Familial hyperaldosteronism: an European Reference Network on Rare Endocrine Conditions clinical practice guideline.

We describe herein the European Reference Network on Rare Endocrine Conditions clinical practice guideline on diagnosis and management of familial forms of hyperaldosteronism. The guideline panel consisted of 10 experts in primary aldosteronism, endocrine hypertension, paediatric endocrinology, and cardiology as well as a methodologist. A systematic literature search was conducted, and because of the rarity of the condition, most recommendations were based on expert opinion and small patient series. The guideline includes a brief description of the genetics and molecular pathophysiology associated with each condition, the patients to be screened, and how to screen. Diagnostic and treatment approaches for patients with genetically determined diagnosis are presented. The recommendations apply to patients with genetically proven familial hyperaldosteronism and not to families with more than one case of primary aldosteronism without demonstration of a responsible pathogenic variant.

Association of the Single Nucleotide Polymorphisms in the Renin-Angiotensin-Aldosterone System with Hypertension in the Uzbek Population.

OBJECTIVE: This research aims to identify the association between the nine polymorphic variants (rs4961, rs699, rs4762, rs5186, rs1403543, rs1799998, rs5443, rs2070744, rs1799983) and the occurrence of hypertension and its clinical manifestations in the Uzbek population. METHODS: The study included 227 individuals, comprising 179 patients with hypertension and 48 controls. Clinical parameters such as age, weight, blood glucose, triglycerides, total cholesterol, low-density lipoprotein and high-density lipoprotein, blood urea nitrogen, creatinine, pulse wave velocity, left ventricular mass, and microalbuminuria levels were identified. We assessed the distribution of allele frequencies of these polymorphic variants in the Uzbek population to establish their association with cardiovascular diseases and their clinical manifestations. RESULTS: Genetic analysis of the polymorphic variants demonstrated a significant association of the AGT 521 C>T variant with arterial hypertension [P ≤ 0.01; Odds Ratio (OR) = 2.91]. The NOS3 -786 T>C variant correlated with left ventricular hypertrophy (P ≤ 0.05; OR = 0.35) and increased pulse wave velocity (P ≤ 0.01; OR = 0.21). The correlations of the AGTR2 1675 G>A variant with left ventricular hypertrophy (P ≤ 0.01; OR = 1.59) and increased pulse wave velocity (P ≤ 0.01; OR = 0.33) were identified. The AGT 704 T>C variant showed a significant association with increased pulse wave velocity (P ≤ 0.05; OR = 2.73). CONCLUSION: Four of the nine studied polymorphic variants were associated with clinical manifestations of hypertension in the Uzbek population. These variants can be used as genetic biomarkers to identify the risks of developing cardiovascular diseases and hypertension in the Uzbek population.

The ALDH2 gene rs671 polymorphism is associated with cardiometabolic risk factors in East Asian population: an updated meta-analysis.

Introduction: Acetaldehyde dehydrogenase 2 (ALDH2) had reported as a prominent role in the development of cardiometabolic diseases among Asians. Our study aims to investigate the relationship between ALDH2 polymorphism and cardiometabolic risk factors in East Asian population. Method: We searched databases of PubMed, Web of Science, and Embase updated to Oct 30th, 2023. We extracted data of BMI, Hypertension, SBP, DBP, T2DM, FBG, PPG, HbA1c, TG, TC, LDL-C and HDL-C. Result: In total, 46 studies were finally included in our meta-analysis, containing, 54068 GG and, 36820 GA/AA participants. All outcomes related to blood pressure revealed significant results (hypertension OR=0.83 [0.80, 0.86]; SBP MD=-1.48 [-1.82, -1.14]; DBP MD=-1.09 [-1.58, -0.61]). FBG showed a significant difference (MD=-0.10 [-0.13, -0.07]), and the lipid resulted significantly in some outcomes (TG MD=-0.07 [-0.09, -0.04]; LDL-C MD=-0.04 [-0.05, -0.02]). As for subgroups analysis, we found that in populations without severe cardiac-cerebral vascular diseases (CCVDs), GG demonstrated a significantly higher incidence of T2DM (T2DM OR=0.88 [0.79, 0.97]), while the trend was totally opposite in population with severe CCVDs (T2DM OR=1.29 [1.00, 1.66]) with significant subgroup differences. Conclusion: Our updated meta-analysis demonstrated that ALDH2 rs671 GG populations had significantly higher levels of BMI, blood pressure, FBG, TG, LDL-C and higher risk of hypertension than GA/AA populations. Besides, to the best of our knowledge, we first report GG had a higher risk of T2DM in population without severe CCVDs, and GA/AA had a higher risk of T2DM in population with severe CCVDs.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023389242.

