Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study

Abstract

Background: Apolipoprotein (apo) E is a constituent of lipoproteins with considerable variation due to cysteine–arginine exchanges. The apo E4 (Arg112-Cys) polymorphism has been associated with dementia and hypercholesterolemia. We investigated the relation of APOE genotype to cardiovascular disease (CVD) in the Framingham Offspring Study. Methods and results: DNA was isolated from 3413 study participants and APOE genotypes were determined utilizing the polymerase chain reaction and restriction isotyping. In the entire group of subjects, 20.7% had apo E4/4 or E3/4 (Group E4); 14.1% had apo E2/2 or E2/3 (Group E2) and 63.9% had the apo E3/3 genotype (Group E3). Subjects with E2/4 (1.3%) were excluded. Period prevalence of CVD between examinations 1 and 5 (1971–1994) (366 events) was related to APOE genotype. Age adjusted period prevalence of CVD in men was 18.6% for Group E4, 18.2% for Group E2 and 12.7% for Group E3 (P=0.004); while in women these rates were 9.9, 4.9, and 6.6%, respectively (P=0.037). After adjustment for non-lipid risk factors the relative odds for CVD in Group E2 men was 1.79 (P=0.0098) and in Group E4 it was 1.63 (P=0.0086) compared with the Group E3; while in Group E4 women it was 1.56 (P=0.054). After adjustment for all CVD risk factors, the relative odds in Group E2 men was 1.94 (P=0.004) and in Group E4 men it was 1.51 (P=0.0262). Conclusions: The presence of the apo E2 or apo E4 alleles in men is associated with significantly greater CVD risk. This genotypic information may help to identify individuals at increased risk for CVD events.

Introduction

Cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, is the major cause of death and disability in developed countries. Major CVD risk factors include advancing age, male sex, hypertension, smoking, diabetes, elevated total serum low-density lipoprotein (LDL) cholesterol (≥160 mg/dl, 4 mmol/l), and decreased high density lipoprotein (HDL) cholesterol (<35 mg/dl, 0.9 mmol/l) [1]. An additional important risk factor is family history of premature coronary disease [1], [2].

A variety of familial lipoprotein disorders have been associated with CVD, and some of them, such as lipoprotein(a) excess and familial hypercholesterolemia (FH) have been linked to specific loci [3], [4], [5], [6]. However, some of these disorders are rare and have a modest effect over the CHD risk in the population at large. More common mutations in the general population include those at the APOE locus. Numerous population studies have clearly implicated APOE genetic variation as a major modulator of LDL cholesterol [7], [8], [9], [10], [11], [12].

Apolipoprotein E is a protein constituent of both triglyceride-rich lipoproteins (TRL) as well as HDL, which plays an important role in liver uptake of TRL remnants. APOE has three common alleles known as ε2, ε3 and ε4. The common ε3 allele contains a cysteine at residue 112 and an arginine at residue 158 [13]. The variant ε4 allele differs from ε3 in that it contains an arginine at residue 112, whereas the variant ε2 allele differs from ε3 in that it contains a cysteine at residue 158 [13]. Many studies assessing the role of APOE genetics on plasma lipids have shown that the presence of the ε4 allele is associated with elevations in LDL cholesterol, while the presence of ε2 is associated with decreased levels of LDL cholesterol [7], [8], [9], [10], [11], [12]. In addition, a meta-analysis has shown that the apo E phenotype is associated with triglyceride levels [14]. Moreover, some studies have reported that the ε4 allele is associated with CHD [15] although most of these have been carried out in male subjects. Our purpose was to assess the relation between APOE genotype, gender and CVD prevalence in a population based sample: the Framingham Offspring Study.