Methods currently used to identify and locate genetic contributors to hypertension are based on association studies with marker loci, linkage studies, and candidate genes [42]. Because of their intimate involvement, two main physiological systems have borne the brunt of genetic studies on blood pressure regulation: the sympathetic-adrenal-medullary (SAM) system and the renin-angiotensin system (RAS). There are positive as well as negative findings for most of the involved genes.
The rate limiting step of the formation of the vasoactive hormone angiotensin II is the cleavage of angiotensinogen by renin. A variant of the gene encoding angiotensinogen results from a substitution of threonine for methionine at position 235 (M235T), and this polymorphism may be a marker for blood pressure variation. Linkage of the angiotensinogen gene locus to hypertension has been reported in sibling pairs of White european origin and African-Caribbeans [43, 44, 45]. In addition, an association has been demonstrated between the T235 allele and both plasma angiotensinogen concentration and elevated blood pressure variation [43, 46]. However, other studies have not replicated this finding. This is probably due to heterogeneity of hypertension, which may mean different variants of the same gene locus are important in different hypertensive individuals [44, 45, 47].
Recently, in a further study of 10 polymorphisms within the angiotensinogen gene, it was found that one particular combination of the T235 allele and a polymorphism which changes a guanine to adenine at position -6, was strongly related to hypertension [48]. Subsequently, this variant has been shown in Japanese hypertensive patients to alter levels of angiotensinogen by altering the transcription rate within the regulatory region of this gene [49, 50].
In the context of conflicting results which have been reported on association between angiotensinogen genotype and blood pressure variation, it is hardly surprising that analyses of the angiotensinogen genotype and blood pressure response to antihypertensive therapy are not consistent.
The ACE gene contains an insertion/deletion polymorphism (I/D) which depends on the presence or absence of a 250 base pair DNA fragment. This polymorphism correlates with plasma ACE activity which is higher in those with the deletion (DD) allele [51, 52, 53]. Studies of the association between ACE genotype and variation in blood pressure are conflicting. A significant association between hypertension and the ACE insertion (II) allele has been reported [54, 55]. However, no association has been reported in several other study groups [53, 56, 57, 58].
In spite of the absence of mortality studies using ACE inhibitors in hypertension, the efficacy of these agents in reducing mortality from left ventricular dysfunction has generated enthusiasm for investigating wether a hypertensive response can be predicted.
In one parallel study in patients with essential hypertension the ACE polymorphism was determined before 15 days’ treatment with either an ACE inhibitor (enalapril), a calcium antagonist (verapamil) or a β-blocker (bisoprolol). The ACE polymorphism was associated with response to antihypertensive therapy, where enalapril produced a greater reduction in blood pressure in the DD variant and verapamil produced a more consistent decrease in blood pressure in the II variant [52].
In contrast, 2 larger studies found no association between ACE genotype and response to antihypertensive therapy [51, 54]. Similarly, in a Japanese study there was no difference between ACE genotype in blood pressure response after treatment with enalapril for 1 year (n = 60) [53].
The angiotensin type 1 (AT1) receptor mediates the haemodynamic effects of angiotensin II. A silent polymorphism where cytosine is substituted for adenine (A1166C) has been associated with severe hypertension [54, 59]. Furthermore, a significant interaction between the ACE and AT1 receptor gene loci in terms of influence on blood pressure variation was reported, the mechanism of which is unclear [54].
A significantly higher expression level of the AT1 receptor has been reported in normotensive (n = 30) and hypertensive (n = 50) individuals in association with the ACE DD genotype [52]. In addition, AT1 receptor expression was higher in hypertensive patients than in normotensive volunteers, and a positive correlation with plasma renin activity was observed in both groups.
The AT1 receptor genotype was not associated with blood pressure response to ACE inhibition [54].
Studies in Milan hypertensive and normotensive rats suggest mutations within a gene encoding a part of the cytoskeleton, α-adducin, which may alter renal tubular sodium reabsorption [60, 61]. In the rat model, mutations within this gene account for 50% of the observed difference in blood pressure between hypertensive and normotensive strains [60]. Since there are strong similarities between humans and rodents for the α-adducin genotype, this represents an important candidate for the study in humans.
Studies in 86 human hypertensive sibling pairs revealed support for linkage of the chromosomal region containing the α-adducin gene to high blood pressure [62]. A polymorphism which exchanges tryptophan for glycine at position 460 in the gene product associates with hypertension and evidence suggests that this polymorphism may influence the response of blood pressure to sodium loading or depletion.
© 2001 Alexander Binder