Blood pressure is one of the parameters in monitoring a person’s health status. Hypertension (high blood pressure) is a strong risk factor for cardiovascular and renal diseases, including coronary heart disease, stroke, heart failure, and kidney failure. The blood pressure in human body is controlled by the renin–angiotensin system (RAS), which is modulated by genetic makeup and environmental factors (diet, life style, stress etc). Many blood pressure controlling drugs target the RAS system.
With regard to blood pressure regulation, the most common and well understood genetic variation is the angiotensin-converting enzyme (ACE) insertion/deletion (ACE I/D) polymorphism and the most influential dietary factor is sodium intake. Interactions between ACE I/D polymorphism, sodium intake and the RAS system dictates effectiveness of most blood pressure management regimens.
A key component of the RAS system, ACE acts as an enzyme that converts the inactive oligopeptides angiotensin I to the active form angiotensin II. The later is a hormone that activates a series of reactions in human body, ultimately leading to blood pressure increase. The ACE I/D polymorphism is characterized by the presence (insertion, I) or absence (deletion, D) of a 287-bp Alu repeat sequence in an intron (non-coding segment) of the ACE gene. The presence of the Alu repeat sequence affects the expression of the ACE gene, resulting in an increased ACE protein level, thus a more active RAS system in the D allele carriers and differential response to environmental factors such as dietary, exercise or medicines.
With regard to dietary interaction, the D allele carriers have a higher risk of blood pressure increase in response to high sodium intake. Therefore, low sodium diets are recommended for them. In hypertensive, diabetic, overweight and obese, and other chronic cardiovascular or renal diseases populations, the harmful effects of high sodium on D allele carriers are aggravated. For D allele carriers in these populations, sodium restriction through low sodium and/or high potassium diet is especially important.
Most natural food does not contain significant amount of sodium. Human dietary sodium comes mostly from added salt, either in the processed food or home cooking meals. In modern Western life style, only a small amount of salt intake comes from the salt added at the table. Processed foods account for most of the added sodium. Therefore, the most effect way to reduce sodium intake is to choose low- or reduced-sodium, or no-salt-added versions of foods and condiments during shopping. Meanwhile, increase potassium intake also have the effect of sodium reduction since the absorption of sodium is operated by the Na+/K+ channel that transport Na+ and K+ at opposite directions. A high sodium intake leads to potassium loss through urine. Vice versa, a high potassium intake leads to sodium excretion to the urine. The following table shows the most common potassium rich food sources.
In responses to exercise and weight loss, D allele carriers response well to short sessions of strength and power oriented exercise and benefit more from weight loss whereas the I allele carriers are better suited for endurance exercise. Long term endurance exercise for D allele carriers actually increases their risk for an increased left ventricular mass, which is associated with increased cardiovascular mortality.
The ACE I/D polymorphism also associate with many chronic diseases. The DD genotype is associated with higher risks for hypertension, atherosclerosis, coronary heart disease, stroke, diabetic nephropathy and migraine. In many cases, the association is only significant in non-Caucasian populations. However, in ethnic background the association is enhanced by other chronic health conditions such as overweight and obese, diabetes and by environment stress such as high altitude, extreme exercise and certain medicines. Interestingly, the DD genotype is associated with a reduced risk for Alzheimer Disease, presumably due to the elevated ACE activity that may help degrade the amyloid beta peptide that causes plaques formation during the development of the disease.
The interactions of ACE I/D polymorphism and blood pressure control drugs have been investigated intensively for its implication in personalized medicine. In brief, differential responses do exist for certain medicines in certain ethnic population toward particular disease conditions.
It is not clear of the ACE I/D polymorphism which the major or ancestral allele is since both are present at high frequency in overall world population. In general, the D allele is more frequent in African or Caucasians and the I allele is more frequent in Asian population (Table 2).
Hypertension & RAS System
Blood pressure is a strong, consistent, continuous, independent, and etiologically relevant risk factor for cardiovascular and renal disease (Chobanian et al, 2003). Hypertension is an important risk factor for cardiovascular and renal diseases, including stroke, coronary heart disease, heart failure, and kidney failure (Appel et al, 2006).
