Subject(s)
Angiotensinogen , Hypertension , Angiotensinogen/genetics , Angiotensinogen/metabolism , Hypertension/genetics , Hypertension/physiopathology , Hypertension/drug therapy , Hypertension/metabolism , Humans , Animals , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Blood Pressure/genetics , RNA Interference , RNA, Small InterferingABSTRACT
BACKGROUND: The lipid-lowering effects of Omega-3 fatty acids have been widely reported, yet their impact on ischemic stroke remains controversial. Reports on the protective effects of unsaturated fatty acids, such as Omega-6 and Omega-7, as well as saturated fatty acids in cardiovascular diseases, including hypertension and ischemic stroke, are less frequent. OBJECTIVES: This study aims to identify fatty acids associated with blood pressure and ischemic stroke through Mendelian randomization. Besides, it seeks to determine whether specific fatty acids can prevent ischemic stroke by managing blood pressure and revealing the specific mechanisms of this action. METHODS: This research involved downloading relevant data from websites and extracting SNPs that met the standard criteria as instrumental variables. Simultaneously, the 'MR-PRESSO' package and 'Mendelian Randomization' package were used to eliminate confounding SNPs that could bias the study results. Then, inverse variance weighting and the weighted median were employed as primary analysis methods, accompanied by sensitivity analysis to assess the validity of the causal relationships. Initially, multivariable Mendelian randomization was used to identify fatty acids linked to blood pressure and the incidence of ischemic stroke. The causal link between certain fatty acids and the initiation of ischemic stroke was then investigated using bidirectional and mediator Mendelian randomization techniques. Stepwise Regression and the Product of Coefficients Method in mediator Mendelian randomization were utilized to ascertain whether specific fatty acids reduce ischemic stroke risk by lowering blood pressure. RESULTS: Multivariable Mendelian randomization analysis indicated a potential inverse correlation between Omega-3 intake and both blood pressure and ischemic stroke. Consequently, Omega-3 was selected as the exposure, with blood pressure and ischemic stroke-related data as outcomes, for further bidirectional and mediation Mendelian Randomization analyses. Bidirectional Mendelian Randomization revealed that Omega-3 significantly influences DBP (P = 1.01e-04) and IS (P = 0.016). It also showed that DBP and SBP significantly affect LAS, SVS, CES, IS, and LS. Mediator Mendelian Randomization identified five established mediating pathways: Omega-3-Diastolic blood pressure-Small vessel stroke, Omega-3-Diastolic blood pressure-Cardioembolic stroke, Omega-3-Diastolic blood pressure-Lacunar stroke, Omega-3-Diastolic blood pressure-Large artery atherosclerosis stroke, and Omega-3-Diastolic blood pressure-Ischemic stroke. Of these, four pathways are complete mediation, and one pathway is partial mediation. CONCLUSIONS: The findings suggest that Omega-3 may indirectly reduce the incidence of ischemic stroke by lowering blood pressure. Thus, blood pressure modulation might be one of the mechanisms through which Omega-3 prevents ischemic stroke. In summary, incorporating an increased intake of Omega-3 in the diet can serve as one of the dietary intervention strategies for patients with hypertension. Additionally, it can act as an adjunctive therapy for the prevention of ischemic strokes and their complications.
Subject(s)
Blood Pressure , Fatty Acids, Omega-3 , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Stroke , Fatty Acids, Omega-3/therapeutic use , Humans , Stroke/prevention & control , Stroke/genetics , Hypertension/genetics , Risk FactorsABSTRACT
OBJECTIVE: Aim: To understand how vitamin D receptor gene polymorphism (VDR rs2228570) affects blood pressure in Iraqi patients with essential hypertension in Al Diwaniya province. PATIENTS AND METHODS: Materials and Methods: This is a single-center observational cross-sectional descriptive study of 90 patients with essential hypertension. Using the PCRTETRA ARM technique, blood samples were genotyped and examined for the polymorphisms of FOKI (rs2228570) gene. RESULTS: Results: The most frequent allele was A (121, 67%) while the most frequent genotype was AG (55, 61%). There was no statistical difference between the actual and expected frequency distribution, according to Hardy-Weinberg equilibrium. The effect of VDR polymorphism rs 2228570 on blood pressure indicates (the mean systolic blood pressure in AA, AG, and GG carrier patients was 149, 150 and 166 respectively, P=0.29. On the other hand, the mean diastolic blood pressure in AA, AG, and GG carrier patients was 89, 89, and 94 respectively P=0.6) there was no statistically significant effect on systolic and diastolic blood pressure. CONCLUSION: Conclusions: there is no statistically significant effect of VDR rs2228570 on SBP and DBP (p = 0.6), vitamin D receptor gene polymorphism rs2228570 was related to vitamin D level.
