Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations -the ECTIM Study

Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4, The epsilon 4 allele of the APOE g ene (APOE) coding for the APOE4 isoform is associated with an increased ris k of myocardial infarction (Mt) and of Alzheimer's disease (AD), Recently, several polymorphisms in the APOE regulatory region have been reported. Som e of these have been associated with AD and modified APOE allelic mRNA expr ession in AD brains, Here, we have investigated whether three of these prom oter polymorphisms (-491AT, -427CT and -219GT) can also modify cardiovascul ar risk. The hypothesis was tested in a large multicentre case-control stud y of MI, the ECTIM Study, on 567 cases and 678 controls, Among the three AP OE promoter polymorphisms tested, only the -219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% Cl: 1.09-1.52, P < 0. 003) and the effect was shown to be independent of the presence of the othe r mutations, including the APOE epsilon 2/epsilon 3/epsilon 4 polymorphism. Moreover, the -219T allele greatly decreased the APOE plasma concentration s in a dose-dependent manner(P < 0.008), These data indicate that the -219G T polymorphism of the APOE regulatory region emerges as a new genetic susce ptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.