The renin angiotensin system (RAS) contributes to regulation of vascular tone, electrolyte and volume homeostasis and its role in blood pressure (BP) has been well established.  Two of the RAS gene polymorphisms that have been extensively studied include AGT M235T and ACE insertion/deletion (I/D).

According to family and twin studies, the heritability of hypertension ranges from 24% to 50%. Essential hypertension accounts for 95% of all cases of hypertension and involves a complex interaction of multiple polymorphisms in numerous genes, with more than 60 SNPs having been reported in European populations, while monogenic hypertension is well defined with 12 causative genes. 

Angiotensinogen (AGT) and angiotensin-1-converting enzyme (ACE), encode proteins of the renin-angiotensin system (RAS).

ACE Overview

The ACE gene codes for the angiotensin converting enzyme and is part of the renin angiotensin system which regulates blood pressure by controlling the balance of fluids and salts in the body.  This angiotensin converting enzyme converts the protein angiotensin 1 into a physiologically active protein called angiotensin 11.  Angiotensin 11 is a potent vasopressor and aldosterone-stimulating peptide, which causes blood vessels to constrict, thereby increasing blood pressure.  It also stimulates the production of the hormone aldosterone, which triggers the absorption of salt and water by the kidneys. This increased amount of fluid in the body also increases blood pressure. The angiotensin-converting enzyme can also cleave other proteins, including bradykinin. Bradykinin causes blood vessels to widen (dilate), which decreases blood pressure. Cleavage by the angiotensin-converting enzyme inactivates bradykinin, helping to increase blood pressure.

ACE is encoded by a 21kb, 26 exon gene located on chromosome 17 at q23. ACE insertion/deletion (I/D) polymorphism is the insertion or deletion (I/D) (or presence/ absence) of a 287-base pair in intron 16 of the ACE gene.

An insertion/deletion polymorphism of the ACE gene predicts approximately 40-50% of the inter-individual variability in serum ACE levels.   DD homozygotes have been shown to demonstrate the highest activity of ACE, II homozygotes the lowest and ID heterozygotes in-between.

The ACE I/D gene polymorphism is most commonly associated with blood pressure and has been found to be affected by gender and race/ethnicity. 

Studies have found that carriers of the DD allele have a higher incidence of hypertension compared to carriers of the II allele with classical studies having found that ACE activity level and susceptibility to hypertension follows the order DD>ID>II. 

Although these DD carriers have higher incidence of hypertension, patients with essential hypertension who are homozygous for the insertion allele of the ACE gene (II) have been found to be more salt sensitive and hence see a greater spike in blood pressure in response to a higher sodium intake.

The gene that encodes angiotensinogen (AGT) is found on chromosome 1q42 to 43. The AGT M235T SNP leads to a tyrosine for cytosine substitution in the second exon of angiotensinogen gene, which results in the substitution of threonine for methionine at amino acid position 235 (M235T) in the translated protein. AGT T235 represents the mutant allele and M235 represents the wild type.

The variant Threonine (C) allele of the AGT M235T SNP has been associated with elevated levels of angiotensinogen, with individual’s homozygote for 235 TT (CC) having between 10% to 20% more plasma angiotensinogen than 235 MM (TT) individuals.  Case control association studies of M235T polymorphism in essential hypertension have found conflicting results with Nigerian, French, Han Chinese and Malaysian populations finding linkage or association while others have not.  There is a general agreement, however, that the T allele of angiotensinogen M235T gene is associated with increased plasma angiotensinogen levels and an increased risk of developing hypertension.

Studies have found a greater prevalence of ID and DD genotypes (presence of D alleles) amongst patients with hypertension. The presence of the D allele is associated with higher plasma concentrations of ACE, resulting in increased peripheral vascular resistance, loss of arterial elasticity and elevated blood pressure. Most studies have found associations between the ACE D allele and hypertension; however, some studies have not confirmed this association.  This may be due to differences in methodologies, ethnicity reasons or regional aspects.  

Heidari et al. (2014) found that patients carrying the DD genotype for ACE gene, had higher blood pressure lowering responses when treated with ACE inhibitors, enalapril and lisinopril than those carrying ID and II genotypes, suggesting that the D allele may be a possible genetic marker for essential hypertension among Malay male subjects. 

Pacholczyk et al. carried out a study to investigate the association of I/D polymorphism with essential hypertension in a Polish population and to analyse the distribution of ACE gene polymorphisms in patients with hypertension. To examine the age dependence in the association of ACE DD genotype with hypertension, the frequency of ACE I/D polymorphism and allele distribution were investigated in two groups; a ‘young’ group with subjects <55 years of age and an ‘elderly’ group >55 years of age.  To examine the sex specific association of hypertension, the genotypes of ACE I/D polymorphisms allele distribution were compared separately between men and women.  To assess the potential modifying effects of body mass index on association between ACE I/D and risk of hypertension, the frequencies of genotypes of ACE I/D polymorphism and alleles distribution were examined separately in patients with normal body weight (BMI<25.0kg/m2) and in overweight or obese patients (BMI>25.0kg/m2). Data concluded that the ACE D allele might be a risk factor for hypertension in the Polish population, where a significant association between ACE I/D polymorphism and prevalence of hypertension was seen in the whole group. Apart from DD genotype, male sex, raised levels of triglycerides, total cholesterol, overweight and obesity and disorders in carbohydrate metabolism were significant risk factors for hypertension.