Treatment for Resistant Hypertension Under the Guidance of Pharmacogenomics: A Randomised Controlled Open-Label Trial.

OBJECTIVE: To evaluate the efficacy and safety of pharmacogenomics (PGx)-guided treatment in individuals with resistant hypertension (RH). STUDY DESIGN: Randomised controlled open-label study. Place and Duration of the Study: Department of Cardiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China, from June 2019 to November 2021. METHODOLOGY: The study assigned RH patients to two groups. The intervention group (IG) received 12 weeks of PGx-guided treatment, while the control group (CG) followed a consensus-based approach. Examining 10 genes and their alleles with 31 antihypertensive drugs in the IG, the study provided specific medication advice. The primary outcome measured the difference in office systolic blood pressure (SBP) change from baseline at 12 weeks. Secondary outcomes included changes in diastolic blood pressure (DBP), hepatic and renal function, and major adverse cardiovascular events. RESULTS: Fifty-nine patients from the First Hospital of China Medical University participated, with 29 in the IG and 30 in the CG. Significant differences were noted in SBP reduction (IG: 31.26 ± 18.64 mmHg; CG: 14.61 ± 17.74 mmHg; p=0.001) and DBP reduction (IG: 19.61 ± 17.32 mmHg; CG: 7.81 ± 11.23 mmHg; p = 0.003) after 12 weeks. One IG patient had a heart attack, and one CG subject developed heart failure. At week 12, hepatic insufficiency was observed in one IG patient and six CG patients, while renal insufficiency occurred in five patients of both groups. CONCLUSION: Treatment guided by PGx demonstrated significant reductions in both SBP and DBP compared to consensus-based treatment. KEY WORDS: Resistant hypertension, Treatment, Pharmacogenomics, Clinical study.

Impact of GSTT1 AND GSTM1 variants and hair mercury concentration in maternal blood pressure among coastal pregnant women in Central Java, Indonesia.

The GSTT1 and GSTM1 genes have a role in mercury metabolism and excretion, as well as blood pressure response, impacting birth outcomes. The present study assesses whether GSTT1 and GSTM1 deletion variants and maternal hair Hg concentration are associated with blood pressure and birth outcomes among the Indonesian coastal pregnant mother population. A cross-sectional study was conducted on 139 pregnant women in the Jepara coastal area of Central Java, Indonesia. Maternal characteristics during pregnancy, including blood pressure and birth outcomes, were collected. GSTT1 and GSTM1 gene variants were detected using polymerase chain reaction (PCR). Hair Hg levels were measured using the reducing-vaporization mercury analyzer. The mean maternal hair Hg concentration was 0.727±0.558 µg/g. GSTT1 genotype homozygous deletion was found in 41.7% of subjects, while no GSTM1 deletion was found. No statistically significant difference was found between deletion and non-deletion groups for hair Hg. GSTT1 deletion genotype shows protection but is inconclusive toward diastolic hypertension (p=0.048, OR 0.285, CI 0.077-1.052) and insignificant with birth outcomes (all p>0.05). High hair Hg concentration and positive history of cardiovascular diseases increase the risk of systolic and diastolic hypertension during pregnancy with OR 6.871 (CI 95% 1.445-32.660) and 8.518 (CI 95% 2.126-34.125), respectively, while not in birth outcomes. Maternal Hg exposure and history of cardiovascular diseases are independent risk factors for pregnant hypertension, whereas the GSTT1 homozygous deletion genotype has no role in diastolic hypertension and birth outcomes among the Indonesian coastal pregnant mother population.

Platelet Microparticle-Derived MiR-320b Inhibits Hypertension with Atherosclerosis Development by Targeting ETFA.

