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Background: The present study aimed to estimate the additive interaction of family history of diabetes and hypertension on the diagnosis of diabetes among individuals aged 45 years and above in India. The coexistence of these two exposures may act synergistically on the risk of diabetes, leading to adverse health outcomes., Methods: The study utilized the data from the Longitudinal Ageing Study in India (LASI) Wave 1 (2017-2018). The total sample size for the current study was 58,612 individuals aged 45 years and above. Multivariable logistic regression models were employed to determine the individual and joint effect of a family history of diabetes with hypertension on diabetes. An additive model was applied to assess the interaction effect of the family medical history of diabetes with hypertension on the diagnosis of diabetes by calculating three different measures of additive interaction such as the relative excess risk ratio (RERI), attribution proportion due to interaction (AP), and synergy index (S)., Results: The prevalence of diabetes was three times higher among individuals with family history of diabetes (27.8% vs. 9.2%) than those without family history. Individuals with family history of diabetes (AOR: 2.47, CI: 2.11 2.89) had 2.47 times higher odds of having diabetes than those without family history. The prevalence of diabetes was significantly higher among individuals with hypertension and family history of diabetes (46.6%, 95% CI: 39.7-53.6) than those without the coexistence of family history of diabetes and hypertension (9.9%, 95% CI: 9.5-10.4), individuals with hypertension and without a family history of diabetes (22.7%, 95% CI: 21.2-24.2), and individuals with family history of diabetes and without hypertension (16.5%, 95% CI: 14.5-18.7). Moreover, the adjusted odds ratio (AOR) of the joint effect between family medical history of diabetes and hypertension on diabetes was 9.28 (95% CI: 7.51-11.46). In the adjusted model, the RERI, AP, and S for diabetes were 3.5 (95% CI: 1.52-5.47), 37% (0.37; 95% CI: 0.22-0.51), and 1.69 (95% CI: 1.31-2.18) respectively, which indicates that there is a significant positive interaction between family history of diabetes and hypertension on the diagnosis of diabetes. The study findings on interaction effects further demonstrate consistent results for two models of hypertension (self-reported hypertension and hypertensive individuals receiving medication) even after adjustment with potential confounding factors on diabetes (self-reported diabetes and individuals with diabetes receiving medication)., Conclusions: The study findings strongly suggest that the interaction of family history of diabetes with hypertension has a positive and significant effect on the risk of diabetes even after adjustment with potential confounding factors. Furthermore, the findings indicate a synergistic effect, emphasizing the importance of considering both family medical history of diabetes and hypertension when assessing diabetes risk and designing preventive strategies or interventions., (© 2024. The Author(s).)

Essential hypertension is a complex trait where the underlying aetiology is not completely understood. Left untreated it increases the risk of severe health complications including cardiovascular and renal disease. It is almost 15 years since the first genome-wide association study for hypertension, and after a slow start there are now over 1000 blood pressure (BP) loci explaining ∼6% of the single nucleotide polymorphism-based heritability. Success in discovery of hypertension genes has provided new pathological insights and drug discovery opportunities and translated to the development of BP genetic risk scores (GRSs), facilitating population disease risk stratification. Comparing highest and lowest risk groups shows differences of 12.9 mm Hg in systolic-BP with significant differences in risk of hypertension, stroke, cardiovascular disease and myocardial infarction. GRSs are also being trialled in antihypertensive drug responses. Drug targets identified include NPR1, for which an agonist drug is currently in clinical trials. Identification of variants at the PHACTR1 locus provided insights into regulation of EDN1 in the endothelin pathway, which is aiding the development of endothelin receptor EDNRA antagonists. Drug re-purposing opportunities, including SLC5A1 and canagliflozin (a type-2 diabetes drug), are also being identified. In this review, we present key studies from the past, highlight current avenues of research and look to the future focusing on gene discovery, epigenetics, gene-environment interactions, GRSs and drug discovery. We evaluate limitations affecting BP genetics, including ancestry bias and discuss streamlining of drug target discovery and applications for treating and preventing hypertension, which will contribute to tailored precision medicine for patients., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Current studies have shown the controversial effect of genetic risk scores (GRSs) in hypertension prediction. Machine learning methods are used extensively in the medical field but rarely in the mining of genetic information. This study aims to determine whether genetic information can improve the prediction of incident hypertension using machine learning approaches in a prospective study. The study recruited 4592 subjects without hypertension at baseline from a cohort study conducted in rural China. A polygenic risk score (PGGRS) was calculated using 13 SNPs. According