Subject(s)
Essential Hypertension , Receptors, Calcitriol , Humans , Receptors, Calcitriol/genetics , Iraq , Male , Female , Cross-Sectional Studies , Essential Hypertension/genetics , Middle Aged , Hypertension/genetics , Adult , Polymorphism, Genetic , Genetic Predisposition to Disease , Blood Pressure/genetics , Polymorphism, Single Nucleotide , Genotype , AgedABSTRACT
OBJECTIVE: Aim: To investigate allele frequencies of rs1799983 polymorphism eNOS genes and to determine association between rs1799983 polymorphism of eNOS gene and essential hypertension in Iraqi hypertensive patients. PATIENTS AND METHODS: Materials and Methods: This is an observational cross sectional descriptive single center study. ninety hypertensive patients were recruited by specialist cardiologist and conducted at AL-Diwaniyah teaching hospital and department of pharmacology and therapeutics, college of medicine, university of Al-Qadisiyah, Iraq. DNA samples were genotyped by PCR-tetra-arm method. NO level was measured by using ELISA kit. RESULTS: Results: Regarding rs1799983 the most frequent allele was G (73%) and the most frequent genotype was GG (55%). Our results indicate lack of substantial link between genotype frequencies of rs1799983 polymorphism and NO level (p=0.88) and thereby there is no statistically significant effect on SBP and DBP (p = 0.051). CONCLUSION: Conclusions: our study demonstrated lack of significant association between this polymorphism and essential hypertension in Iraqi hypertensive patients.
Subject(s)
Essential Hypertension , Nitric Oxide Synthase Type III , Humans , Iraq , Nitric Oxide Synthase Type III/genetics , Male , Female , Cross-Sectional Studies , Essential Hypertension/genetics , Middle Aged , Hypertension/genetics , Adult , Polymorphism, Single Nucleotide , Gene Frequency , Genetic Predisposition to Disease , GenotypeABSTRACT
OBJECTIVE: Aim: To investigate lipid profile parameters depending the polymorphism of the A1166C I type gene receptor of the angiotensin II as a predictor of arterial hypertension. PATIENTS AND METHODS: Materials and Methods: The study involved 86 patients with arterial hypertension. The control group consisted of 30 practically healthy individuals. Indicators of lipid metabolism in the blood serum of patients were determined using "Lachema" kits on an analyzer. The the polymorphism of the A1166C I type gene receptor of the angiotensin II was studied by polymerase chain reaction with electrophoretic detection of the results. RESULTS: Results: Higher levels of total cholesterol were found in patients with CC genotype compared to AA genotype carriers ((8.94±0.09) vs (5.18±0.02) mmol/L). The level of low-density lipoprotein in CC-genotype carriers was (7.43±0.03) versus (3.66±0.02) mmol/L in A-allele homozygotes. Triglycerides and very low density lipoproteins were also significantly higher in CC genotype carriers compared to patients with AA genotype. The level of high-density lipoprotein was lower in homozygotes with C-allele than in patients with the AA genotype, and was (0.59±0.12) versus (0.99±0.03) mmol/L. CONCLUSION: Conclusions: The presence in the CC genotype the I type gene receptor of the angiotensin II type is a predictor of dyslipidemia. In patients with arterial hypertension, the presence in the C-allele of the I type gene of the angiotensin II type contributes to a significant increase in serum adipokines and a decrease in ghrelin levels.
