems to reduce CHD risk in FH patients, in contrast to the increased risk that APOE4 confers in the general population."
However, "it should be stressed that having an LDLR mutation is detrimental for CHD in the first place," they add.
"Further studies are needed to unravel the biological basis of our finding and to find therapeutic approaches using this interaction in the prevention of CHD," the team concludes.
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By Nikki Withers