Hypertension and atherosclerosis often occur simultaneously. This study aimed to explore the role and mechanism of platelet microparticle (PMP) -derived microRNA-320b (miR-320b) in patients with hypertension accompanied by atherosclerosis.We collected samples from 13 controls without hypertension and atherosclerosis and 20 patients who had hypertension accompanied by atherosclerosis. In vitro, platelets were activated by Thrombin receptor-activating peptide to produce PMPs. HUVECs were induced by CoCl2 to mimic a hypoxic environment in vitro. RT-qPCR was employed to detect the expression levels of CD61, miR-320b, and ETFA. The protein expression level of ETFA was evaluated via Western blotting. Furthermore, 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine, and wound healing assays were employed to assess the proliferation and migration of HUVECs. Enzyme-linked immunosorbent assay was used to measure the oxidative stress and inflammation-related factor expression.The expression of miR-320b was reduced in both platelets and PMPs but increased in plasma. MiR-320b promoted CoCl2-induced HUVEC viability, proliferation, and migration. The levels of the oxidative stress factors SOD and GSH as well as the inflammatory factor IL-10 were elevated in the CoCl2 + miR-320b mimics group compared with both the CoCl2 + mimics NC and CoCl2 groups. Conversely, the levels of the oxidative stress factors MDA and ROS as well as the inflammatory factors IL-6, TNF-α, and IL-1ß were decreased. These results were regulated by miR-320b targeting ETFA.PMP-derived miR-320b inhibits the development of hypertension accompanied by atherosclerosis by targeting ETFA.

ATP2B1 gene polymorphisms associated with resistant hypertension in the Japanese population.

Single-nucleotide polymorphisms (SNP) of ATP2B1 gene are associated with essential hypertension but their association with resistant hypertension (RHT) remains unexplored. The authors examined the relationship between ATP2B1 SNPs and RHT by genotyping 12 SNPs in ATP2B1 gene of 1124 Japanese individuals with lifestyle-related diseases. Patients with RHT had inadequate blood pressure (BP) control using three antihypertensive drugs or used ≥4 antihypertensive drugs. Patients with controlled hypertension had BP controlled using ≤3 antihypertensive drugs. The association between each SNP and RHT was analyzed by logistic regression. The final cohort had 888 (79.0%) and 43 (3.8%) patients with controlled hypertension and RHT, respectively. Compared with patients homozygous for the minor allele of each SNP in ATP2B1, a significantly higher number of patients carrying the major allele at 10 SNPs exhibited RHT (most significant at rs1401982: 5.8% vs. 0.8%, p = .014; least significant at rs11105378: 5.7% vs. 0.9%, p = .035; most nonsignificant at rs12817819: 5.1% vs. 10%, p = .413). After multivariate adjustment for age, sex, systolic BP, and other confounders, the association remained significant for rs2681472 and rs1401982 (OR: 7.60, p < .05 and OR: 7.62, p = .049, respectively). Additionally, rs2681472 and rs1401982 were in linkage disequilibrium with rs11105378. This study identified two ATP2B1 SNPs associated with RHT in the Japanese population. rs1401982 was most closely associated with RHT, and major allele carriers of rs1401982 required significantly more antihypertensive medications. Analysis of ATP2B1 SNPs in patients with hypertension can help in early prediction of RHT and identification of high-risk patients who are more likely to require more antihypertensive medications.

Omega-3 fatty acids and their influence on hypertension and coronary atherosclerosis: Insights from a Mendelian randomization approach.

It has been suggested that Omega-3 fatty acids may improve endothelial thickness and thereby reduce the onset of cardiovascular diseases such as coronary atherosclerosis and hypertension. However, published observational epidemiological studies on the relationship between cardiovascular disease (CVD) and Omega-3 fatty acids remain inconclusive. Here, we performed a two-sample Mendelian randomisation analysis using publicly available GWAS pooled statistics to study a GWAS dataset of 16 380 466 SNPs in 23 363 cases and 195 429 controls (also of European ancestry) to determine genetic susceptibility to hypertension. We performed random-effects Inverse Variance Weighted (IVW) Mendelian Randomization (MR) analyses supplemented by a series of sensitivity assessments to measure the robustness of the findings and to detect any violations of the MR assumptions. During the course of the study, we used IVW, MR-Egger, and weighted median regression to infer that Omega-3 intake has a potentially adverse effect against atherosclerosis, although the trend was not significant (OR = 1.1198; 95%; CI: 0.9641-1.3006, p = .130). Meanwhile, our analyses showed a statistically significant negative association between Omega-3 fatty acid levels and risk of hypertension (OR = 0.9006; 95% CI: 0.8179-0.9917, p = .033). In addition, we explored the causal relationship between atherosclerosis and hypertension and found a significant correlation (OR = 1.3036; 95% CI: 1.0672-1.5923, p = .009). In conclusion, our extensive data investigated by MR suggest that elevated levels of Omega-3 fatty acids may be associated with an decreased risk of hypertension. Although there is no direct link between hypertension and atherosclerosis, the possibility of a subtle association cannot be categorically excluded.

