Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.
ABSTRACT: 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: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:<h4>Background</h4>Atrial fibrillation (AF) is the most common cardiac arrhythmia. Type 2 diabetes (T2D) is an independent risk factor for AF. The cardioembolic stroke (CS) risk is increased when both conditions coexist. Whether angiotensin-converting enzyme 2 (ACE2) genetic variants predict increased risks AF and CS in Uygur patients with T2D remain elusive.<h4>Methods</h4>A total of 547 Uygur subjects (272 controls and 275 T2D patients) were recruited to the study from south Xinjiang. Eight ACE2 variants were identified by MassARRAY system.<h4>Results</h4>ACE2 rs2074192 (CC, adjusted RR?=?2.55, 95% CI 1.35-4.80, P?=?0.004), rs4240157 (CC?+?CT, adjusted RR?=?2.26, 95% CI 1.27-4.04, P?=?0.006) and rs4646188 (TT, adjusted RR?=?2.37, 95% CI 1.16-4.86, P?=?0.018) were associated with higher AF risk. ACE2 rs4240157 (CC?+?CT, adjusted RR?=?2.68, 95% CI 1.36-5.27, P?=?0.004) and rs4646188 (TT, adjusted RR?=?2.56, 95% CI 1.06-6.20, P?=?0.037) were further associated with higher CS risk. The 3 ACE2 variants were related to larger left atrial end-systolic diameter (LAD) (all P?<?0.05), but not all of the 3 ACE2 variants were related to increased levels of serum sodium (rs4240157 and rs4646188, all P?<?0.05), HsCRP (rs4240157 and rs4646188, all P?<?0.05) as well as decreased serum potassium levels (rs2074192 and rs4646188, all P?<?0.05). The 3 ACE2 variants exhibited heterogeneity on circulating RAAS activation. In particular, ACE2 rs4646188 was associated with higher levels of ACE (P?=?0.017 and 0.037), Ang I (P?=?0.002 and 0.001), Ang II (both P?<?0.001) and ALD (P?=?0.005 and 0.011).<h4>Conclusion</h4>These results indicated ACE2 rs4646188 was associated with increased risk of AF and CS among diabetic patients in Uygurs, which could be a promising genetic predisposition marker for early and personalized prevention strategies for the aforementioned clinical pathologies.
Project description:BACKGROUND:Type 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. METHODS:275 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. RESULTS:ACE2 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). CONCLUSION:ACE2 SNP rs879922 may be a common genetic loci and optimal genetic susceptibility marker for T2D and T2D related cardiovascular risks in Uygurs.
Project description:<h4>Background</h4>The ongoing outbreak of SARS-CoV-2 represents a significant challenge to international health. Several reports have highlighted the importance of ACE2 on the pathogenesis of COVID-19. The spike protein of SARS-CoV-2 efficiently binds to the angiotensin-converting enzyme 2 (ACE2) receptors and facilitates virus entry into the host cell. In the present study, we hypothesize that a functional insertion/deletion polymorphism-rs4646994 I/D and rs4240157 T > C in the ACE gene could be associated with SARS-CoV-2 infection and mortality.<h4>Methodology</h4>This study included 117 consecutive COVID-19 patients and 150 age matched healthy controls (ACE2-rs4646994 I/D) and 100 age matched healthy controls with ACE2 rs4240157 T > C. We used Mutation specific PCR (MSP) for ACE2-rs4646994 I/D genotyping and amplification refractory mutation system (ARMS-PCR) for ACE2 rs4240157 T > C genotyping.