Subject(s)
Hypertension , Polymorphism, Genetic , Receptor, Angiotensin, Type 1 , Humans , Hypertension/genetics , Hypertension/blood , Male , Female , Receptor, Angiotensin, Type 1/genetics , Middle Aged , Lipids/blood , Adult , GenotypeABSTRACT
OBJECTIVE: To explore the relationship between rs1410996 polymorphism of CFH gene and essential hypertension (EH) in the Yunnan Han population. METHODS: rs1410996 of CFH gene was genotyped based on the collected clinical phenotypes of the EH patients (n = 520) and healthy people (n = 494). RESULTS: On the genotype model and dominance model, there was no relationship between rs1410996 of CFH gene and EH after adjustment (P > 0.05). On the dominance model of male EH patients, the pulse pressure (PP) level of CC genotype carriers was higher than that of (CT + TT) genotype carriers after adjustment (P < 0.05). CONCLUSION: rs1410996 of CFH gene has no correlation with the genetic susceptibility to EH in the Yunnan Han population, but it is related to the PP level in male patients.
Subject(s)
Asian People , Complement Factor H , Essential Hypertension , Genetic Predisposition to Disease , Genotype , Polymorphism, Single Nucleotide , Humans , Male , Essential Hypertension/genetics , Middle Aged , Female , China , Complement Factor H/genetics , Polymorphism, Single Nucleotide/genetics , Asian People/genetics , Gene Frequency/genetics , Aged , Case-Control Studies , Adult , Hypertension/genetics , Genetic Association Studies/methods , Alleles , Blood Pressure/geneticsABSTRACT
Hypertension is a disease associated with epigenetic aging. However, the pathogenic mechanism underlying this relationship remains unclear. We aimed to characterize the shared genetic architecture of hypertension and epigenetic aging, and identify novel risk loci. Leveraging genome-wide association studies (GWAS) summary statistics of hypertension (129,909 cases and 354,689 controls) and four epigenetic clocks (N = 34,710), we investigated genetic architectures and genetic overlap using bivariate casual mixture model and conditional/conjunctional false discovery rate methods. Functional gene-sets pathway analyses were performed by functional mapping and gene annotation (FUMA) protocol. Hypertension was polygenic with 2.8 K trait-influencing genetic variants. We observed cross-trait genetic enrichment and genetic overlap between hypertension and all four measures of epigenetic aging. Further, we identified 32 distinct genomic loci jointly associated with hypertension and epigenetic aging. Notably, rs1849209 was shared between hypertension and three epigenetic clocks (HannumAge, IEAA, and PhenoAge). The shared loci exhibited a combination of concordant and discordant allelic effects. Functional gene-set analyses revealed significant enrichment in biological pathways related to sensory perception of smell and nervous system processes. We observed genetic overlaps with mixed effect directions between hypertension and all four epigenetic aging measures, and identified 32 shared distinct loci with mixed effect directions, 25 of which were novel for hypertension. Shared genes enriched in biological pathways related to olfaction.
Subject(s)
Aging , Epigenesis, Genetic , Genetic Predisposition to Disease , Genome-Wide Association Study , Hypertension , Humans , Hypertension/genetics , Aging/genetics , Polymorphism, Single Nucleotide , Multifactorial Inheritance/genetics , Genetic Loci , Quantitative Trait LociABSTRACT
Background: Depression ranks as a leading contributor to the global disease burden. The potential causal relationship between the use of antihypertensive medications and depression has garnered significant interest. Despite extensive investigation, the nature of this relationship remains a subject of ongoing debate. Therefore, this study aims to evaluate the influence of antihypertensive medications on depression by conducting a Mendelian randomization study focused on drug targets. Method: We focused on the targets of five antihypertensive drug categories: ACE Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), Calcium Channel Blockers (CCBs), Beta-Blockers (BBs), and Thiazide Diuretics (TDs). We collected single-nucleotide polymorphisms (SNPs) associated with these drug targets from genome-wide association study (GWAS) statistics, using them as proxies for the drugs. Subsequently, we conducted a Mendelian randomization (MR) analysis targeting these drugs to explore their potential impact on depression. Results: Our findings revealed that genetic proxies for Beta-Blockers (BBs) were associated with an elevated risk of depression (OR [95%CI] = 1.027 [1.013, 1.040], p < 0.001). Similarly, genetic proxies for Calcium Channel Blockers (CCBs) were linked to an increased risk of depression (OR [95%CI] = 1.030 [1.009, 1.051], p = 0.006). No significant associations were identified between the genetic markers of other antihypertensive medications and depression risk. Conclusion: The study suggests that genetic proxies associated with Beta-Blockers (BBs) and Calcium Channel Blockers (CCBs) could potentially elevate the risk of depression among patients. These findings underscore the importance of considering genetic predispositions when prescribing these medications, offering a strategic approach to preventing depression in susceptible individuals.