The renin–angiotensin system (RAS), also known as the renin–angiotensin-aldosteron system (RAAS), is the master regulator of long-term blood pressure, blood volume and electrolyte balance in human body. Through interactions with genetic makeup and environmental factors (diet, life style, stress), the blood pressure of an individual is so tightly regulated that it remains almost invariable when measured repeatedly or between long period of time. Dysfunction of RAS system normally leads to hypertension, cardiovascular diseases and renal disorders.
The RAS system includes components in the liver, the kidney, the cardiovascular system, the lungs and the central neuron system. Its activation starts with renin, a protease that is synthesized as a prorenin and matured by proteolysis removal of the N-terminus. The mature rennin is normally stored in the juxtaglomerular cells in the kidneys. Under conditions of salt, volume loss, or sympathetic activation (flight or fight response), renin is released by the juxtaglomerular cells into blood circulation, where renin cleaves the N-terminal portion of the protein angiotensinogen to convert it to the biologically inactive decapeptide Angiotensin (Ang) I. Angiotensinogen is secreted constitutively by the liver, so plasma levels are generally stable and do not change acutely. The Ang I is hydrolyzed by angiotensin-converting enzyme (ACE), a membrane-bound peptidase that localizes on the plasma membranes of mainly the lung capillaries but also various endothelial and epithelial cells, which removes two amino acid residues from the C-terminal of Ang I to form the biologically active octapeptide Ang II, a potent vasoconstrictor hormone that regulates the blood pressure through multiple pathways (Figure 1).
Acting through cell surface receptors (angiotensin receptors, at least four are identified), Ang II performs its functions in whole body: 1) in the cardiovascular system, it directly causes blood vessel contraction; 2) in the kidney, it leads to renal tubular sodium reabsorption by stimulating Na+/H+ exchangers 3) in the adrenal gland, it stimulates the adrenal cortex to release the hormone aldosterone. Aldosterone regulates sodium and potassium balance by stimulating tubules in the kidneys to reabsorb sodium and water from urine accompanied by the excretion of potassium; 4) in the pituitary gland, it stimulates the release of anti-diuretic hormone (ADH), which exhibits vasoconstriction function as well as the reabsorption of water in the kidneys. ADH also acts on the central nerve system to increase people’s appetite for salt and to stimulate the sensation of thirst; 5) in the sympathetic nerve system, it also stimulates sympathetic adrenergic nerve neurons to release norepinephrine (noradrenaline) and epinephrine (adrenaline) which increase blood vessel constriction, release storage glucose to blood and increase oxygen supply to the brain; and 6) Ang II also suppresses the release of renin through a negative feedback. The overall effects of Ang II are the increased amount of fluid in the blood and to increase blood pressure.
ACE also cleaves the vasodilator peptides bradykinin to inactive fragment by sequential removal of the two C-terminal amino acid residuals. Hence its actions result in decreased vasodilatation effect by bradykinin and increased vasoconstriction by Ang II. The net result is blood pressure increase.
Figure 1. Major components of the renin–angiotensin system (RAS). The two proteases rennin and ACE are shown in boldface. Active hormones (red) and inactive forms (green) are colored coded. Solid blue arrows represent functional stimulation. Dotted blue ones represent functional inhibition. Solid black ones represent the substrates conversion flow. The three major factors that regulate renin release are shown in shaded pink ovals.
As shown in Fig. 1, three major factors activate the RAS system. Blood loss and sympathetic response are rare situations. In contrast, dietary sodium/potassium balance is the daily effecter. Long term high sodium and low potassium dietary keep the RAS active. In an otherwise healthy population, when the RAS system is more active, blood pressure will be higher. Long term active RAS system will eventually lead to hypertension. Therefore, low sodium high potassium diet is generally recommended for high blood pressure prevention.
Many blood pressure control drugs act by interrupting different steps in the RAS system. These drugs include ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), aldosterone antagonists and β-blockers (BBs).