to a ratio of 7:3, subjects were randomly allocated to the train and test datasets. Models with and without the PGGRS were established using the train dataset with Cox regression, artificial neural network (ANN), random forest (RF), and gradient boosting machine (GBM) methods. The discrimination and reclassification of models were estimated using the test dataset. The PGGRS showed a significant association with the risk of incident hypertension (HR (95% CI), 1.046 (1.004, 1.090), P = 0.031) irrespective of baseline blood pressure. Models that did not include the PGGRS achieved AUCs (95% CI) of 0.785 (0.763, 0.807), 0.790 (0.768, 0.811), 0.838 (0.817, 0.857), and 0.854 (0.835, 0.873) for the Cox, ANN, RF, and GBM methods, respectively. The addition of the PGGRS led to the improvement of the AUC by 0.001, 0.008, 0.023, and 0.017; IDI by 1.39%, 2.86%, 4.73%, and 4.68%; and NRI by 25.05%, 13.01%, 44.87%, and 22.94%, respectively. Incident hypertension risk was better predicted by the traditional+PGGRS model, especially when machine learning approaches were used, suggesting that genetic information may have the potential to identify new hypertension cases using machine learning methods in resource-limited areas. CLINICAL TRIAL REGISTRATION: The Henan Rural Cohort Study has been registered at the Chinese Clinical Trial Register (Registration number: ChiCTR-OOC-15006699). http://www.chictr.org.cn/showproj.aspx?proj=11375 ., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Objective: The present study aimed to conduct a systematic review and meta-analysis to evaluate the relationships between ATP2B1 gene polymorphisms with blood pressure (BP) level and susceptibility to hypertension., Methods: PubMed, Web of Science, Embase and China National Knowledge Infrastructure (CNKI) Databases were systematically searched by 2 independent researchers to screen studies on ATP2B1 gene polymorphisms and BP related phenotypes. The records retrieval period was limited from the formation of the database to March 4, 2021. Pooled odds rations (ORs) or β and their 95% confidence intervals (95%CI) were calculated to assess the association between ATP2B1 gene polymorphisms and the risk of hypertension or BP levels. Publication bias and sensitivity analysis were conducted to find potential bias. All the statistical analysis were conducted with Stata version 11.0 software., Results: A total of 15 articles were ultimately included in the present study, including 15 polymorphisms of ATP2B1 gene. Nine articles (N = 65,362) reported the polymorphism rs17249754, and 7 articles(N = 91,997) reported rs2681472 (both loci were reported in 1 article). Meta-analysis showed that rs17249754 (G/A) and rs2681472 (A/G) were associated with the susceptibility to hypertension (rs17249754: OR = 1.19, 95%CI: 1.10-1.28; rs2681472: OR = 1.15, 95%CI: 1.12-1.17), and were positively associated with systolic BP (SBP) and diastolic blood pressure (DBP) (rs17249754: SBP, β=1.01, 95%CI: 0.86-1.16, DBP, β=0.48, 95%CI: 0.30-0.66; rs2681472: SBP, β=0.92, 95%CI: 0.77-1.07, DBP, β=0.50, 95%CI: 0.42-0.58) in the additive genetic model. Subgroup analysis stratified by race, population, sample size, and BP measurement method revealed that the association between A allele in rs2681472 polymorphism and risk of hypertension was slightly stronger in European (EUR) populations (OR = 1.16, 95%CI: 1.13-1.20) than in East Asians (OR = 1.14, 95%CI: 1.10-1.17). While in East Asians, relation between rs17249754 with risk of hypertension (OR = 1.19, 95%CI: 1.10-1.28) is stronger than rs2681472 (OR = 1.14, 95%CI: 1.10-1.17)., Conclusions: Our study demonstrated that ATP2B1 gene polymorphism rs2681472 and rs17249754 were associated with BP levels and the susceptibility to hypertension., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Genetic risk factors for hypertension may have age or gender specificity and pleiotropic effects. This study aims to measure the risk of genetic and non-genetic factors in the occurrence of hypertension and related diseases, with consideration of potential confounding factors and age-gender stratification. A discovery set of 352,228 genotyped plus 1.8 million imputed single-nucleotide polymorphisms were analyzed for 2,886 hypertensive cases and 3,440 healthy controls obtained from two community-based cohorts in Korea, and selected gene variants were replicated in the Health Examinee cohort (665 cases and 1,285 controls). Genome-wide association analyses were conducted in 12 groups stratified by age and gender after adjusting for potential covariates under three genetic models. Age, rural area residence, body mass index, family history of hypertension, male gender, current alcohol drinking status, and current smoking status were significantly associated with hypertension (P = 4 × 10(-151) to 0.011). Five gene variants, rs11066280 (C12orf51), rs12229654 and rs3782889 (MYL2), rs2072134 (OAS3), rs2093395 (TREML2), and rs17249754 (ATP2B1), were found to be associated with hypertension mostly in men (P = 4.76 × 10(-14) to 4.46 × 10(-7) in the joint analysis); three SNPs (rs11066280, rs12229654, and rs3782889) remained significant after Bonferroni correction in an independent population. Three gene variants, rs12229654, rs17249754, and rs11066280, were significantly associated with metabolic disorders such as hyperlipidemia and diabetes (P = 0.00071 to 0.0097, respectively). Careful consideration of the potential confounding effects in future genome-wide association studies is necessary to uncover the genetic underpinnings of complex diseases.