Subject(s)
Antihypertensive Agents , Depression , Genome-Wide Association Study , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Humans , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/adverse effects , Depression/genetics , Depression/drug therapy , Hypertension/drug therapy , Hypertension/genetics , Calcium Channel Blockers/therapeutic use , Calcium Channel Blockers/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , Adrenergic beta-Antagonists/adverse effects , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/therapeutic use , Sodium Chloride Symporter Inhibitors/adverse effects , Sodium Chloride Symporter Inhibitors/therapeutic useSubject(s)
Hypertension , Life Style , Humans , Hypertension/genetics , Hypertension/epidemiology , Asia/epidemiologyABSTRACT
Objective. Genetic factors substantially contribute to the development and duration of arterial hypertension. The study of the A1166C polymorphism of the angiotensin II type 1 receptor gene (AGTR1) in arterial hypertension is an auspicious area for assessing the relationship between heredity, hypertension development, and adipokines, but it still remains debatable. The purpose of the current study was to investigate serum adipokines levels depending on the AGTR1 A1166C polymorphism. Methods. A total of 86 patients with arterial hypertension were examined, who underwent the evaluation of the allelic A1166C polymorphism of AGTR1 by polymerase chain reaction with electrophoretic detection and determination of serum adipokines levels using enzyme-linked immunosorbent assay. Results. In the group of patients with arterial hypertension, a significant increase in serum adipokines (resistin, adiponectin, and leptin) levels was found against the background of a decrease in the antianorexic hormone ghrelin with a predominance of CC genotype carriers compared with AA genotype carriers of the AGTR1. A statistically significant decrease in ghrelin and an increase in serum adipokines (resistin, adiponectin, and leptin) in CC genotype carriers compared with AA genotype carriers of the AGTR1 were found suggesting that CC genotype carriers may be predictors of the development of arterial hypertension in our patients. Conclusions. Statistically significant decrease in ghrelin and increase in serum adipokines (resistin, adiponectin, and leptin) were found in CC genotype carriers compared with AA genotype carriers of the AGTR1, which suggests that carriers of the CC genotype are predictors of the arterial hypertension development in our patients.
Subject(s)
Adipokines , Hypertension , Receptor, Angiotensin, Type 1 , Humans , Receptor, Angiotensin, Type 1/genetics , Female , Male , Hypertension/genetics , Hypertension/blood , Middle Aged , Adipokines/blood , Adipokines/genetics , Adult , Leptin/blood , Leptin/genetics , Polymorphism, Single Nucleotide , Adiponectin/blood , Adiponectin/genetics , Aged , Ghrelin/genetics , Ghrelin/blood , Genotype , Genetic Predisposition to Disease , Resistin/genetics , Resistin/bloodABSTRACT
BACKGROUND: Understanding the complex interactions between genes and their causal effects on diseases is crucial for developing targeted treatments and gaining insight into biological mechanisms. However, the analysis of molecular networks, especially in the context of high-dimensional data, presents significant challenges. METHODS: This study introduces MRdualPC, a computationally tractable algorithm based on the MRPC approach, to infer large-scale causal molecular networks. We apply MRdualPC to investigate the upstream causal transcriptomics influencing hypertension using a comprehensive dataset of kidney genome and transcriptome data. RESULTS: Our algorithm proves to be 100 times faster than MRPC on average in identifying transcriptomics drivers of hypertension. Through clustering, we identify 63 modules with causal driver genes, including 17 modules with extensive causal networks. Notably, we find that genes within one of the causal networks are associated with the electron transport chain and oxidative phosphorylation, previously linked to hypertension. Moreover, the identified causal ancestor genes show an over-representation of blood pressure-related genes. CONCLUSIONS: MRdualPC has the potential for broader applications beyond gene expression data, including multi-omics integration. While there are limitations, such as the need for clustering in large gene expression datasets, our study represents a significant advancement in building causal molecular networks, offering researchers a valuable tool for analyzing big data and investigating complex diseases.