ACE and its polymorphism
ACE is a membrane-bound, chloride-dependent zinc metallopeptidase. A major component of the RAS system, ACE converts the inactive Ang I to the active Ang II, the main activator of the system. ACE also breaks down bradykinin, a strong vasodilator. Therefore, the action of ACE leads to blood pressure increase. Besides the functions in the RAS system, ACE may also function in central neuron system. It has been demonstrated that ACE degrades amyloid beta peptide in vitro, one of the primary adverse biological agents implicated in Alzheimer disease (AD) pathogenesis. Thus, ACE may prevent or reduce the formation of senile plaques, a hallmark of AD.
The 21 kb long human ACE gene is located on chromosome 17. It contains 26 exons and 25 introns. Alternative transcription result in two variants. The longer form, transcribed from exons 1-12 and 14-26, is known as the 170 kDa somatic ACE (sACE), whereas the shorter form, transcribed from exons 13-26, is known as the 100 kDa germinal ACE (gACE). The expression of sACE is especially strong in the capillaries of the lung and epithelial cells in the kidney, although it is detected in all tissues. The gACE isoform is expressed only in developing sperm cells and mature sperm. Throughout this review, the name ACE simply refers sACE.
To date, there are more than 160 SNPs found in human ACE gene. The ACE I/D polymorphism (rs# 4646994) represents the most common and well understood one with regard to its association with blood pressure, cardiovascular and renal diseases, dietary sodium response, exercise and blood pressure control medicine response.
ACE I/D polymorphism
The ACE I/D polymorphism was first reported by Rigat et al (1990). It is characterized by the presence or absence of a 287-bp Alu repeat sequence in intron 16 of the ACE gene. It is well known that ACE levels remains constant in the same individual over long period of time but varies greatly (up to 5-fold difference) between individuals. In the study group (80 healthy Caucasians) reported by Rigat et al, mean ACE activity levels in DD carriers were approximately twice of that found in II genotype individuals. The ACE I/D polymorphism accounted for approximately half (47%) of the observed variance in ACE levels. The increased ACE level in the DD genotype is confirmed repeatedly in many subsequent studies. However, it is also observed that in children and adolescents, serum ACE activity is related to the ACE gene I/D polymorphism in whites but not in blacks, indicating a potentially important ethnic variation in genetic regulation of serum ACE activity and the relationship of the I/D polymorphism to cardiovascular disease (Bloem et al, 1996).
The ACE I/D polymorphism also showed effect on the degradation of the vasodilatation peptides bradykinin. In a study of venous infusion of bradykinin, significant correlations were observed between the number of D alleles and the inactive product BK1-5 concentrations, and the ratio of BK1-5 to bradykinin. BK1-5 concentrations were 1113, 1520, and 1887 fmol/mL in the II, ID, and DD groups, respectively and the ratio of BK1-5 to bradykinin were 1.87, 3.09, and 4.31 in the II, ID, and DD volunteers (Murphy et al, 2000). Therefore, the D allele renders a higher activity to bread down bradykinin, leading to less vasodilatation activity of bradykinin and thus higher blood pressure.
ACE I/D polymorphism and sodium intake
Sodium status affects the phenotype in the ACE I/D polymorphism. In a well controlled study, healthy Caucasian (18-35 years old) participants were given 7 days of low sodium diet and 7 days of high sodium diet in separate sessions. Except for the sodium level, the low sodium diet (50 mmol sodium/d) and the high sodium diet (200 mmol sodium/d) were the same in calorie, potassium and other nutrition. Test results showed that baseline mean arterial pressure (MAP) values, renal hemodynamic parameters, and renin-angiotensin system parameters were all similar for all genotypes at either sodium level. In general, higher sodium suppresses the conversion of angiotensin I (Ang I) to angiotensin II (Ang II). However, the degree of suppression in DD genotype (16% less Ang II converted) was less than in DI or II genotypes (63%-71% less Ang II converted). A series of Ang I infusion studies showed that at high sodium intake, the activity of ACE, as indicated by the baseline increases in MAP, renal vascular resistance, and aldosterone levels and decrease of GFR (Glomerular Filtration Rate) were significantly higher for the DD genotype than for the ID and II genotypes (Table 3). Increase of MAP, renal vascular resistance, aldosteron and decease of GFR all lead to blood pressure increase. In contrast, at low sodium intake, the responses to Ang I infusion were similar for all genotypes. In conclusion, the responses of MAP, renal hemodynamic parameters, and aldosterone concentrations to Ang I were enhanced for the DD genotype with high but not low sodium intake (van der Kleij, 2002). These results suggest that high sodium intake is more harmful for DD genotypes.