Single nucleotide polymorphism (SNP) rs4291 of the angiotensin-converting enzyme (ACE) gene is associated with the response to losartan treatment in hypertensive patients.

Arterial hypertension is characterized by systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg and its treatment consists of the use of antihypertensive drugs, as losartan and hydrochlorothiazide. Blood pressure is regulated by angiotensin-converting enzyme (ACE) and polymorphisms in the ACE gene are associated to a greater predisposition to hypertension and response to treatment. The aim of this study was to evaluate the association of genetic polymorphisms of ACE rs4363, rs4291 and rs4335 and the response to antihypertensive drugs in hypertensive patients from Ouro Preto/MG, Brazil. A case-control study was carried out with 87 hypertensive patients being treated with losartan and 75 with hydrochlorothiazide, who answered a questionnaire and had blood samples collected. Biochemical analyzes were performed on serum using UV/Vis spectrophotometry and identification of ACE variants rs4363, rs4291 and rs4335 was performed by real-time PCR using the TaqMan® system. Univariate logistic regression test was performed to compare categorical data in STATA 13.0 software. The results showed that there was an influence of ACE polymorphisms on the response to losartan, demonstrating that AT or TT genotypes of rs4291 were more frequent in the group of controlled AH (54.9%), indicating that these individuals are 2.8 times more likely to of being controlled AH (95% CI 1.12-6.80, p. =0.026) compared to those with AA genotype. In contrast, no influence of ACE polymorphisms on the response to hydrochlorothiazide was observed. In conclusion, the presence of the T allele of the rs4291 variant was associated to controled blood pressure when losartan was used as an antihypertensive agent. These results show the importance of pharmacogenetic studies to detect genetic characteristics, enabling therapeutic individuality and reducing costs for the healthcare system.

Causal effect of interleukin (IL)-6 on blood pressure and hypertension: A mendelian randomization study.

To examine whether circulating interleukin-6 (IL-6) levels (CirIL6) have a causal effect on blood pressure using Mendelian randomization (MR) methods. We used data from genome-wide association studies (GWAS) of European ancestry to obtain genetic instruments for circulating IL-6 levels and blood pressure measurements. We applied several robust MR methods to estimate the causal effects and to test for heterogeneity and pleiotropy. We found that circulating IL-6 had a significant positive causal effect on systolic blood pressure (SBP) and pulmonary arterial hypertension (PAH), but not on diastolic blood pressure (DBP) or hypertension. We found that as CirIL6 genetically increased, SBP increased using Inverse Variance Weighted (IVW) method (for ukb-b-20175, ß = 0.082 with SE = 0.032, P = 0.011; for ukb-a-360, ß = 0.075 with SE = 0.031, P = 0.014) and weighted median (WM) method (for ukb-b-20175, ß = 0.061 with SE = 0.022, P = 0.006; for ukb-a-360, ß = 0.065 with SE = 0.027, P = 0.014). Moreover, CirIL6 may be associated with an increased risk of PAH using WM method (odds ratio (OR) = 15.503, 95% CI, 1.025-234.525, P = 0.048), but not with IVW method. Our study provides novel evidence that circulating IL-6 has a causal role in the development of SBP and PAH, but not DBP or hypertension. These findings suggest that IL-6 may be a potential therapeutic target for preventing or treating cardiovascular diseases and metabolic disorders. However, more studies are needed to confirm the causal effects of IL-6 on blood pressure and to elucidate the underlying mechanisms and pathways.