<h4>Results</h4>Results indicated that there were significant differences in the genotype distributions of ACE2-rs4646994 I/D polymorphisms (<i>p</i> < 0.030) and ACE2 rs4240157 T > C between COVID-19 patients and controls (<i>p</i>-values < 0.05). Higher frequency of DD genotype (48.71%) and D allele (0.67) was reported in COVID-19 patients than controls. Our results showed that the ACE2-DD genotype was strongly associated with increased COVID-19 severity (OR 2.37 (95%) CI = (1.19-4.70), RR = 1.39 (1.09-1.77), <i>p</i> < 0.013) and also a strong association was seen with ACE2-ID genotype with COVID-19 severity (OR 2.20 (95%) CI = (1.08-4.46), <i>p</i> < 0.020) in the codominant model. In allelic comparison, the D allele was strongly associated with COVID-19 severity (OR 1.58 (95% CI) (1.11-2.27), RR 1.21 (1.05-1.41) <i>p</i> < 0.010). A significant correlation of ACE2-I/D genotypes was reported with Age (<i>p</i> < 0.035), T2D (<i>p</i> < 0.0013), hypertension (<i>p</i> < 0.0031) and coronary artery disease (<i>p</i> < 0.0001). Our results indicated ACE2-DD genotype was strongly associated with increased COVID-19 mortality (OR 8.25 (95%) CI = (2.40 to 28.34), <i>p</i> < 0.008) and also ACE2-DD + DI genotype was strongly associated with increased COVID-19 mortality with OR 4.74 (95%) CI = (1.5214 to 14.7915), <i>p</i> < 0.007. A significant correlation was reported between COVID-19 patients and age matched controls (<i>p</i> < 0.0007). Higher frequency of heterozygosity TC (40%) followed by ACE2-CC genotype (24.78%) was reported among COVID-19 patients. Using multivariate analysis, ACE2-CT genotype was strong associated with SARS-CoV-2 severity with an OR 2.18 (95% CI) (1.92-3.99), <i>p</i> < 0.010 and also ACE2-CC genotype was linked with COVID-19 severity with an OR 2.66 (95% CI) (1.53-4.62), <i>p</i> < 0.005. A significant correlation of ACE2-T > C genotypes was reported with gender (<i>p</i> < 0.04), T2D (<i>p</i> < 0.035). ACE2-CC genotype was strongly associated with increased COVID-19 mortality OR 3.66 (95%) CI = (1.34 to 9.97), <i>p</i> < 0.011 and also ACE2-C allele was associated with COVID-19 mortality OR 2, 01 (1.1761-3.45), <i>p</i> < 0.010.<h4>Conclusions</h4>It is concluded that ACE-DD genotype and D allele was strongly associated with increased COVID-19 patient severity. In addition, ACE I/D polymorphism were strongly associated with advanced age, diabetes and ischemic heart disease in COVID-19 patients whereas ACE-II genotype was a protective factor against the development of severe COVID-19. ACE2-DD genotype was strongly associated with increased COVID-19 mortality. Additionally, ACE2-CC and CT genotypes were strongly associated with COVID-19 severity. Therefore, our study might be useful for identifying the susceptible population groups for targeted interventions and for making relevant public health policy decisions.
Project description:To examine the association of Angiotensin I converting enzyme 2 (ACE2) gene polymorphisms and retinopathy in a Chinese type 2 diabetes mellitus (T2DM) cohort.A total of 743 T2DM participants were involved in this study including 408 female and 335 male cases. Female cases were divided into two groups: diabetes without retinopathy (DNR group, n=171) and with retinopathy (DR group, n=237), the latter was further subclassified into nonproliferative DR (NPDR group, n=121) and proliferative DR (PDR group, n=116). Male cases were assigned to DNR group (n=153) and DR group (n=182) which was further grouped into NPDR group (n=86) and PDR group (n=96). Two single nucleotide polymorphisms (SNPs; rs2074192 and rs714205) in ACE2 gene were genotyped.In female cases, the frequency of genotypes TT in rs2074192 and CC in rs714205 were higher in DR and PDR group than in DNR group (P<0.05). The frequency of alleles T in SNP rs2074192 and C in SNP rs714205 was higher in DR group (P<0.05) and PDR group (P<0.05) than in DNR group. The frequency of allele T in SNP rs2074192 was higher in PDR group (P=0.04) than in NPDR group. The frequency of haplotype TC and CG was higher in DR and PDR groups, respectively (P<0.05). No positive results were found in male cases.Our results revealed that SNPs rs2074192 and rs714205 in ACE2 gene were associated with the susceptibility of DR and PDR.