Table 3. Responses to Ang I infusion at high sodium intake (Derived from van der Kleij, 2002).
| Genotype |
DD |
DI |
II |
| MAP (Mean Arterial Pressure) |
22% ↑ |
13% ↑ |
12% ↑ |
| Renal Vascular Resistance |
100% ↑ |
73% ↑ |
63% ↑ |
| Aldosteron |
6.5 fold ↑ |
3.5 fold ↑ |
2.5 fold ↑ |
| GFR decrease |
17.9% ↓ |
8.8% ↓ |
6.4% ↓ |
The harmful effect of high salt on D allele carriers is consistent with an earlier study of 35 older (62.9 ± 1.2 years) hypertensive subjects. Individuals differ in their blood pressure response to changes in dietary sodium intake. After 8 days of low (20 mmol/day) and high (200 mmol/day) Na+ intake, the mean arterial pressure responses to the increase in dietary Na+ was 9 ± 2 mm Hg in D allele carriers, on contrast to hardly any change (0 ± 3 mm Hg) in II genotype. Of the 35 subjects, 24 were classified as sodium-sensitive (5 mm Hg or more MAP increase in response to the high salt) and 11 were classified as sodium-resistant (5 mm Hg or less MAP increase). The prevalence of sodium sensitivity was higher in DD (71%) and ID (83%) compared to II (25%) genotype groups. Therefore, in older hypertensive individuals, the ACE gene ID and DD genotypes are associated with an increase in BP during a high Na+ diet (Dengel et al, 2001).
ACE I/D polymorphism and weight loss impact
Weight loss and sodium reduction are two highly interactive non-pharmacologic factors in the management of hypertension. In a study of the ACE I/D polymorphism on blood pressure change after weight loss in 86 overweight white elderly hypertensive participants, it was observed that while the weight loss was similar across all ACE genotypes, the blood pressure decrease was significantly greater among the DD genotype than DI or II genotypes. In addition, DD participants had a higher probability of remaining normal blood pressure after the weight loss. This study suggested that the DD genotype may be associated with higher “weight sensitivity” in overweight white hypertensive persons, potentially through reduced activity of the renin-angiotensin and sympathetic systems after weight loss (Kostis et al, 2002). Therefore, maintaining a normal weight is more effective for D allele carriers to prevent blood pressure increase.
ACE polymorphism and exercise performance
The ACE insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. The I allele has been consistently demonstrated to be associated with endurance-orientated sports. Its frequency is much higher in triathletes, long distance runners, long distance swimmers, rowers, cyclists and mountain climbers. Meanwhile, the D allele is associated with strength- and power-orientated performance, and has been found in significant excess among elite short distance runners or swimmers (less than 200 meters). A comprehensive review of the ACE insertion/deletion (I/D) polymorphism and sports performance was published recently (Puthucheary et al, 2011).
In cardiac muscle, ACE genotype has associations with left ventricular mass changes in response to stimulus, in both the health and diseased states. Increased left ventricular mass is associated with excess cardiovascular mortality. In a study of ACE polymorphism and physical exercise among 156 military recruits, it was observed that the left ventricular mass associated with the D allele. After 10 weeks of physical training, mean left ventricular mass increased by 2.0, 38.5, and 42.3 g in II, ID, and DD carriers, respectively (Montgomery et al, 1997; 1998). Therefore, the D allele is associated with an exaggerated response to training, and the I allele with the lowest cardiac growth response. Similarly in skeletal muscle, the D allele is associated with greater strength gains in response to training, in both healthy individuals and chronic disease states.