Subject(s)
Algorithms , Gene Regulatory Networks , Hypertension , Machine Learning , Hypertension/genetics , Humans , Transcriptome/genetics , Gene Expression Profiling/methods , Computational Biology/methods , Cluster AnalysisABSTRACT
BACKGROUND: Association of asthma with the risk of cardiovascular disease has not been fully elucidated. So, this study tried to explore the genetic effect of asthma on five cardiovascular diseases and 90 peripheral cardiovascular proteins to answer the above topic. METHODS: Instrumental variables predicting asthma was extracted from its genome-wide association study data. Two-sample and multivariate MR approaches were used to assess the genetic association of exposure factor (i.e., asthma) with outcome factors (i.e., hypertension, atrial fibrillation, angina pectoris, myocardial infarction, heart failure, and 90 peripheral cardiovascular proteins). RESULTS: First, asthma nominally increased the risk of hypertension and atrial fibrillation (OR = 1.009, 95%CI = 1.003-1.016, P = 0.004; OR = 1.074, 95%CI = 1.024-1.127, P = 0.003). Second, of the 90 cardiovascular proteins, asthma was associated with the increased levels of tumor necrosis factor ligand superfamily member 14 and CC motif chemokine 4 (ß = 0.145, 95%CI = 0.077-0.212, P = 2.936e-05; ß = 0.128, 95%CI = 0.063-0.193, P = 1.036e-04). Third, CC motif chemokine 4 increased the risk of hypertension (P = 0.043); and after adjusting for this protein, asthma still increased the risk of hypertension, but the strength of its P-value changed from 0.004 to 0.011. CONCLUSION: Asthma was a risk factor for hypertension and atrial fibrillation at the genetic level, and CC motif chemokine 4 might play a mediating role in the mechanism by which asthma promoted hypertension. Thus, effective control of asthma may help reduce the risk of some cardiovascular diseases in older adults.
Subject(s)
Asthma , Cardiovascular Diseases , Genome-Wide Association Study , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Humans , Asthma/genetics , Asthma/epidemiology , Cardiovascular Diseases/genetics , Atrial Fibrillation/genetics , Hypertension/genetics , Risk Factors , Genetic Predisposition to Disease , Male , FemaleABSTRACT
OBJECTIVE: Hypertension refers to the elevated blood pressure (BP) in arteries, with a BP reading of 140/90 mm Hg or higher in adults. Over 40% of >25-year-old population have suffered from hypertension. Thus, this study aimed to find novel diagnostic biomarkers for hypertension. METHODS: All hypertension-related mRNA and methylation datasets were downloaded from the GEO database. Liner model method was used to identify differentially expressed genes (DEGs) between hypertension and control groups. Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes enrichment analysis was employed to obtain functional information. CpG sites and the corresponding genes associated with hypertension were screened using epigenome-wide association study (EWAS) analysis. RESULTS: There were 37 DEGs between the hypertension group and control group, which were significantly enriched in 84 Biological Process terms, 31 Cellular Component terms, 18 Molecular Function terms and 9 signalling pathways. EWAS results indicated that 1072 CpG sites were associated with hypertension occurrence, corresponding to 1029 genes. After cross-analysis, complement factor D (CFD) and OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) with methylation modification were identified as diagnostic markers for hypertension. CONCLUSION: In conclusion, CFD and OTUB2 were potential biomarkers of hypertension occurrence. Our results will provide more information for hypertension diagnosis and would be more reliable combined with multiple biomarkers.
In the GSE24752 dataset, there were 37 differentially expressed genes between the hypertension group and the normal group.In the GSE42774 dataset, there were 1072 CpG sites, corresponding to 1029 genes, associated with hypertension occurrence.CFD and OTUB2 were potential biomarkers that were associated with hypertension occurrence.
