The combination of ACE I/D and ACE2 G8790A polymorphisms revels susceptibility to hypertension: A genetic association study in Brazilian patients

Abstract

Background Systemic arterial hypertension (SAH) is a multifactorial condition that already affects one third of the worldwide population. The identification of candidate genes for hypertension is a challenge for the next years. Nevertheless, the small contribution of each individual genetic factor to the disease brings the necessity of evaluate genes in an integrative manner and taking into consideration the physiological interaction of functions. Angiotensin I–converting enzymes, ACE and ACE2, are key regulators of blood pressure that have counterbalance roles by acting on vasoactive peptides from Renin-Angiotensin-Aldosterone System (RAAS). Insertion/deletion (I/D) polymorphism of ACE gene and single nucleotide polymorphism G8790A of ACE2 gene have been associated with susceptibility to SAH, but the literature is controversial. We proposed to evaluate these two polymorphisms jointly exploring the combined effects of ACE and ACE2 genotypes on SAH susceptibility, an approach that have not been done yet for ACE and ACE2 polymorphisms. Methods and findings This genetic association study included 117 hypertensive (mean age 59.7 years) patients and 123 normotensive and diabetes-free controls (mean age 57.5 years). ACE and ACE2 polymorphisms were genotyped by SYBR Green real-time PCR and RFLP-PCR, respectively. Crude and adjusted odds ratio (OR) values were calculated to estimate the susceptibility to SAH development. It was obtained homogeneity regarding distribution by sex, age range, smoking, alcohol consumption and body mass index (BMI) between case and control groups. No-association was verified for each gene individually, but the combination of ACE and ACE2 polymorphisms on female gender revealed a significative association for DD/G_ carriers who had a 3-fold increased risk to SAH development (p = 0.03), with a stronger susceptibility on DD/GG carriers (7-fold increased risk, p = 0.01). The D allele of ACE showed association with altered levels of lipid profile variables on case group (VLDL-cholesterol, p = 0.01) and DD genotype in all individuals analysis (triglycerides, p = 0.01 and VLDL-cholesterol, p = 0.01). Conclusion These findings indicate that the combination of ACE and ACE2 polymorphisms effects may play a role in SAH predisposition been the DD/G_ genotype the susceptibility profile. This result allowed us to raise the hypothesis that an increased activity of ACE (prohypertensive effects) in conjunction with reduced ACE2 activity (antihypertensive effects) could be the underlining mechanism. The association of ACE D allele with lipid alterations indicate t...

Association of Angiotensin I Converting Enzyme Insertion/287 bp Deletion Polymorphisms and Proliferative Prostatic Diseases among Lebanese Men

“…Uemura et al [10] observed a statistically significant association of the D allele and high systolic and diastolic blood pressure in the Japanese population and obesity, hyperlipidemia, hypertension, and diabetes mellitus more prevalent among the ID and DD genotypes, compared to the II genotype. In another study involving a Brazilian population, no direct association of I/D polymorphism of the ACE gene and G8790A polymorphism of the ACE2 gene and systemic arterial hypertension was observed although significant association of the combination of the DD genotype and GG genotype with systemic arterial hypertension was observed [11]. A study in southeast Turkey indicated that women with DD or ID genotypes had a 72% increased risk of idiopathic recurrent pregnancy loss [12], while another study in northern Iran found the DD genotype to be more prevalent among women who have experienced recurrent pregnancy loss [13].…”

“…Given that ACE plays a key role in the renin-angiotensin system that regulates fluid volume and controls blood pressure, it is highly likely that I/D polymorphism of the ACE gene could have diverse physiological consequences. Indeed, the I and D alleles of the ACE gene have been associated with an increased risk for many diseases [7][8][9][10][11][12]. Uemura et al [10] observed a statistically significant association of the D allele and high systolic and diastolic blood pressure in the Japanese population and obesity, hyperlipidemia, hypertension, and diabetes mellitus more prevalent among the ID and DD genotypes, compared to the II genotype.…”

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“…Actually, these effects are being investigated in ongoing clinical trials (ClinicalTrials.gov NCT04287686), alongside the use of losartan as first therapy for COVID-19 in hospitalized (NCT04312009) or not hospitalized patients (NCT04311177). A major role in the pathogenesis of (as well as in the clinical response to) COVID-19 could also be played by ACE2 polymorphisms, which are relatively under-investigated if compared to ACE [129,130].…”

Renin-angiotensin system at the heart of COVID-19 pandemic

“…The ACE2 gene (which is located on X chromosome) is characterized by a large polymorphism, and significant associations between polymorphisms and occurrence of arterial hypertension have been reported for women of different race and ethnicity and in Han Chinese men [10][11]. More recently, the combination of ACE1 and ACE2 polymorphisms has been associated with susceptibility to hypertension in Brazilian patients [12]. Within the Chinese population, the polymorphism distribution seems different between regions; polymorphisms of ACE2 are associated with different blood pressure response to the cold pressor test.…”