ACE I/D polymorphism and blood pressure, atherosclerosis, coronary heart disease and stroke
The association of the ACE I/D polymorphism and blood pressure seem to be gender and race/ethnicity dependent. Many early reports on the association of DD genotype with hypertension were not repeated in later larger samples of Caucasian population. However, a significant relationship between the D allele and hypertension in women and non-Caucasian does exist. For example, a recent meta-analysis of 10 547 hypertension patients and 9217 controls concluded that the DD genotype were 61% more likely to develop hypertension in Han Chinese population (Ji et al, 2010). Another recently study in United States involving 5561 subjects reported a significant association between the D allele and high blood pressure in non-Hispanic blacks or in female Mexican Americans whereas no association was detected for non-Hispanic Whites or male Mexican Americans (Ned et al, 2012). When the relationship between ACE gene and blood pressure was tested in mice having 1, 2, or 3 functional copies of the gene at its normal chromosomal location, although serum ACE activity increased progressively from the 1-copy animals to the 3-copy animals, the blood pressures of the mice did not differ significantly. Therefore, a quantitative change in ACE level does not necessarily lead to higher blood pressure directly. Any effect of the D allele on hypertension must be triggered by secondary factors including the interaction between ACE and other genes or environmental factors (Sayed-Tabatabaei et al, 2006).
The association between the ACE I/D polymorphism and atherosclerosis is normally studied by using carotid artery intima media thickness (IMT) measurements. A positive association between the D allele and common carotid IMT was detected in Caucasians and Asians, but the association was stronger among high-risk populations (i.e., subjects with underlying diseases such as cerebrovascular disease, diabetes, or hypertension). In low-risk/general populations, the weighted mean difference between DD and II was 0.01 mm whereas in high-risk populations this difference was seven fold higher (0.07 mm). In general, a modest positive association between the D allele and atherosclerosis exists, particularly in those who carry other (genetic or environmental) cardiovascular risk factors (Sayed-Tabatabaei et al, 2003).
The D allele carriers also have a higher risk for myocardial infarction (MI) and ischemic stroke. Both commonly result from thrombosis superimposed on atherosclerotic plaques. Meta-analysis of 48 small studies (each with fewer than 200 cases), which totaled 5092 cases, yielded a pooled odds ratio for MI and other coronary heart disease associated with the DD genotype of 1.43. Meta-analysis of 29 larger studies with a total of 14,868 cases yielded a combined odds ratio of 1.04. The odds ratio for ischemic stroke associated with the D allele were 1.10 – 1.22 (Sayed-Tabatabaei et al, 2006).
ACE polymorphism and diabetic nephropathy
In a meta-analysis performed on 58 studies comprising 14 727 subjects, a 28% higher risk of diabetic nephropathy in carriers of the D allele than the II genotype group was observed (Ng et al, 2005). This association is more pronounced in type II diabetic Asian population, in which the DD genotype exhibits three fold higher risk of progressing to the stage when chronic renal dialysis is needed. In French, Danish and Finish type I diabetic population, the DD genotype is also associated with persistent albuminuria (Hadjadj et al, 2007). Therefore, D allele confers adverse effect in diabetic population.
ACE polymorphism and migraine
Migraine is a chronic symptom characterized by recurrent headache attacks and combinations of gastrointestinal and autonomic nervous system symptoms. Up to one third of migraine patients experience an aura prior to or during the migraine headache. In a meta-analysis of nine studies on the association of the ACE I/D polymorphism with migraine, the II genotype was associated with a reduced risk for migraine with (pooled OR=0.71) and without aura (pooled OR=0.84). But the associations are only detectable in non-Caucasian populations (Chinese, Indians, Japanese and Turks). Results among Caucasians in all four studies did not suggest any association (Schürks et al, 2010). The ethnicity specific effect is consistent with the observed ACE I/D association with other diseases discussed in the above sections.
