Apolipoprotein E alleles and hypertension: controversy or lack of understanding?

Apolipoprotein E, the major component of chylomicrons, is an essential part of the removal pathway for chylomicron remnants and very low density lipoproteins via its capacity to bind specific receptors in liver and other cells. This binding capacity is influenced, to a large degree, by the presence of arginine or cysteine residues at positions 112 and 158, defining the three major isoforms of apolipoprotein E: cysteine/cysteine for E2, cysteine/arginine for E3, and arginine/arginine for E4. In addition, these residues, which confer electrophoretic differences to apolipoprotein E isoforms, are responsible for their diverse isoelectric focusing migration, which defines ∊2, ∊3 and ∊4 alleles. The wild-type form is ∊3, with ∊2 and ∊4 having variable frequencies in different populations [1,2]. The major phenotypes related to these alleles include type III hyperlipoproteinemia, myocardial infarction susceptibility and sea-blue histiocyte disease, as well as predisposition to Alzheimer's disease. The complexity of apolipoprotein E is exemplified by the fact that, although almost always present in type III hyperlipoproteinemia (i.e. homozygous for cysteine residues), only a few individuals with the apolipoprotein E2 isoform have the disease. Clearly, this specific allele is absolutely required but not sufficient. Thus, the input of environment and/or other genetic factors or gene–gene interactions are involved, which is the confounding mystery of apolipoprotein E. Knockout experiments have clearly demonstrated the importance of the apolipoprotein E gene, which potentiates atherosclerosis and myocardial dysfunction in affected mice [3]. However, this acceleration of atherosclerosis does not appear to be related to hypertension, as tested by lowering blood pressure with hydralazine [4]. Nevertheless, it is useful to remember that some antihypertensive agents affect the proliferative and apoptotic biology of the vessel wall (including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists and calcium channel blockers) while others do not, as in the case of hydralazine [5]. The association of apolipoprotein E gene polymorphism remains controversial in cerebrovascular diseases. Recent data suggest that apolipoprotein E/∊4 allele carriers have four-fold higher relative odds for developing stroke, but that this happens only in conjunction with triglycerides, age and hypertension [6]. The Honolulu Heart Program was re-analysed for the association of the apolipoprotein E gene and mid-life systolic blood pressure with late-life cognitive impairment, and a gradient of relative risk for poor cognitive function was found, ranging from 1.3 in subjects with normal systolic blood pressure and ∊4 category to 2.6 in those with high systolic blood pressure and no ∊4, and up to 13.0 (confidence interval 1.9–83.8) for high systolic blood pressure and the ∊4 allele. Even adjustment for diabetes, stroke, coronary disease and the ankle/brachial index reduced this risk only to 10.8. Systolic blood pressure appears to have an adverse effect on cognitive function, particularly in subjects with the ∊4 allele. However, in the Hawaii–Los Angeles–Hiroshima Study, the ∊2 allele has been recently associated with hypertension in Japanese-Americans. This association appears to be mediated by high serum levels of triglycerides and the ∊2 allele [7]. Some of this controversy is perhaps connected to the need for more finely defined phenotypes. Thus, the intracerebral haemorrhage association with apolipoprotein E alleles is dependent on its localization, lobar intracerebral haemorrhage being attributable to apolipoprotein E4 or apolipoprotein E2, and non-lobar intercerebral haemorrhage being mostly linked with hypertension itself. If these regional differences are substantiated, they may explain the controversy in the literature concerning the relationship between apolipoprotein E and intracerebral accidents [8]. Novel associations were recently described in a family-based study from Micronesia, confirming the importance of apolipoprotein E alleles in the determination of total cholesterol, apolipoprotein A1 and apolipoprotein B levels [9]. In this issue of the journal, Katsuya et al. [10] have reported that the ∊4 allele of apolipoprotein E is actually associated with low blood pressure in healthy young Japanese subjects of the Suita study. This finding is not necessarily controversial. The study reports that the polymorphism is mainly associated with systolic blood pressure, underlying its haemodynamic component, while the apolipoprotein ∊4 allele is usually associated with metabolic abnormalities. Hyperinsulinemia was increased three-fold in carriers of the ∊4 allele in a Spanish study [11], leading to an atherogenic profile of plasma lipids. In preliminary investigations, we have demonstrated that subjects with the apolipoprotein E2 allele do not appear to show any relationship between waist circumference and their hypertension, in sharp contrast to those with the wild-type E3 allele as well as E4 [12], where the correlation between diastolic blood pressure and waist circumference is highly significant. Finally, the apolipoprotein E2 allele seems to modulate the maximal velocity of the sodium–lithium countertransporter, as described recently by Wierzbicki et al. [13]. Thus, the apolipoprotein E2 allele may have an impact on the haemodynamic component that is quite distinct from the more metabolic impact of apolipoprotein E4, which was even proposed to be the ‘ancestral', and perhaps the ‘thrifty’ allele [14], susceptible to the novel environment of modern civilization [1]. The apparent controversies concerning apolipoprotein E alleles and their involvement in the pathogenesis of different forms of cardiovascular disorders are even further complicated when allelic variants of these alleles are considered (45 have been described to date). It appears that a lack of understanding rather than controversy is at the basis of this problem, calling for further studies of gene–environment interaction, and also essential gene–gene interaction, before we can begin to comprehend more clearly the relevance of this major component of lipid metabolism for hypertension and its associated complications.