ACE2 Polymorphisms Research Articles

Genetic variability of human angiotensin-converting enzyme 2 (hACE2) among various ethnic populations.

BackgroundThere appears to be large regional variation for susceptibility, severity, and mortality for COVID‐19 infections. Numerous potential factors could explain the wide variability in the number of infections and death among the countries. We examined genetic differences in the human angiotensin‐converting enzyme 2 (hACE2) gene, as its receptor serves as a cellular entry for SARS‐CoV‐2. At present, there is a paucity of data regarding the differences for ACE2 polymorphisms and expression levels between ethnicities.MethodsWe compared the allele frequency of mutations between European and East Asians. Molecular dynamic simulation were performed to investigate the influences of significant mutant on protein structure. The binding free energies were calculated between S protein and hACE2. We also examined hACE2 gene expression in eight global populations from HapMap3.ResultsFour missense mutations showed significant minor allele frequency difference between Asians and Caucasians. Molecular dynamic demonstrated that two of these variants (K26R and I468V) may affect binding characteristics between S protein of the virus and hACE2 receptor. We also noted marginal differences in gene expression for some populations in HapMap3 as compared to the Chinese population.ConclusionOur studies reveal subtle changes in the genetics of hACE2 between human populations, but the magnitude of the difference was small and the significance is not clear in the absence of further in vitro and functional studies.

A systematic review and meta-analysis to evaluate the clinical outcomes in COVID-19 patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

IntroductionAngiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) share their target receptor site with the SARS-CoV-2 virus, that may cause ACE2 receptor up-regulation which raised concerns regarding ACEI and ARB use in COVID-19 patients. However, many medical professional societies recommended their continued use given the paucity of clinical evidence, but there is a need for an updated systematic review and meta-analysis of the latest clinical studies.Methods and resultsA search was conducted on PubMed, Google Scholar, EMBASE, and various preprint servers for studies comparing clinical outcomes and mortality in COVID-19 patients on ACEIs and/or ARBs, and a meta-analysis was performed. A total of 16 studies were included for the review and meta-analysis. There were conflicting findings reported in the rates of severity and mortality in several studies. In a pooled analysis of four studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of developing severe disease vs. non-users [odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.41–1.58, I2=50.52, P-value = 0.53). In a pooled analysis of six studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of mortality as compared with non-users (OR = 0.86, 95% CI = 0.53–1.41, I2 = 79.12, P-value = 0.55).ConclusionIt is concluded that ACEIs and ARBs should be continued in COVID-19 patients, reinforcing the recommendations made by several medical societies. Additionally, the individual patient factors such as ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further.

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

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.

Association of ACE2 genetic polymorphisms withhypertension-related target organ damages in south Xinjiang

Essential hypertension (EH) is a principal contributing factor inworldwide cardiovascular disease mortality. Although interventions that minimizeenvironmental risk factors for EH are associated with reduced cardiovasculardisease, such approaches are limited for individuals with high genetic EH risk. Inthis study, we investigated possible associations between ACE2 polymorphisms andhypertension-related target organ damages in south Xinjiang, China. Four hundred andtwo hypertensive patients were enrolled as study participants in an EH group, and233 normotensive individuals were enrolled as control subjects. Participants wererecruited from the south Xinjiang region. Fourteen ACE2 polymorphisms were genotypedby 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 patientscarrying the control genotype of rs2074192 (CC, OR = 2.37, 95% CI: 1.28–4.39) wereassociated 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), orrs4830542 (CC+CT, OR = 2.20, 95% CI: 1.03–4.69) were associated with atrialfibrillation (AF), larger left atrial diameter, and higher levels ofrenin–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 associatedwith EH- and hypertension-related AF and left atrial remodeling in south Xinjiang,China.

Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China

BackgroundCardiovascular 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.MethodsFour 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.ResultsParticipants 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.ConclusionThe ACE2 rs4646188 variant may be a potential and optimal genetic susceptibility marker for EH, dyslipidemia and its related ischemic stroke.