ACE I/D polymorphism and Alzheimer Disease (AD)
The association between the I/D polymorphism and AD was first reported in 2003. In this case control study, a positive association was found between the I allele and AD (odds ratio = 2.43 for II/ID versus DD genotypes). Subsequently, the same group of researchers tested the same association in two independent case-control samples and successfully replicated their finding (Kehoe et al, 2003). This association was subsequently examined in several studies. A cumulative meta-analysis that included 39 samples, comprising 6,037 cases of Alzheimer's disease and 12,099 controls revealed that the DD genotype individuals were at reduced risk (odds ratio = 0.81) of AD (Lehmann et al, 2005).
ACE I/D polymorphism and medicine response
In healthy population, the ACE I/D polymorphism did not show significant difference in response to either single dose or long term (10 years) treatment with ACE inhibitor drugs benazepril or lisinopril, but showed inconsistent responses to treatment with captopril. It is speculated that other potential confounding factors such as gender, sodium intake, and ethnicity that are known to affect rennin level, interact with the ACE I/D polymorphism to exhibit any differential medicine treatment out come. This topic is reviewed in detail by Dancer et al (2007).
For certain patient population, however, the ACE I/D polymorphism did exhibit significant effects. For example, ACE inhibitors are particularly effective at the stage of normoalbuminuria or microalbuminuria in both type I and type II diabetics with the II genotype, whereas the DD genotype is associated with a better response to ARA (Angiotensin II Receptor Antagonists) therapy in overt nephropathy of type II diabetes and to ACE inhibitors in male patients with nondiabetic proteinuric nephropathies (Ruggenenti et al, 2008).
The ACE I/D polymorphism effect is also reflected in the drug dosage response. During ACE inhibitor therapy at standard doses the risk of events in II, ID, and DD patients with congestive heart failure was identical, whereas during ACE inhibitor under dosing (i.e., treatment at ≤50% of target dose) the risk of events in DD patients was increased versus II and ID patients (McNamara et al., 2004). Otherwise, at normal dosage, the overall effect of ACE I/D polymorphism on various ACE inhibitor drugs are not consistent.
ACE polymorphism and hormone replacement therapy
Hormone replacement therapy (HRT) reverses the menopausal decline in maximum voluntary force of the adductor pollicis muscle and reduces serum ACE levels. The insertion (I) allele of the ACE gene polymorphism is associated with lower ACE activity and improved muscle efficiency in postmenopausal women in response to HRT. Those taking HRT showed a significant gain in normalized muscle maximum voluntary force slope, the rate of which was strongly influenced by ACE genotype (16.0%, 14.3%, and 7.8% for II, ID, and DD genotype, respectively). There was also a significant ACE gene effect in the response of BMD (bone mineral density) to HRT with the I allele showing much favorable results. These data suggests that low ACE activity associated with the I allele confers an improved muscle and BMD response in postmenopausal women treated with HRT (Woods, 2001).
ACE I/D polymorphism evolution
The prevalence of both the D and I alleles in populations worldwide suggest that they both have survival advantages. The I allele may relate to improved endurance performance, and enhanced oxygen utilization in times of both exercise and illness. The D allele, being associated with gains in strength with training, may offer separate advantages related directly to strength itself, but also to the acquisition of increased muscle bulk in response to muscle strength training/high loading. In addition, ACE genotype influences a variety of other phenotypes. Polymorphism study suggested that the II genotype could be associated with altitude adaptation, which might influence physical efficiency. For example, the II genotype distribution is significantly higher in the Quechua-speaking native people living above 3000m in South America (Bigham et al, 2008) and those in the Ladakh region of India living above 3600 m (Qadar Pasha et al, 2001)
Conclusions
The ACE I/D polymorphism interacts with dietary sodium, exercise, medicine and associates with a variety of cardiovascular and renal diseases. The D allele carriers are more likely to response unfavorably to high sodium intake and the interaction is aggravated by stress conditions or in high risk populations. Meanwhile, the D allele also proves some degree of protection against AD. With regards to dietary intervention, sodium restriction through low-sodium and high-potassium diet is the choice.
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