Abstract

BackgroundSystemic 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 findingsThis 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).ConclusionThese 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 that this can be a marker of poor prognostic on SAH evolution and contribute to CVD development. Although these preliminary findings must be confirmed by further researches with larger sample size, we could observe that the integrative analysis of ACE and ACE2 can be an informative tool in hypertension understanding that needs to be explored in new studies.

Highlights

  • Systemic arterial hypertension (SAH) is a leading cause of cardiovascular diseases (CVD) reaching the prevalence of 30% in the world population [1]

  • Angiotensin I-converting enzyme (ACE) and ACE2 present several other roles besides their functions as angitensinases [8,9,10,11,12], ACE main role is the conversion of angiotensin I (Ang-I) to angiotensin I/D polymorphism were 20.5% (II) (Ang-II), a potent vasoactive peptide that leads to effects mainly hypertensives, while ACE2 has predominantly opposite effects by two mechanisms: conversion of Ang-I in Angiotensin 1–9, that is converted by ACE in the vasodilator peptide Angiotensin 1–7 (Ang 1–7); and directly conversion of Ang-II in Ang 1–7 [5,6,7]

  • Blood pressure and laboratory data of lipid profile and blood glucose were significantly different between the groups due to the very more altered values for these variables observed in hypertensive patients, reflecting the incidence of type 2 diabetes mellitus (T2DM) [37% of patients] and dyslipidemia (47% of patients), that are comorbidities frequent in these patients

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Summary

Introduction

Systemic arterial hypertension (SAH) is a leading cause of cardiovascular diseases (CVD) reaching the prevalence of 30% in the world population [1]. To tackle this disease the environmental factors and the emerging weight of genetic factors need to be considered for years to come, with application on genetic risk scores development [2], once genetics can be responsible for about 40% of the interindividual variance in blood pressure levels [3] In this sense, several research groups have dedicated to studying the genetic basis of hypertension, but it has been pointed out the small contribution of each one of the genetic factors and the interaction among them as a problem in identifying genetic markers for the disease [4]. 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

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