Subject(s)
Biomarkers , DNA Methylation , Hypertension , Humans , Hypertension/genetics , Hypertension/diagnosis , Genome-Wide Association Study , CpG Islands , FemaleABSTRACT
Although Akkermansia muciniphila (Am) plays a beneficial role as a probiotic in the treatment of metabolic syndrome, the mechanisms remain elusive. We tested the hypothesis that Am extracellular vesicles (AmEVs) protect against hypertension through modulation of gene expression in the kidneys of spontaneously hypertensive rats (SHRs). Extracellular vesicles purified from anaerobically cultured Am (1.0 × 108 or 1.0 × 109 particles/kg) or vehicles were injected into the tail veins of Wistar-Kyoto rats (WKYs) and SHRs weekly for 4 weeks. Renal cortical tissues isolated from both rat strains were analyzed by trichrome stain and RT-qPCR. AmEVs protect against the development of hypertension in SHRs without a serious adverse reaction. AmEVs increased the expression of vasocontracting Agt and At1ar as well as vasodilating At2r, Mas1 and Nos2 in the kidneys of both strains. These results indicate that AmEVs have a protective effect against hypertension without a serious adverse reaction. Therefore, it is foreseen that AmEVs may be utilized as a novel therapeutic for the treatment of hypertension.
Subject(s)
Akkermansia , Extracellular Vesicles , Hypertension , Kidney , Rats, Inbred SHR , Rats, Inbred WKY , Animals , Extracellular Vesicles/metabolism , Rats , Kidney/metabolism , Hypertension/metabolism , Hypertension/genetics , Male , Administration, Intravenous , Verrucomicrobia/genetics , Gene Expression Regulation , Probiotics/administration & dosageABSTRACT
Two researchers independently assessed studies published up to February 5, 2023, across PubMed, Web of Science, Embase, and Cochrane Library, to investigate the associations of sleep traits with cardiometabolic risk factors, as well as with cardiovascular diseases. Fourteen systematic reviews consisting of 23 meta-analyses, and 11 Mendelian randomization (MR) studies were included in this study. Short sleep duration was associated with a higher risk of obesity, type 2 diabetes (T2D), hypertension, stroke, and coronary heart disease (CHD) in observational studies, while a causal role was only demonstrated in obesity, hypertension, and CHD by MR. Similarly, long sleep duration showed connections with a higher risk of obesity, T2D, hypertension, stroke, and CHD in observational studies, none was supported by MR analysis. Both observational and MR studies indicated heightened risks of hypertension, stroke, and CHD in relation to insomnia. Napping was linked to elevated risks of T2D and CHD in observational studies, with MR analysis confirming a causal role in T2D. Additionally, snoring was correlated with increased risks of stroke and CHD in both observational and MR studies. This work consolidates existing evidence on a causal relationship between sleep characteristics and cardiometabolic risk factors, as well as cardiovascular diseases.
Subject(s)
Cardiometabolic Risk Factors , Cardiovascular Diseases , Mendelian Randomization Analysis , Sleep , Humans , Sleep/physiology , Diabetes Mellitus, Type 2/genetics , Observational Studies as Topic , Obesity/complications , Obesity/genetics , Hypertension/genetics , Stroke , Risk FactorsABSTRACT
BACKGROUND: Clinical observational study demonstrated that hypertension is an independent risk factor for stroke. Furthermore, both hypertension and stroke exhibit genetic predispositions. However, the genetic relationship between hypertension and stroke in first-degree relatives remains unclear. METHOD: The Genetic effects were validated using an across-Mendelian randomization (MR) approach. The Genome-Wide Association Study summary data used in this study were obtained from a publicly available platform. The primary MR effect employed was inverse-variance weighted (IVW), and the other analysis methods included MR-Egger, weighted median, simple mode, and weighted mode. Prior to MR analysis, tests for MR_PRESSO, pleiotropy, and heterogeneity were conducted. RESULT: The presence of family history of hypertension significantly contributed to the genetic predisposition to various types of stroke, including ischemic stroke, subarachnoid hemorrhage, lacunar stroke, cardioembolic ischemic stroke, small vessel ischemic stroke, and large artery atherosclerosis-related ischemic stroke. CONCLUSION: Briefly, hypertension in first-degree relatives has a genetic impact on the risk of stroke development. Shared genetic factors may exist between hypertension and stroke.
Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Heredity , Hypertension , Mendelian Randomization Analysis , Stroke , Humans , Hypertension/genetics , Hypertension/epidemiology , Hypertension/physiopathology , Hypertension/diagnosis , Risk Factors , Stroke/genetics , Stroke/diagnosis , Stroke/epidemiology , Risk Assessment , Phenotype , Pedigree , Polymorphism, Single Nucleotide , Blood Pressure/genetics , Databases, GeneticABSTRACT
OBJECTIVE: To assess the role of the systolic blood pressure polygenic risk score (SBP-PRS) in antihypertensive treatment initiation and its comparative efficacy with coronary artery calcium (CAC) scores. PATIENTS AND METHODS: This retrospective cohort study included participants with whole genome sequencing data who underwent CAC scanning between 1971 and 2008, were free of prevalent cardiovascular disease (CVD), and were not taking antihypertensive medications. The cohort was stratified by blood pressure (BP) treatment group and SBP-PRS (low/intermediate, first and second tertiles; high, third tertile) and CAC score (0 vs >0) subgroups. The primary outcome was the first occurence of adjudicated coronary heart disease, heart failure, or stroke during 10-year follow-up. The 10-year number needed to treat (NNT) to prevent 1 event of the primary outcome was estimated. A relative risk reduction of 25% for the primary outcome based on the treatment effect of intensive control (SBP <120 mm Hg) of hypertension in SPRINT (Systolic Blood Pressure Intervention Trial) was used for estimating the NNT. RESULTS: Among the 5267 study participants, the median age was 59 years (interquartile range, 51-68 years); 2817 (53.5%) were women and 2880 (54.7%) were non-White individuals. Among 1317 individuals with elevated BP/low-risk stage 1 hypertension not recommended treatment, the 10-year incidence rate of the primary outcome was 5.6% for low/intermediate SBP-PRS and 6.3% for high SBP-PRS with NNTs of 63 and 59, respectively. Similarly, the 10-year incidence rate of the primary outcome was 2.9% for CAC score 0 and 9.7% for CAC score greater than 0, with NNTs of 117 and 37, respectively. CONCLUSION: Including genetic information in risk estimation of individuals with elevated BP/low-risk stage 1 hypertension has modest value in the initiation of antihypertensive therapy. Genetic risk and CAC both have efficacy in personalizing antihypertensive therapy.
Subject(s)
Antihypertensive Agents , Coronary Artery Disease , Hypertension , Humans , Female , Middle Aged , Male , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Hypertension/genetics , Hypertension/epidemiology , Retrospective Studies , Aged , Coronary Artery Disease/genetics , Coronary Artery Disease/epidemiology , Coronary Artery Disease/drug therapy , Precision Medicine/methods , Vascular Calcification/genetics , Vascular Calcification/epidemiology , Risk Assessment , Blood Pressure/drug effects , Risk Factors , Genetic Predisposition to Disease , Coronary Vessels/diagnostic imaging , Cohort StudiesABSTRACT
Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension.