Vitamin D deficiency and the vitamin D receptor (VDR) gene polymorphism rs2228570 (FokI) are associated with an increased susceptibility to hypertension among the Bangladeshi population.

Vitamin D receptor (VDR) gene is implicated in hypertension vulnerability due to its role in regulating the renin-angiotensin system (RAS) and blood pressure. In this case-control study, a carefully selected cohort of 111 hypertensive individuals and 100 healthy controls underwent serum analysis using HPLC to measure 25-hydroxy vitamin D levels. Polymorphic variations in the VDR gene were detected and characterized using the PCR-RFLP method. At first, lower 25-hydroxy vitamin D levels were observed in hypertensive individuals compared to controls (p<0.001). The genotype frequency of the VDR gene TaqI showed no significant difference between cases and controls (p>0.05). Similarly, no significant difference was found in the VDR gene BsmI genotype frequency between hypertensive patients and controls (p>0.05). However, a statistically significant distinction was observed in the VDR gene FokI genotype frequency between cases and controls (p<0.01). The odds ratios for FokI genotypes (CC, CT, TT, and CT+TT) were 1.0, 0.590, 1.566, and 0.963, respectively. Furthermore, serum 25-hydroxy vitamin D levels were significantly higher in control subjects compared to hypertensive patients across all genotypes of VDR (p<0.001). Hypertensive patients, excluding those with the FokI VDR gene CC genotype, exhibited significantly higher systolic blood pressure levels compared to the control group (p<0.05). Similarly, hypertensive subjects displayed elevated diastolic blood pressure levels compared to the control group (p<0.001). Overall, the results suggest the presence of a potential inverse correlation between serum 25-hydroxy vitamin D levels and hypertension. The association analysis conducted indicated that there is no significant association between TaqI and bsmI genotypic variants and the risk of developing hypertension. However, it was observed that VDR gene polymorphisms do have a clear association with hypertension susceptibility, as evidenced by the significantly higher occurrence of FokI genotypic variants in hypertensive patients. Our study therefore introduces the possibility of utilizing 25-hydroxy vitamin D deficiency and VDR gene polymorphisms as a biomarker for hypertension.

Mendelian randomization study on insulin resistance and risk of hypertension and cardiovascular disease.

Observational studies have suggested that insulin resistance (IR) is associated with hypertension and various cardiovascular diseases. However, the presence of a causal relationship between IR and cardiovascular disease remains unclear. Here, we applied Mendelian randomization (MR) approaches to address the causal association between genetically determined IR and the risk of cardiovascular diseases. Our primary genetic instruments comprised 53 SNPs associated with IR phenotype from a GWAS of up to 188,577 participants. Genetic association estimates for hypertension and venous thromboembolism (VTE) were extracted from UK Biobank, estimates for atrial fibrillation (AF) were extracted from the hitherto largest GWAS meta-analysis on AF, estimates for heart failure were extracted from HERMES Consortium, estimates for peripheral artery disease (PAD) and aortic aneurysm were extracted from the FinnGen Study. The main analyses were performed using the random-effects inverse-variance weighted approach, and complemented by sensitivity analyses and multivariable MR analyses. Corresponding to 55% higher fasting insulin adjusted for body mass index, 0.46 mmol/L lower high-density lipoprotein cholesterol and 0.89 mmol/L higher triglyceride, one standard deviation change in genetically predicted IR was associated with increased risk of hypertension (odds ratio (OR) 1.06, 95% CI 1.04-1.08; P = 1.91 × 10-11) and PAD (OR 1.90, 95% CI 1.43-2.54; P = 1.19 × 10-5). Suggestive evidence was obtained for an association between IR and heart failure (OR per SD change in IR: 1.19, 95% CI 1.01-1.41, P = 0.041). There was no MR evidence for an association between genetically predicted IR and atrial fibrillation, VTE, and aortic aneurysm. Results were widely consistent across all sensitivity analyses. In multivariable MR, the association between IR and PAD was attenuated after adjustment for lipids (P = 0.347) or BMI (P = 0.163). Our findings support that genetically determined IR increases the risk of hypertension and PAD.

A genome-wide association study based on the China Kadoorie Biobank identifies genetic associations between snoring and cardiometabolic traits.

