Renin AngiotensinAldosterone System RAAS

The Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the development and progression of CVD by promoting sodium absorption, cardiac remodeling and norepinephrine release, and other potentially detrimental effects (Fig. 1). It also plays a significant role in controlling several elements of the extracellular matrix components; manipulating this system can however reverse experimental cardiac fibrosis (11). Drugs that interfere with this system have proved to be among the most successful therapeutic agents for a variety of CVDs.

Table 1 Examples of Gene Polymorphisms Associated with Cardiovascular Function and Their Frequencies'1

Allele frequency (%)a

Chromosome Disease/cardiovascular

Gene location Polymorphism Caucasians African Americans function References

Angiotensinogen Iq41-q45 Met235Thr 42.2 77 Angiotensinogen levels (185)a

(.AGT) Coronary artery disease (12)

Blood pressure (18)

Angiotensin {ACE) 17q23 I/D 56.2 60.3 Angiotensin-Converting enzyme (185)a levels (20)

Carotid wall thickness (26)

Heart failure (31)

Pulse pressure (27)

Angiotensin II type 1 3q21-q25 A1166C 29 9 Blood pressure (185)a receptor (ATR1) Arterial stiffness (159)

Aldosterone synthase 8q21-q22 T-344C 50.3 79 Left ventricle size and mass (186)a

(■CYP11B2) Aldosterone levels (35)

Arterial stiffness (33)

ß-2 adrenergic 5q31-q32 Argl6Gly 43 49 Coronary artery disease (187)a receptor (ADRB2) Gln27Glu 35 18 Heart failure (45)

Nitric oxide synthase 7q35-q36 (.NOS3)

Elastin (ELN) 7qll.2

Fibrillin (FBN1) 15q21.1

Apolipoprotein E 19ql3.2

Choslesteryl ester 16ql3

transfer protein (CETP)

C-reactive protein Iq21-q23

Interleukin-6 7p21

Glu298Asp 39.6

Ser425Gly 36

E4 13.4

Taql B1B2 0.42

14440T 26

"Frequency of the allele in bold type.

Coronary artery disease


Myocardial infarction


Essential hypertension


Large artery stiffness





Large artery stiffness


Pulse pressure



Coronary heart disease/


myocardial infaction


Cholesterol level


Aortic wall thickness


Cholesteryl ester transfer


protein levels



C-reactive protein levels


Coronary heart disease risk


Arterial stiffness


Interleukin-6 levels


Coronary heart disease mortality


Interleukin And Myocardial Infarction
Figure 1 Components and effects of renin-angiotensin-aldosterone system and polymorphisms.


Angiotensinogen (AGT) is the most extensively studied of the candidate genes in CVD and sits at the head of the RAAS pathway. A number of studies have linked the AGT locus on chromosome 1 to essential hypertension. The Met235Thr polymorphism in the AGT gene is associated with an increase in plasma AGT levels (12). The relationship of AGT gene variants to human CVD/myocardial infarction is less certain, with several studies reporting a positive association (13,14) but others reporting no association (15,16). In coronary artery disease patients, AGT concentrations were found to be higher in 235Thr (TT) homozygotes (14). A recent meta-analysis of 45,267 subjects also confirmed that TT homozygotes and MT heterozygotes for the Met235Thr polymorphism exhibited increased AGT levels (17). Tiret et al. (16) also showed that the number of antihypertensive medications being taken by 235Thr carriers was greater than in controls. Further, in untreated essential hypertensives, the AGT gene was found to be an independent predictor of the blood pressure response to ACE inhibitor therapy (18); the best response occurred in carriers of the 235 Thr allele.

Angiotensin-Converting Enzyme

Another gene in this pathway that has been studied extensively is the ACE gene, on account of the variable clinical efficacy of drugs that interfere with this pathway, inhibition of which leads to a decrease in both blood pressure and cardiovascular mortality (19). ACE not only plays a central role in the renin-angiotensin system but also in the kallikrein-kinin pathways, thereby promoting the formation of angiotensin II and inactivating bradykinin. The insertion

(I)/deletion (D) polymorphism in intron 16 of the ACE gene located on chromosome 17 (due to the presence/absence of a 287-bp Alu repeat sequence) has received particular attention because of its influence on circulating ACE activity (9). In fact, some 50% of the genetic variance in serum ACE levels has been attributed to polymorphic variation in the ACE gene. Individuals homozygous for the deletion allele (DD) have been shown to have twice the serum levels compared with those homozygous for the insertion allele

(II), with heterozygous individuals (ID) having intermediate levels (20). The morbidity associated with the ACE DD genotype (21) and the D allele (22) in left ventricular hypertrophy (23), myocardial infarction (24), cerebral ischemic stroke (25), and increasing carotid wall thickness (26) suggests that polymorphic variation in ACE gene exerts an important influence on a variety of different aspects of the heart and vascular tree. The I/D polymorphism also appears to exert an influence on pulse pressure with age and hence may increase cardiovascular risk (27). Although the D allele has been associated with an increased risk of various cardiovascular conditions, the situation in hypertension is controversial. The inconsistent results are exemplified by the fact that the I allele has tended to track with high blood pressure in some studies, albeit below the level of statistical significance (18,28).

In summary, the homozygous DD genotype of the insertional ACE gene polymorphism may be an independent risk factor for coronary heart disease, especially in individuals who lack other conventional risk factors, such as hypertension or hypercholesterolemia. If confirmed, this suggests the possibility of using drugs that act on the renin-angiotensin system (such as ACE inhibitors) in individuals genetically defined as being at high risk of heart disease.

The human I/D polymorphism may also play a role in pharmacogenetics (see section "Renin-Angiotensin System Drugs"). Thus, although some studies have failed to demonstrate a difference in blood pressure response to ACE inhibitors or other drugs (18,29,30), recent data indicate that knowledge of ACE genotype may help in the partitioning of patients into potential responders and nonresponders and also in helping to determine the overall prognosis (31).

Aldosterone Synthase

Aldosterone is a mineralocorticoid hormone that controls sodium balance and intravas-cular volume, thereby helping to regulate blood pressure. It is synthesized in the adrenal cortex from deoxycorticosterone by a mitochondrial CYP450 enzyme, aldosterone synthase (known as CYP11B2). The CYP11B2 gene encoding this enzyme is located on chromosome 8 and several polymorphisms have been identified in its upstream regulatory region. The polymorphism at — 344 C/T in the promoter region has been associated with elevated plasma aldosterone levels (32) and also left ventricular diameter and mass in young adults free of clinically overt disease. In these studies, individuals with a CC genotype exhibited increased aldosterone levels (33), increased arterial stiffness (34), and increased left ventricular size and mass. The left ventricular size, mass, and to some extent, diastolic function have also been associated with the — 344CC genotype (35). By contrast, the —344 C/T polymorphism was not found to influence the risk of myocar-dial infarction either directly or via interaction with other drugs.

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