ACE2 polymorphisms associated with cardiovascular risk in Uygurs with type 2 diabetes mellitus

BackgroundType 2 diabetes mellitus (T2D), rapidly increasing to epidemic proportions, globally escalates cardiovascular disease risk. Although intensive interventions and comprehensive management of environmental risks factors for T2D are associated with reduced cardiovascular disease, such approaches are limited for individuals with high genetic T2D risk. In this study we investigated possible associations of ACE2 polymorphisms and cardiovascular risks in Uygur patients with T2D.Methods275 Uygur T2D patients and 272 non-diabetic Uygur individuals were enrolled as study participants. 14 ACE2 polymorphisms were genotyped by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry.ResultsACE2 SNP rs1978124, rs2048683, rs2074192, rs233575, rs4240157, rs4646156, rs4646188 and rs879922 were associated with T2D (all P < 0.05). The 8 diabetic risk related ACE2 SNPs were further associated with diabetic related cardiovascular complications or events but exhibited heterogeneity as fellows: firstly, almost all diabetic risk related ACE2 SNPs (all P < 0.05) were associated with increased SBP except rs1978124 and rs2074192, while rs2074192, rs4646188 and rs879922 were associated elevated DBP (all P < 0.05). Secondly, SNP rs4646188 was not correlated with any type of dyslipidemia (TRIG, HDL-C, LDL-C or CHOL), and the other 7 diabetic risk related loci were at least correlated with one type of dyslipidemia (all P < 0.05). In particular, rs879922 were simultaneously correlated with four type of dyslipidemia (all P < 0.05). Thirdly, ACE2 SNP rs2074192 and rs879922 were associated with carotid arteriosclerosis stenosis (CAS) ≥ 50% (both P < 0.05). Fourthly, ACE2 SNP rs2074192, rs4240157, rs4646188 and 879922 were associated with increased MAU (all P < 0.05). In addition, ACE2 SNP rs2048683, rs4240157, rs4646156, rs4646188 and rs879922 were linked to heavier LVMI (all P < 0.05), but only rs4240157, rs4646156 and rs4646188 were associated with lower LVEF (all P < 0.05).ConclusionACE2 SNP rs879922 may be a common genetic loci and optimal genetic susceptibility marker for T2D and T2D related cardiovascular risks in Uygurs.

Angiotensin converting enzyme 2 polymorphisms and postexercise hypotension in hypertensive medicated individuals.

The renin-angiotensin aldosterone system (RAAS) is associated with diverse physiological responses and adaptations to exercise. The angiotensin converting enzyme (ACE) 2 has vasodilatory effects, which might be associated with the blood pressure (BP) responses to acute exercise. The aim of this study was to investigate the role of ACE2 polymorphisms in postexercise hypotension (PEH). Thirty-four medicated hypertensive (61·3±1·7years, 76·1±2·7kg, 160±1·6cm) men (n=12) and women (n=22), participated in a control and a moderate intensity exercise session in a randomized order. After both experimental sessions, they left the laboratory wearing an ambulatory BP device for 24-h monitoring. ACE2 polymorphisms (Int-1 and Int-3) were assessed by polymerase chain reaction. Over the course of 5-h monitoring, we observed a significant reduction in SBP and DBP following exercise in the AA/AG of the Int-1 polymorphism (p-interaction=0·02 and 0·001, respectively), whereas this could not be found in the individuals homozygous G (p-interaction=0·76 and 0·51, respectively). With regard to Int-3 polymorphism, individuals AA/AG showed a significant reduction in SBP following exercise (p-interaction <0·0001) but not for DBP (p-interaction=0·06) whereas GG individuals showed only a significant reduction in DBP following exercise (p-interaction=0·02). Our results suggest that ACE2 polymorphism could affect PEH; however, larger trials are needed to confirm our findings.

The ACE2 G8790A Polymorphism: Involvement in Type 2 Diabetes Mellitus Combined with Cerebral Stroke.

We aimed to investigate the correlations between ACE2 polymorphisms and type 2 diabetes mellitus (T2DM) combined with cerebral stroke (CS). A total of 346 patients treated or hospitalized in our hospital were enrolled, including 181 cases without cerebrovascular complications (T2DM group) and 165 cases combined with CS (T2DM + CS group); 284 healthy individuals were selected as the control group. PCR-RFLP and ELISA were used to analyze ACE2 G8790A polymorphisms and serum ACE2 levels, respectively. Significant differences were observed in the genotype/allele frequency of ACE2 G8790A between the T2DM + CS and control groups, and the T2DM and T2DM + CS groups, and in the genotype frequency of ACE2 G8790A between the T2DM and the control groups. The A allele may increase the risk of T2DM combined with CS. The AA genotype may also increase the risk of T2DM combined with CS (OR = 3.733, 95%CI = 2.069-6.738; OR = 3.597, 95%CI = 1.884-6.867). Serum ACE2 levels showed statistically significant differences among the groups. Systolic pressure and diastolic pressure were protective factors of T2DM combined with CS. The ACE2 G8790A polymorphism in T2DM patients was correlated with CS, and the A allele might be a risk factor of T2DM combined with CS.