Despite the high prevalence of snoring in Asia, little is known about the genetic etiology of snoring and its causal relationships with cardiometabolic traits. Based on 100,626 Chinese individuals, a genome-wide association study on snoring was conducted. Four novel loci were identified for snoring traits mapped on SLC25A21, the intergenic region of WDR11 and FGFR, NAA25, ALDH2, and VTI1A, respectively. The novel loci highlighted the roles of structural abnormality of the upper airway and craniofacial region and dysfunction of metabolic and transport systems in the development of snoring. In the two-sample bi-directional Mendelian randomization analysis, higher body mass index, weight, and elevated blood pressure were causal for snoring, and a reverse causal effect was observed between snoring and diastolic blood pressure. Altogether, our results revealed the possible etiology of snoring in China and indicated that managing cardiometabolic health was essential to snoring prevention, and hypertension should be considered among snorers.

Major depressive disorder increased the risk of hypertension: A Mendelian randomization study.

BACKGROUND: Despite the high prevalence of comorbid hypertension in patients with major depressive disorder (MDD), the relationship between the two diseases has received little attention. Previous observational studies have descripted the association between MDD and hypertension, the causality from MDD on hypertension remained unknown. The present Mendelian randomization (MR) study aimed to assess the causal effect of MDD on hypertension. METHODS: A set of genetics instrument was used for analysis, derived from publicly available genetic meta-analysis data. A total of 44 single-nucleotide polymorphisms (SNPs) associated with MDD. The largest genome-wide association study (GWAS) for hypertension (54,358 cases and 408,652 controls) was used to assess the effect of MDD on hypertension. Inverse variance weighted method (IVW), weighted median method (WM), and MR-Egger regression were used for MR analyses. The MR-Egger_intercept test and Cochran's Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. RESULTS: A total of 28 independent and effective MDD genetic instrumental variables were extracted from the hypertension GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 28 selected MDD genetic instrument variants in hypertension GWAS datasets. As MDD based on genetic changes increased, the risk of hypertension increased using MR-Egger (OR = 1.004436, 95%CI 0.9884666-1.020663, P = 0.5932928), WM (OR = 1.000499, 95%CI 1.0000188-1.000980, P = 0.0416871), and IVW (OR = 1.000573, 95%CI 1.0000732-1.001074, P = 0.0246392). Our results were robust, with no obvious bias based on investigating the single MDD SNP on hypertension. CONCLUSIONS: Our result suggested a causal associated between genetically increased MDD and increased hypertension risk in European population.

Role of Raptor Gene Variants in Hypertension: Influence on Blood Pressure Independent of Salt Intake in White Population.

BACKGROUND: The mTOR (mechanistic target of rapamycin) is an essential regulator of fundamental biological processes. mTOR forms 2 distinct complexes, mTORC1 (mTOR complex 1) when it binds with RAPTOR (Regulatory-associated Protein of mTOR) and mTORC2 (mTOR complex 2) when it associates with RICTOR (Rapamycin-insesitive companion of mTOR). Due to the previous link between the mTOR pathway, aldosterone, and blood pressure (BP), we anticipated that variants in the mTOR complex might be associated with salt-sensitive BP. METHODS: BP and other parameters were assessed after a one-week liberal Na+ (200 mmol/d) and a one-week restricted Na+ (10 mmol/d) diet in 608 White subjects from the Hypertensive Pathotype cohort, single-nucleotide variants in MTOR, RPTOR, and RICTOR genes were obtained for candidate genes analyses. RESULTS: The analysis revealed a significant association between a single nucleotide variants within the RPTOR gene and BP. Individuals carrying the RPTOR rs9901846 homozygous risk allele (AA) and heterozygous risk allele (GA) exhibited a 5 mm Hg increase in systolic BP on a liberal diet compared with nonrisk allele individuals (GG), but only in women. This single nucleotide variants effect was more pronounced on the restricted diet and present in both sexes, with AA carriers having a 9 mm Hg increase and GA carriers having a 5 mm Hg increase in systolic BP compared with GG. Interestingly, there were no significant associations between MTOR or RICTOR gene variants and BP. CONCLUSIONS: The RPTOR gene variation is associated with elevated BP in White participants, regardless of salt intake, specifically in females.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

Meteorin-like (METRNL) attenuates hypertensive induced cardiac hypertrophy by inhibiting autophagy via activating BRCA2.