ACE I/D And Sodium Sensitivity

Freire et al. conducted a study to analyse the relationship between ACE I/D gene polymorphisms, environmental/behavioural factors and hypertension in community dwelling elderly individuals. 234 elderly participants from Bahia, Brazil participated in this study. The mean prevalence of hypertension was 59.3%.  Hypertension was defined by self reporting the condition and confirmed by treatment with antihypertensive drugs.  The main study finding was that ACE D allele carriers were not significantly associated with hypertension but carriers of the II genotype showed a greater prevalence of high estimated daily sodium intake, resulting in them being more prone to hypertension.  Elderly patients with hypertension with the ACE II genotype showed poorer blood pressure control compared to D allele carriers (ID and DD) but had a higher sodium intake, with a mean estimated daily sodium intake of 2,57g (minimum of 0.15 and maximum 8.64g) compared to a mean intake of 1.67g in in those carrying the D allele (minimum of 0.09 and max 11.20g).  The data from the study indicated that elderly patients carrying the II genotype of the ACE I/D gene polymorphism have a predisposition to sodium sensitivity and possibly poorer BP control and they should maintain strict control on their sodium intake, even if they are on taking antihypertensive medication.

The mechanism behind ACE II genotype carriers having a higher blood pressure response to salt intake may be that since sodium sensitive patients exhibit greater suppression of renin-angiotensin aldosterone system when exposed to sodium intake, it is plausible that II genotype carriers, who have lower levels of plasmatic ACE, may have a reduced suppressive response after a plasmatic sodium increase (due to lower levels of plasmatic ACE), indicating that there may be inefficiencies of an important regulatory mechanism of the renin-angiotensin aldosterone system when they are exposed to a high sodium diet.

In conclusion, interactions between II genotype and high sodium diet (>2g/day) increased the predisposition of hypertension in elderly patients and tended to impair BP control in elderly patients with raised BP being pharmacologically treated. Results from this study suggested that pharmacologically treated patients with hypertension with II genotype have poor BP control when following a high sodium diet.  

Another study by Poch et al. also found the I allele of ACE I/D polymorphism to be significantly associated to salt-sensitive hypertension.  They analysed the association between salt sensitivity in essential hypertension and 8 genetic polymorphisms in 6 genes (including ACE I/D and AGT M235T) of the renin angiotensin aldosterone system. Seventy-one patients with essential hypertension were classified as either salt sensitive (49%/ 35 patients) or salt resistant (51%/ 36 patients). Of the 6 candidate genes for salt sensitive hypertension, only 2 of them, ACE I/D and 11BHSD2 G534A polymorphisms, showed an association with BP response to a high salt diet.  

AGT M235T gene polymorphism has been associated with essential hypertension with a hypertensive group of patients having 3x the frequency of the TT (CC) gene variation for AGT than normotensive controls, in a group of 1166 adults studied.

AGT And Salt Sensitivity

In a large cross-sectional study in a large free-living population, Norat et al. found that people with the TT (CC) genotype of AGT M235T polymorphism showed the greatest response to intervention compared to people with MM (TT) or MT (CT) genotype and that in populations with a low sodium exposure, genotype effects are not likely to be seen. In this large study of 11384 men and women, interactions between systolic blood pressure (SBP) and diastolic blood pressure (DBP), angiotensinogen genotype and urinary excretion of sodium and potassium were examined. Subjects with the AGT M235T homozygous MM (TT) genotype saw the weakest associations between sodium and blood pressure. Women homozygous for TT (CC) genotype had higher SBP and DBP than those with MT (CT) or MM (TT) genotypes. Blood pressure did not vary in men.   

There are mixed results around the ACE I/D gene polymorphism and the AGT M235T gene polymorphism and salt sensitivity.

Overall, studies indicate individuals who are homozygous DD for ACE I/D are at a higher risk for having raised blood pressure, however individuals who are homozygous II genotype for ACE I/D, have been found to be salt sensitive i.e. they are likely to see an increase in blood pressure with a high salt intake compared to those carrying the DD genotype.  Individuals carrying the ID genotype may also experience raised blood pressure in response to salt intake.  Even though some studies did not find this association, given the available evidence, it would be advisable for individuals carrying the insertion allele (II or ID) to reduce their salt intake to avoid spikes in blood pressure and for overall management of blood pressure.

It should be noted that gender and ethnicity have both been found to affect risk of hypertension and/or sodium sensitivity for this SNP.

With regard to the AGT M235T SNP, studies have also shown mixed results, with some studies finding no association between this SNP and risk of blood pressure/ salt sensitivity, however some studies have found evidence that points towards the M235 TT (CC) genotype being a risk factor for hypertension. Others found that individuals carrying the TT (CC) genotype who have a high salt intake, may see a good blood pressure response to a reduced sodium intake.  It would therefore be advisable that individuals with the AGT TT (CC) genotype reduce their sodium intake if they are consuming a high salt diet.