Subject(s)
DNA Methylation , Epigenesis, Genetic , Hypertension , Renin-Angiotensin System , Renin-Angiotensin System/genetics , Hypertension/genetics , Hypertension/metabolism , Animals , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Angiotensinogen/genetics , Angiotensinogen/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Cytochrome P-450 CYP11B2/genetics , Cytochrome P-450 CYP11B2/metabolismABSTRACT
BACKGROUND: Previous studies have shown that peptides encoded by noncoding RNAs (ncRNAs) can be used as peptide drugs to alleviate diseases. We found that microRNA-31 (miR-31) is involved in the regulation of hypertension and that the peptide miPEP31, which is encoded by the primary transcript of miR-31 (pri-miR-31), can inhibit miR-31 expression. However, the role and mechanism of miPEP31 in hypertension have not been elucidated. METHODS: miPEP31 expression was determined by western blot analysis. miPEP31-deficient mice (miPEP31-/-) were used, and synthetic miPEP31 was injected into Ang II-induced hypertensive mice. Blood pressure was monitored through the tail-cuff method. Histological staining was used to evaluate renal damage. Regulatory T (Treg) cells were assessed by flow cytometry. Differentially expressed genes were analysed through RNA sequencing. The transcription factors were predicted by JASPAR. Luciferase reporter and electrophoretic mobility shift assays (EMSAs) were used to determine the effect of pri-miR-31 on the promoter activity of miPEP31. Images were taken to track the entry of miPEP31 into the cell. RESULTS: miPEP31 is endogenously expressed in target organs and cells related to hypertension. miPEP31 deficiency exacerbated but exogenous miPEP31 administration mitigated the Ang II-induced systolic blood pressure (SBP) elevation, renal impairment and Treg cell decreases in the kidney. Moreover, miPEP31 deletion increased the expression of genes related to Ang II-induced renal fibrosis. miPEP31 inhibited the transcription of miR-31 and promoted Treg differentiation by occupying the Cebpα binding site. The minimal functional domain of miPEP31 was identified and shown to regulate miR-31. CONCLUSION: miPEP31 was identified as a potential therapeutic peptide for treating hypertension by promoting Treg cell differentiation in vivo. Mechanistically, we found that miPEP31 acted as a transcriptional repressor to specifically inhibit miR-31 transcription by competitively occupying the Cebpα binding site in the pri-miR-31 promoter. Our study highlights the significant therapeutic effect of miPEP31 on hypertension and provides novel insight into the role and mechanism of miPEPs.
Subject(s)
Angiotensin II , Blood Pressure , Disease Models, Animal , Hypertension , Kidney , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs , Promoter Regions, Genetic , T-Lymphocytes, Regulatory , Animals , MicroRNAs/metabolism , MicroRNAs/genetics , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , Hypertension/genetics , Binding Sites , Blood Pressure/drug effects , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/immunology , Kidney/metabolism , Kidney/pathology , Male , Mice , Gene Expression Regulation , Signal Transduction , CCAAT-Enhancer-Binding Proteins/metabolism , CCAAT-Enhancer-Binding Proteins/genetics , Antihypertensive Agents/pharmacology , HumansABSTRACT
Background: Left ventricular hypertrophy (LVH) is a common consequence of hypertension and can lead to heart failure. The immune response plays an important role in hypertensive LVH; however, there is no comprehensive method to investigate the mechanistic relationships between immune response and hypertensive LVH or to find novel therapeutic targets. This study aimed to screen hub immune-related genes involved in hypertensive LVH as well as to explore immune target-based therapeutic drugs. Materials and methods: RNA-sequencing data from a mouse model generated by angiotensin II infusion were subjected to weighted gene co-expression network analysis (WGCNA) to identify core expression modules. Machine learning algorithms were applied to screen immune-related LVH characteristic genes. Heart structures were evaluated by echocardiography and cardiac magnetic resonance imaging (CMRI). Validation of hub genes was conducted by RT-qPCR and western blot. Using the Connectivity Map database and molecular docking, potential small-molecule drugs were explored. Results: A total of 1215 differentially expressed genes were obtained, most of which were significantly enriched in immunoregulation and collagen synthesis. WGCNA and multiple machine learning strategies uncovered six hub immune-related genes (Ankrd1, Birc5, Nuf2, C1qtnf6, Fcgr3, and Cdca3) that may accurately predict hypertensive LVH diagnosis. Immune analysis revealed that fibroblasts and macrophages were closely correlated with hypertensive LVH, and hub gene expression was significantly associated with these immune cells. A regulatory network of transcription factor-mRNA and a ceRNA network of miRNA-lncRNA was established. Notably, six hub immune-related genes were significantly increased in the hypertensive LVH model, which were positively linked to left ventricle wall thickness. Finally, 12 small-molecule compounds with the potential to reverse the high expression of hub genes were ruled out as potential therapeutic agents for hypertensive LVH. Conclusion: This study identified and validated six hub immune-related genes that may play essential roles in hypertensive LVH, providing new insights into the potential pathogenesis of cardiac remodeling and novel targets for medical interventions.