Hypertension, a prevalent cardiovascular ailment globally, can precipitate numerous complications, notably hypertensive cardiomyopathy. Meteorin-like (METRNL) is demonstrated to possess potential protective properties on cardiovascular diseases. However, its specific role and underlying mechanism in hypertensive myocardial hypertrophy remain elusive. Spontaneously hypertensive rats (SHRs) served as hypertensive models to explore the effects of METRNL on hypertension and its induced myocardial hypertrophy. The research results indicate that, in contrast to Wistar-Kyoto (WKY) rats, SHRs exhibit significant symptoms of hypertension and myocardial hypertrophy, but cardiac-specific overexpression (OE) of METRNL can partially ameliorate these symptoms. In H9c2 cardiomyocytes, METRNL suppresses Ang II-induced autophagy by controlling the BRCA2/Akt/mTOR signaling pathway. But when BRCA2 expression is knocked down, this effect will be suppressed. Collectively, METRNL emerges as a potential therapeutic target for hypertensive cardiomyopathy.

Circulating microRNA Biomarkers of Thiazide Response in Hypertension.

BACKGROUND: Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response. METHODS AND RESULTS: We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5-fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide-treated European Americans, chlorthalidone-treated European Americans, and hydrochlorothiazide-treated Black individuals. Different blood pressure phenotypes including categorical (responder versus nonresponder) and continuous diastolic blood pressure and systolic blood pressure were tested for association with the candidate miRNA expression using multivariate regression analyses adjusting for age, sex, and baseline blood pressure. After quality control, 74 miRNAs were available for screening, 19 of which were considered for validation. In the validation cohort, miR-193b-3p and 30d-5p showed significant associations with continuous SBP or diastolic blood pressure response or both, to hydrochlorothiazide in European Americans at Benjamini-Hochberg adjusted P<0.05. In the combined analysis of validation cohorts, let-7g (odds ratio, 0.6 [95% CI, 0.4-0.8]), miR-142-3p (odds ratio, 1.1 [95% CI, 1.0, 1.2]), and miR-423-5p (odds ratio, 0.7 [95% CI, 0.5-0.9]) associated with categorical diastolic blood pressure response at Benjamini-Hochberg adjusted P<0.05. Predicted target genes of the 5 miRNAs were mapped to key hypertension pathways: lysine degradation, fatty acid biosynthesis, and metabolism. CONCLUSIONS: The above identified circulating miRNAs may have a potential for clinical use as biomarkers for thiazide diuretic selection in hypertension. REGISTRATION: URL: ClinicalTrials.gov. Unique identifiers: NCT00246519, NCT01203852, NCT00005520.

Association between leisure sedentary behaviors and hypertension risk: A prospective cohort study and two-sample Mendelian randomization analysis in Europeans.

OBJECTIVE: This study aimed to investigate the potential causal relationship between domain-specific sedentary behaviors (including television watching, computer use, and driving) and hypertension risk in European populations. METHODS: Initially, we conducted a multivariable Cox regression analysis to evaluate the associations between domain-specific sedentary behaviors and the risk of developing hypertension using data from 261,829 hypertension-free participants in the UK Biobank. To validate the findings of observational analysis, we employed two-sample univariable mendelian randomization (UVMR) analysis utilizing summary statistics from genome-wide association study conducted on European populations. We then performed multivariable mendelian randomization (MVMR) analysis to account for the influence of the risk factors for hypertension. RESULTS: In this prospective observational analysis, individuals who spent >3 h per day watching television had significantly higher risk of developing hypertension (HR = 1.24, 95% CI: 1.20-1.29, P < 0.001) compared to those who watched television for 0-1 h per day. The mendelian randomization analysis provided consistent evidence for a causal relationship between prolonged television watching time and hypertension risk (OR = 1.45, 95% CI: 1.25-1.69, P < 0.001; all PMVMR < 0.05) in both UVMR and MVMR results. No significant associations were found between computer use, driving behaviors and the risk of hypertension in either the observational or UVMR/MVMR analyses. CONCLUSIONS: These findings provide evidence for a causal effect specifically linking higher television watching time to an increased risk of hypertension and indicate the potential effectiveness of reducing television viewing time as a preventive measure to mitigate the risk of hypertension.