Association between circulating levels of ACE2-Ang-(1-7)-MAS axis and ACE2 gene polymorphisms in hypertensive patients.

The angiotensin-converting enzyme 2-angiotensin-(1–7)-MAS axis (ACE2-Ang-[1–7]-MAS axis) plays an important role in the control of blood pressure. Some previous studies indicated that the genetic variants of ACE2 may have a potential to influence this axis. Therefore, the present study aimed at examining the association of ACE2 polymorphisms with circulating ACE2 and Ang-(1–7) levels in patients with essential hypertension.Hypertensive patients who met the inclusion criteria were enrolled in the present study. Three Tag single-nucleotide polymorphisms (rs2106809, rs4646155, and rs879922) in ACE2 gene were genotyped for all participants. Circulating ACE2 and Ang-(1–7) levels were detected by enzyme-linked immunosorbent assay.There were 96 (53.0%) females and 85 (47.0%) males participating in the present study. The circulating Ang-(1–7) levels were significantly greater in female patients carrying the rs2106809 CC or CT genotype compared with those carrying the TT genotype (1321.9 ± 837.4 or 1077.5 ± 804.4 pg/mL vs 751.9 ± 612.4 pg/mL, respectively; P = 0.029, analysis of variance), whereas the circulating Ang-(1–7) levels were comparable among genotypes in male patients. In addition, there was no significant difference in the circulating ACE2 levels among rs2106809 CC, CT, and TT genotype groups in both female and male patients. The circulating ACE2 and Ang-(1–7) levels were related to neither rs4646155 nor rs879922 in female or male patients.In conclusion, the rs2106809 polymorphism of the ACE2 gene may be a determinant of the circulating Ang-(1–7) level in female patients with hypertension, suggesting a genetic association between circulating Ang-(1–7) levels and ACE2 gene polymorphisms in patients with hypertension.

From gene to protein-experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension.

Hypertension is a major risk factor for stroke, coronary events, heart and renal failure, and the renin-angiotensin system (RAS) plays a major role in its pathogenesis. Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II. An “alternate” arm of the RAS now exists in which ACE2 counterbalances the effects of the classic RAS through degradation of Ang II, and generation of the vasodilator Ang 1-7. ACE2 is highly expressed in the heart, blood vessels, and kidney. The catalytically active ectodomain of ACE2 undergoes shedding, resulting in ACE2 in the circulation. The ACE2 gene maps to a quantitative trait locus on the X chromosome in three strains of genetically hypertensive rats, suggesting that ACE2 may be a candidate gene for hypertension. It is hypothesized that disruption of tissue ACE/ACE2 balance results in changes in blood pressure, with increased ACE2 expression protecting against increased blood pressure, and ACE2 deficiency contributing to hypertension. Experimental hypertension studies have measured ACE2 in either the heart or kidney and/or plasma, and have reported that deletion or inhibition of ACE2 leads to hypertension, whilst enhancing ACE2 protects against the development of hypertension, hence increasing ACE2 may be a therapeutic option for the management of high blood pressure in man. There have been relatively few studies of ACE2, either at the gene or the circulating level in patients with hypertension. Plasma ACE2 activity is low in healthy subjects, but elevated in patients with cardiovascular risk factors or cardiovascular disease. Genetic studies have investigated ACE2 gene polymorphisms with either hypertension or blood pressure, and have produced largely inconsistent findings. This review discusses the evidence regarding ACE2 in experimental hypertension models and the association between circulating ACE2 activity and ACE2 polymorphisms with blood pressure and arterial hypertension in man.