Project description:Limited information is available when it comes to the impact of genetic on Calcific Aortic Stenosis (CAS). Apolipoprotein B (apoB) is a key component in lipid metabolism and plays an important role in the dynamic equilibrium of cholesterol. We performed a case-control study to explore the association of apoB genetic polymorphisms with CAS in Chinese subjects, in Xinjiang, China.We designed a case-control study including 314 CAS patients and 652 age- and sex-matched control subjects. Using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method, we genotyped two SNPs (rs6725189 and rs693) of apoB gene in all subjects.We found that the rs693 T allele was associated with a significantly elevated CAS risk [TT/CT vs. CC: adjusted odds ratio (AOR)?=?1.58, 95% confidence interval (CI)?=?1.82-2.10, P?=?0.002] and the rs6725189 T allele was also associated with a significantly elevated CAS risk (GT vs. GG: AOR?=?1.82, 95% CI?=?1.14-2.92, P?=?0.013). Furthermore, we also found that the TC levels were significantly higher in rs693 TT/CT genotypes than that in CC genotypes (P < 0.05).Both rs693 and rs6725189 of the apoB gene are associated with CAS in Chinese subjects, in Xinjiang, China.
Project description:Essential Hypertension (EH) results in the burden of cardiovascular disease (CVD) such as Heart Failure (HF) and Ischemic Stroke (IS). A rapidly emerging field involving the role of Wnt/β-catenin signaling pathway in cardiovascular development and dysfunction has recently drawn extensive attention. In the present study, we conducted a genetic association between genomic variants in Wnt/β-catenin signaling pathway and EH, HF, IS. A total of 95 SNPs in 12 Wnt signaling genes (<i>WNT3A, WNT3, WNT4, DKK1, DKK2, LRP5, LRP6, CTNNB1, APC, FZD1, FRZB, SFRP1</i>) were genotyped in 1,860 participants (440 patients with EH, 535 patients with HF, 421 patients with IS and 464 normal control subjects) using Sequenom MassArray technology. <i>WNT3A</i> rs752107(C > T) was strongly associated with an increased risk of EH, HF and IS. Compared with <i>WNT3A</i> rs752107 CC genotype, the CT genotype carriers had a 48% increased risk of EH (OR = 1.48, 95% CI = 1.12-1.96, <i>P</i> = 0.006), the TT genotype conferred a 139% increased risk of EH (OR = 2.39, 95% CI = 1.32-4.34, <i>P</i> = 0.003). Regarding HF and IS, the risk of HF in the T allele carriers (CT + TT) was nearly increased by 58% (OR = 1.58, 95% CI = 1.22-2.04, <i>P</i> = 4.40 × 10<sup>-4</sup>) and the risk of IS was increased by 37% (OR = 1.37, 95% CI = 1.04-1.79, <i>P</i> = 0.025). Expression quantitative trait loci (eQTL) analysis indicated that rs752107 C allele corresponded to a significant reduction of <i>WNT3A</i> expression. We described a genetic variant of <i>WNT3A</i> rs752107 in Wnt/β-catenin signaling strongly associated with the risk of EH, HF and IS for the first time.
Project description:MicroRNAs like miR-143 are increasingly linked to disease pathogenesis. miR-143 is enriched in vascular smooth muscle, and several single nucleotide polymorphisms have been identified in this miRNA. The aim of the current study was to explore a potential correlation between a polymorphism in the miR-143 promoter region, rs4705342, and essential hypertension (EH). Genotyping for miR-143 rs4705342 was performed from blood samples of 156 EH patients (case group) and 187 healthy individuals (control group) using a TaqMan assay. Participant demographic and clinical characteristics were also collected. Logistic regression was used to identify an association between genotype and EH, and odds ratios of EH risk were also determined. Frequencies of the CC, CT, and TT genotypes differed significantly between case (7.7%, 40.4%, 51.9%) and control (15.0%, 48.1%, 36.9%) groups (?(2) = 9.400, P = 0.009). Further, the frequency of the C allele was lower in the case group than in the control group (27.9% vs. 39.0%, P = 0.002). Compared with those having the TT genotype, patients carrying the CC and CT genotypes had a significantly reduced risk for EH (OR = 0.541, 95% CI = 0.351-0.834, P = 0.005), particularly for females, nonsmokers, and those not consuming alcohol (P < 0.05). Thus, the rs4705342 polymorphism in the miR-143 appears to be associated with essential hypertension, and further study is needed to understand the molecular mechanism producing this effect.
