Analysis of renin-angiotensin-aldosterone system gene polymorphisms in resistant hypertension

Abstract

Essential hypertension is a disease multifactorially triggered by genetic and environmental factors. The contribution of genetic polymorphisms of the renin-angiotensin-aldosterone system and clinical risk factors to the development of resistant hypertension was evaluated in 90 hypertensive patients and in 115 normotensive controls living in Southwestern Brazil. Genotyping for insertion/deletion of angiotensin-converting enzyme, angiotensinogen M235T, angiotensin II type 1 receptor A1166C, aldosterone synthase C344T, and mineralocorticoid receptor A4582C polymorphisms was performed by PCR, with further restriction analysis when required. The influence of genetic polymorphisms on blood pressure variation was assessed by analysis of the odds ratio, while clinical risk factors were evaluated by logistic regression. Our analysis indicated that individuals who carry alleles 235-T, 1166-A, 344-T, or 4582-C had a significant risk of developing resistant hypertension (P < 0.05). Surprisingly, when we tested individuals who carried the presumed risk genotypes A1166C, C344T, and A4582C we found that these genotypes were not associated with resistant hypertension. However, a gradual increase in the risk to develop resistant hypertension was detected when the 235-MT and TT genotypes were combined with one, two or three of the supposedly more vulnerable genotypes -A1166C (AC/AA), C344T (TC/TT) and A4582C (AC/CC). Analysis of clinical parameters indicated that age, body mass index and gender contribute to blood pressure increase (P < 0.05). These results suggest that unfavorable genetic renin-angiotensin-aldosterone system patterns and clinical risk variables may contribute to increasing the risk for the development of resistant hypertension in a sample of the Brazilian population. Correspondence

The interaction ofAGTandNOS3gene polymorphisms with conventional risk factors increases predisposition to hypertension

“…This is also supported by other studies that have shown a relationship between this genotype and blood pressure in an ethnically mixed Brazilian urban population. 33,34 In relation to the Glu298Asp polymorphism, others have reported similar results, in which the A allele may determine the susceptibility to hypertension. [35][36][37][38] These findings suggested a protective effect of the M and G alleles of the AGT and NOS3 genes, respectively, against the development of hypertension, whereas the T and A alleles increase the susceptibility to hypertension, respectively.…”

“…40 Currently, it has also been demonstrated that the T allele of Met235Thr polymorphism increases the risk of CAD associated with the presence of hypercholesterolaemia 41 and reduced life span. 34,42 Nevertheless, it has also been indicated that the unfavourable allele of the Met235Thr polymorphism had an interaction with clinical parameters, such as BMI and gender, which contributed to increased blood pressure. 34 Similarly to the AGT gene, it was also found for the NOS3 polymorphisms that the A allele had an interaction with sedentary lifestyle, and also presented a significant combination with smoking towards the development of hypertension.…”

“…34,42 Nevertheless, it has also been indicated that the unfavourable allele of the Met235Thr polymorphism had an interaction with clinical parameters, such as BMI and gender, which contributed to increased blood pressure. 34 Similarly to the AGT gene, it was also found for the NOS3 polymorphisms that the A allele had an interaction with sedentary lifestyle, and also presented a significant combination with smoking towards the development of hypertension. These data coincided with other studies that demonstrated that the GA/AA genotypes of the Glu298Asp polymorphism may increase the risk of hypertension when associated with high total cholesterol level, [43][44][45] while the AA genotype may increase the risk of premature CAD.…”

Daily sodium intake influences the relationship between angiotensin‐converting enzyme gene insertion/deletion polymorphism and hypertension in older adults

“…Indeed, the presence of the D allele is associated with high plasma concentrations of ACE, leading to an increased peripheral vascular resistance, loss of arterial elasticity, and elevated BP . Although most studies have observed the association between the D allele and hypertension, especially involving young and middle‐aged individuals, some studies have not confirmed this association . In addition, the study by Almada and colleagues involving 241 older Brazilian adults also did not observe a higher prevalence of D allele carriers among patients with hypertension.…”

Angiotensinogen Variants among Resistant Hypertensive Patients

“…Interestingly, the main finding was the association of two genetic variants in the angiotensinogen ( AGT ) gene, the M allele of rs699 and the G allele of rs5051, and TRH in white but not in African-American subjects. Previous Brazilian studies [2, 3] found the association with this SNP but at an opposite direction; carriers of the AGT M235T T allele, not Met allele, were at increased risk for resistant hypertension. The divergence among those studies might be explained by the differences between the genetic structure of the studied populations.…”