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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 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.

SUBMITTER: Pinheiro DS

PROVIDER: S-EPMC6701835 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Pinheiro Denise S DS Santos Rodrigo S RS Jardim Paulo C B Veiga PCBV Silva Elisangela G EG Reis Angela A S AAS Reis Angela A S AAS Pedrino Gustavo R GR Ulhoa Cirano J CJ

PloS one 20190820 8

<h4>Background</h4>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 an ...[more]

PMID: 31430320

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Project description:BACKGROUND:Cardiovascular benefits by reversing environmental risks factors for essential hypertension (EH) and dyslipidemia could be weaken by high genetic risk. We investigated possible associations between ACE2 polymorphisms and dyslipidemia in patients with EH. METHODS:Four hundred and two hypertensive patients were enrolled in an EH group and 233 normotensive individuals were enrolled as control group from the Xinjiang region of China. Fourteen ACE2 polymorphisms were genotyped by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry. RESULTS:Participants carrying T allele (TT?+?CT) of rs2074192 (P?=?0.006), rs4646155 (P?=?0.030) and rs4646188 (P?<?0.001), C allele (CT?+?CT or CC?+?CG) of rs4240157 (P?=?0.012), rs4830542 (P?=?0.020) and rs879922 (P?<?0.001) and TT genotype of rs2106809 (P?=?0.012) were associated with EH. Meanwhile,ACE2 SNPs also exhibited association with dyslipidemia but exhibited obvious heterogeneity. rs1978124 (TT?+?CT, P?=?0.009), rs2106809 (TT, P?=?0.045), rs233575 (CC?+?CT, P?=?0.018), rs4646188 (CC, P?=?0.011) and rs879922 (CC?+?CG, P?=?0.003) were association with increased LDL-C (?1.8 mmol/L). rs2106809 (CC?+?CT, P?<?0.001), rs2285666(TT?+?CT, P?=?0.017), rs4646142(CC?+?CG, P?=?0.044), rs4646155(TT?+?CT, P?<?0.001) and rs4646188(TT?+?CT, P?=?0.033) were association with decreased HDL-C (<?1.0 mmol/L). rs2074192 (TT?+?CT, P?=?0.012), rs4240157 (CC?+?CT, P?=?0.027), rs4646156 (AA+AT, P?=?0.007), rs4646188 (TT?+?CT, P?=?0.005), rs4830542 (CC?+?CT, P?=?0.047) and rs879922 (CC?+?CG, P?=?0.001) were association with increased TC (?5.2 mmol/L). rs2106809 (P?=?0.034) and rs4646188 (P?=?0.013) were associated with hypertriglyceridemia. Further, ischemic stroke was more prevalent with rs4240157 (CC?+?CT, P?=?0.043), rs4646188 (CC?+?CT, P?=?0.013) and rs4830542 (CC?+?CT, P?=?0.037). In addition, rs2048683 and rs6632677 were not association with EH, dyslipidemia and ischemic stroke. CONCLUSION:The ACE2 rs4646188 variant may be a potential and optimal genetic susceptibility marker for EH, dyslipidemia and its related ischemic stroke.

Project description:Essential hypertension (EH) is a principal contributing factor in worldwide cardiovascular disease mortality. Although interventions that minimize environmental risk factors for EH are associated with reduced cardiovascular disease, such approaches are limited for individuals with high genetic EH risk. In this study, we investigated possible associations between ACE2 polymorphisms and hypertension-related target organ damages in south Xinjiang, China. Four hundred and two hypertensive patients were enrolled as study participants in an EH group, and 233 normotensive individuals were enrolled as control subjects. Participants were recruited from the south Xinjiang region. Fourteen ACE2 polymorphisms were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Risk genotypes of rs2074192 (TT+CT, OR = 1.72, 95% CI: 1.17-2.53), rs2106809 (TT, OR = 1.71, 95% CI: 1.13-2.58), rs4240157 (CC+CT, OR = 1.99, 95% CI: 1.17-3.41), rs4646155 (TT+CT, OR = 1.94, 95% CI: 1.06-3.54), rs4646188 (TT+CT, OR = 3.25, 95% CI: 1.95-5.41), rs4830542 (CC+CT, OR = 1.88, 95% CI: 1.10-3.23), and rs879922 (CC+CG, OR = 4.86, 95% CI: 2.74-8.64) were associated with EH. Hypertensive patients carrying the control genotype of rs2074192 (CC, OR = 2.37, 95% CI: 1.28-4.39) were associated with CAS ≥50%, while those carrying a high-EH-risk genotype of rs4240157 (OR = 2.62, 95% CI: 1.24-5.54), rs4646155 (OR = 2.44, 95% CI: 1.16-5.10), or rs4830542 (CC+CT, OR = 2.20, 95% CI: 1.03-4.69) were associated with atrial fibrillation (AF), larger left atrial diameter, and higher levels of renin-angiotensin-aldosterone system (RAAS) activation (renin and angiotensin I/II). In conclusion, the ACE2 variant rs2074192 was associated with EH and EH with CAS ≥50%, while 3 ACE2 variants (rs4240157, rs4646155, and rs4830542) were associated with EH- and hypertension-related AF and left atrial remodeling in south Xinjiang, China.

Project description:BackgroundA number of studies were carried out to assess the association of angiotensin I converting enzyme (ACE) I/D and plasminogen activator inhibitor-1 (PAI-1-1) 4G/5G polymorphisms with susceptibility to type 2 diabetes mellitus (T2DM). However, there are a few studies in Iranian patients with T2DM. Here, we tested for an association of ACE I/D and PAI-1 4G/5G polymorphisms with T2DM risk.MethodsOne hundred-eighteen patients with T2DM and 125 healthy subjects were participates in this study. The ACE I/D (rs4340) and PAI-1 4G/5G (rs1799889) polymorphisms was genotyped by conventional and PCR-RFLP assays, receptively. The associations was evaluated by calculating the odds ratio (OR) and 95% confidence interval (95% CI).ResultsThe genotype distribution of ACE I/D and PAI-1 4G/5G polymorphisms were not deviated from the Hardy-Weinberg equilibrium in healthy controls. The ACE II, ID, and DD genotype frequencies were 18.6%, 48.3%, and 33.1% in the T2DM patients versus 24.0%, 45.6% and 30.4% in healthy subjects, respectively. The PAI-1 4G/4G, 4G/5G, and 5G/5G genotype frequencies were 16.9%, 51.7%, and 31.4% in cases versus 24.8%, 57.6% and 17.6% in controls, respectively. There is a significant distribution in genotype/allele of PAI-1 4G/4G between cases with T2DM and healthy control, but not for ACE I/D. Moreover, the 5G/5G genotype is significantly (OR = 2.139, CI 95% 1.171-3.907, p = 0.013) increased the risk of T2DM by two folds in the cases than healthy controls.ConclusionsOur findings suggest that PAI-1 4G/5G may be likelihood risk factor for the development of T2DM in the Iranian patients. The higher frequency of PAI-1 5G/5G genotype in patients with T2DM revealed that individuals with the 5G allele may be at higher risk of T2DM development than those with 4G. However, there was no significant association between ACE I/D polymorphism and T2DM in our population. Future rigorous, well-designed studies with larger sample should replicate this study to confirm our findings in Iranian T2DM patients.

Dataset Information

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

Publications

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

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