Modifier Genes in Hypertrophic Cardiomyopathy Patients of South Indian Cohort

Hypertrophic cardiomyopathy is an autosomal dominant disorder, characterized by thickening of the myocardium with a variable clinical course. Mutations in 14 sarcomeric genes have been implicated resulting in phenotypic and genotypic heterogeneity. The phenotypic expression of HCM is not only determined by the sarcomeric gene mutations but the genetic predilection of an individual also account for the inter-individual variability and genes with such functional variants that affect phenotypic expression are referred to as Modifier genes. Hence genetic variants of Angiotensin converting enzyme (ACE-2), Tumor necrosis factor- alpha (TNF-α) and Heat shock protein -70 (HSP70) genes have been considered in the present study to understand their role as modifiers of HCM. The study was carried out by Genotyping of 100 HCM and 100 controls by Polymerase chain reaction based restriction fragment length polymorphism analysis. The present study revealed a significant association of the HSP70-1 and HSP70-2 polymorphisms while ACE-2 and TNF-α genes were found to be statistically insignificant. However patients with the rare/variant genotypes were observed to have stronger clinical manifestations and echocardiographic parameters. This was further confirmed by Linkage disquillibrium analysis wherein individuals with the haplotypes GCGC and GCGT seemed to have increased susceptibility to HCM. The MDR analysis revealed a synergistic interaction of TNF-α with ACE-2 and HSP70 polymorphisms indicating their modifying effect in the presence of other environmental factors. Hence the present study emphasized the role of ACE-2, TNF-α and HSP70 polymorphisms as modifiers of the phenotypic expression in conjunction with other sarcoemric mutations and single nucleotide variations.

Impact of interaction of cigarette smoking with angiotensin-converting enzyme polymorphisms on end-stage renal disease risk in a Han Chinese population

Several polymorphisms in the angiotensin-converting enzyme (ACE) and ACE2 genes are associated with the development of end-stage renal disease (ESRD). Certain genetic polymorphisms may modify the deleterious effects of environmental factors such as cigarette smoking and may also modify the inherited risk. We investigated the association of six ACE and ACE2 polymorphisms with ESRD to determine whether a relationship exists between gene-smoking interactions and ESRD. We performed a case-control association study and genotyped 683 ESRD patients and 653 healthy controls. All subjects were genotyped for ACE (I/D, G2350A and A-240T) and ACE2 (G8790A, A1075G and G16854C) gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Significant associations were observed between ACE I/D and G2350A polymorphisms and ESRD. There was no difference in ACE2 genotype distribution between ESRD patients and healthy controls. Haplotype analysis showed that DAA and DAT haplotypes were risk factors for ESRD. Moreover, a gene-environment interaction was observed between ACE I/D polymorphism and cigarette smoking. ACE I/D and ACE G2350A polymorphisms were associated with the development of ESRD. The interaction between ACE I/D polymorphism and smoking is also associated with an enhanced risk of ESRD.

Association of ACE2 Genetic Variants With Blood Pressure, Left Ventricular Mass, and Cardiac Function in Caucasians With Type 2 Diabetes

Cardiovascular disease is common in diabetes, and is associated with activation of the renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE)2 is a recently described member of the RAS, and this study investigated whether ACE2 polymorphisms are associated with hypertension, left ventricular (LV) mass, and cardiac function in type 2 diabetes. Variants in ACE2 (rs1978124, rs2074192, rs4240157, rs4646156, rs4646188) were examined in 503 Caucasian subjects with type 2 diabetes. As ACE2 is located on the X chromosome, analyses were performed separately for men and women. Hypertension was defined by a history of hypertension, and/or antihypertensive medications or blood pressure (BP) >130/80 mm Hg. LV mass and systolic function (ejection fraction) were assessed by transthoracic echocardiography. In men, hypertension was more prevalent with the ACE2 rs2074192 C allele (P = 0.023), rs4240157 G allele (P = 0.016) and rs4646188 T allele (P = 0.006). In men, the rs1978124 A allele was associated with a significantly lower ejection fraction compared to the G allele (62.3 ± 13.3 vs. 67.2 ± 10.9%, P = 0.002). This association remained significant after covariate adjustment for age, body mass index, hypertension, antihypertensive treatment, and BP. In women, the prevalence of hypertension was higher (P = 0.009) with the rs4240157 G allele, and the rs1978124 A allele was associated with significantly higher LV mass (P = 0.008). In Caucasians with type 2 diabetes, genetic variation in ACE2 is associated with hypertension and reduced systolic function in men, and hypertension and increased LV mass in women.

ACE2 polymorphism linked with high BP and captopril response

ACE2 polymorphism linked with high BP and captopril response

Polymorphisms of ACE2 Gene are Associated With Essential Hypertension and Antihypertensive Effects of Captopril in Women

ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the reninangiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two casecontrol studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6-fold risk for hypertension in women (95% confidence interval (CI), 1.132.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34-fold (95% CI, 1.754.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.