Changes in kidney function and the progression of chronic kidney disease (CKD) are associated with the risk of cardiovascular disease (CVD) and influenced by genetic factors. However, the association between genetic variants and kidney function in patients treated with antihypertensive drugs remains uncertain. This study aimed to examine the association between 30 variants locating at the 22 genes and the risk of kidney function evaluated by the estimated glomerular filtration rate (eGFR) in 1911 patients with hypertension from a Chinese community-based longitudinal cohort (including 1220 participants with CKD and 691 without CKD at baseline). By using multivariate linear regression analysis after adjustment for age, sex, traditional cardiovascular risk factors, and the use of antihypertensive drugs, as well as after correction for multiple comparison, patients with rs10767873T allele of the metallophosphoesterase domain containing 2 (MPPED2) gene were associated with higher level of eGFR (β = 0.041, p = 0.01) and lower levels of serum creatinine (β = -0.068, p = 0.001) and serum uric acid (β = -0.047, p = 0.02). But variant rs10767873 was not found to be associated with the risk of CKD, regardless of the types of antihypertensive drugs used. During a median 2.25-year follow-up, 152 CVD events were documented. Interestingly, patients with the rs10767873TT genotype had an increased risk of CVD events (hazard ratio, 1.74, 95% confidence interval, 1.11 to 2.73; p = 0.02) compared with patients carrying the wild-type genotype of rs10767873CC. In conclusion, our findings suggest variant rs10767873 of the MPPED2 gene is associated with kidney function and risk of CVD in Chinese hypertensive patients., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: High dietary salt confers a risk of elevating blood pressure (BP) and the development of hypertension. BP to salt intake may be determined in part by individual genetic predisposition. Identifying these genetic underpinnings will enhance our understanding of the biological mechanisms of BP regulation. This study aims to assess the genetic association with salt sensitivity of BP (SSBP) within two well-phenotyped multinational cohorts., Methods: A total of 720 white participants from the HyperPATH consortium program were selected and genotyped using a multiethnic genotyping array. Individuals consumed two study diets containing high (>200 mEq/day) and low (<10 mEq/day) sodium content, after which SSBP, aldosterone, and plasma renin activity (PRA) were assessed in a controlled inpatient research setting., Results: A top signal (rs10887801; beta = 4.57, P  = 5.03E - 07) at the renalase gene ( RNLS ) region was significantly associated with SSBP. We also identified seven single nucleotide variants with linkage disequilibrium to the top signal at this region that comprised a significant haplotype (TCTTAGTT, P  = 0.00081). Homozygous carriers of the T-risk allele of the key single nucleotide variant had higher SSBP ( P  ≤ 0.00001) and lower PRA ( P  = 0.0076) compared with the nonrisk allele., Conclusion: We identified significant associations between genetic variants of the RNLS gene and BP responses to dietary salt intervention and PRA that suggest susceptibility to volume-driven hypertension. These findings may contribute to a better understanding of the genetic mechanisms underlying BP regulation, support the role of RNLS in the pathogenesis of SSBP, and identify individuals who may be at risk from excess dietary salt intake., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage 1) followed by replication study of up to 28,783 participants (stage 2). For novel loci, statistical significance was determined by a P<5.0×10(-8) in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10(-3). No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 (P=7.5×10(-15)), rs2681492 at ATP2B1 (P=3.4×10(-7)), rs11191593 at NT5C2 (1.1×10(-6)), rs3824755 at CYP17A1 (P=1.2×10(-6)), and rs13149993 at FGF5 (P=2.4×10(-4)). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10(-5)) and rs11191593 at NT5C2 (P=1.1×10(-3)), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10(-3)) and rs2681492 at ATP2B1 (P=9.0×10(-3)). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.