Project description:BACKGROUND:Acyl-CoA: cholesterol acyltransferases (ACAT) is the only enzyme that catalyzes the synthesis of cholesterol esters (CE) from free cholesterol and long-chain fatty acyl-CoA and plays a critical role in cellular cholesterol homeostasis. In the present study, our primary objective was to explore whether the single-nucleotide polymorphisms (SNPs) in ACAT-2 gene were associated with coronary artery disease (CAD) in Uygur subjects, in Xinjiang, China. METHODS:We designed a case-control study including 516 CAD patients and 318 age- and sex-matched control subjects. Using the improved multiplex ligation detection reaction (iMLDR) method, we genotyped two SNPs (rs28765985 and rs7308390) of ACAT-2 gene in all subjects. RESULTS:We found that the genotypes, the dominant model (CC + CT vs TT) and over-dominant model (CT vs CC + TT) of rs28765985 were significantly different between CAD patients and the controls (P=0.027, P=0.012 and P=0.035, respectively). The rs28765985 C allele was associated with a significantly elevated CAD risk [CC/CT vs TT: odds ratio (OR) = 1.48, 95% confidence interval (CI) = 1.02-2.16, P=0.04] after adjustment for confounders. The TC and LDL-C levels were significantly higher in rs28765985 CC/CT genotypes than that in TT genotypes (P<0.05). CONCLUSIONS:Rs28765985 of ACAT-2 gene are associated with CAD in Uygur subjects. Subjects with CC/CT genotype or C allele of rs28765985 were associated with an increased risk of CAD.
Project description:Numerous studies have implicated the Wnt pathway in the development and progression of myocardial infarction (MI); however, there are very few investigations addressing the effects of polymorphisms in the Wnt pathway genes on MI susceptibility. We investigated the possible correlation between genetic variations in Wnt pathway genes and MI risk. Three polymorphisms (rs7832767 C > T in SFRP1 gene, rs2293303 C > T in CTNNB1 gene, rs16893344 C > T in WISP1 gene) were finally selected and genotyped in 465 MI patients and 485 healthy controls, using the PCR-RFLP method. We found that the SFRP1 rs7832767 variant allele (T) was associated with a significantly increased risk of MI [TT vs. CC: adjusted odds ratio (AOR) = 3.13, 95% CI = 1.78-5.51; CT/TT vs. CC: AOR = 1.53, 95% CI = 1.12-2.08; TT vs. CC/CT:AOR = 2.87, 95% CI = 1.66-4.97)]. The significant association with MI risk was also found for the CTNNB1 rs2293303 (CT vs. CC: AOR = 3.48, 95% CI = 2.28-5.33; TT vs. CC: AOR = 7.37, 95% CI = 2.08-26.16; CT/TT vs. CC: AOR = 3.72, 95% CI = 2.46-5.62; TT vs. CC/CT:AOR = 5.52, 95% CI = 1.58-19.28), and WISP1 rs16893344 polymorphisms (CT vs. CC: AOR = 2.43, 95% CI = 1.70-3.47; TT vs. CC: AOR = 5.17, 95% CI = 1.85-14.41; CT/TT vs. CC: AOR = 2.58, 95% CI = 1.83-3.66; TT vs. CC/CT:AOR = 3.88, 95% CI = 1.41-10.64). The associations remain significant in stratified analysis by demographic and clinical characteristics of participants, with few exceptions. Our study provided the first evidence of the association between polymorphisms in the Wnt pathway genes and MI susceptibility in Chinese Han population. Epidemiological studies with larger samples and functional analyses are warranted to further verify our results.