In this study, we determined the association of 1180 non-synonymous single-nucleotide polymorphisms (SNPs) with systolic blood pressure (SBP) and hypertensive status. A total of 8842 subjects were taken from two community-based cohorts--Ansung (n=4183) and Ansan (n=4659), South Korea--which had been established for genome-wide association studies (GWAS). Five SNPs (rs16835244, rs2286672, rs6265, rs17237198 and rs7312017) were significantly associated (P-values: 0.003-0.0001, not corrected for genome-wide significance) with SBP in both cohorts. Of these SNPs, rs16835244 and rs2286672 correlated with risk for hypertension. The rs16835244 SNP replaces Ala288 in arginine decarboxylase (ADC) with serine, and rs2286672 replaces Arg172 in phospholipase D2 (PLD2) with cysteine. A comparison of peptide sequences between vertebrate homologues revealed that the SNPs identified occur at conserved amino-acid residues. In silico analysis of the protein structure showed that the substitution of a polar residue, serine, for a non-polar alanine at amino-acid residue 288 affects a conformational change in ADC, and that Arg172 in PLD2 resides in the PX domain, which is important for membrane trafficking. These results provide insights into the function of these non-synonymous SNPs in the development of hypertension. The study investigating non-synonymous SNPs from GWAS not only by statistical association analysis but also by biological relevance through the protein structure might be a good approach for identifying genetic risk factors for hypertension, in addition to discovering causative variations.

Essential hypertension causes high rates of morbidity and mortality, primarily due to its complications, and its development is regulated by genetic risk and environmental factors. However, until recent genomewide association studies (GWASs) were reported, the genetic factors were unknown. Two GWASs on systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypertension in Caucasians-Global Blood Pressure Genetics (Global BPgen) and Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE)-reported 51 single-nucleotide polymorphisms (SNPs) in 12 loci at P<4 x 10(-7). Because the prevalence, age of onset and severity of complications of hypertension vary between ethnic groups, we wanted to investigate these results in other ethnic groups. We examined the association of 27 of the 51 SNPs in 8512 unrelated individuals from Korean Association REsource (KARE), a GWAS that was based on epidemiological cohorts in Korea. Four loci-ATP2B1 (ATPase, Ca(++) transporting, plasma membrane 1), CSK (c-src tyrosine kinase), CYP17A1 (cytochrome P450 17A1) and PLEKHA7 (pleckstrin homology domain-containing family A member 7)-were associated with blood pressure and hypertension in the Korean population.

Blood pressure, one of the important vital signs, is affected by multiple genetic and environmental factors. Recently, several genome-wide association (GWA) studies have successfully identified genetic factors that influence blood pressure and hypertension risk. In this study, we report results of the Korean Association REsource (KARE, 8842 subjects) GWA study on blood pressure and hypertension risk. In all, 10 single-nucleotide polymorphisms (SNPs) that showed significant association with hypertension were further analysed for replication associations in the Health2 project (7861 subjects). Among these 10 SNPs, 3 were replicated in the Health2 cohort for an association with systolic or diastolic blood pressure. The most significant SNP (rs17249754 located in ATPase, Ca(++) transporting, plasma membrane 1 (ATP2B1)) has been previously reported, and the other two SNPs are rs1378942 in the c-src tyrosine kinase (CSK) gene and rs12945290 in the arylsulphatase G (ARSG) gene. An additional hypertension case-control study confirmed that rs17249754 (in ATP2B1) increases hypertension risk in both the KARE and Health2 (meta-analysis, P-value=4.25 x 10(-9)) cohorts. One more SNP, rs995322, located in the CUB and Sushi multiple domains 1 (CSMD1), is also associated with increased risk of hypertension (meta-analysis, P-value=1.00 x 10(-4)). Despite the difficulty of obtaining replication results for a complex trait genetic association between blood pressure and hypertension, we were able to identify consistent genetic factors in both the Korean cohorts in ATP2B1, CSK, ARSG and CSMD1 genes.

Hypertension is the definitive risk factor for cardiovascular disease. Primary aldosteronism (PA), a typical form of secondary hypertension, is responsible for treatment-resistant hypertension and carries an even higher risk of causing cardiovascular complications than essential hypertension. Several genes involved in the pathogenesis of hypertension have been identified recently using genome-wide association studies (GWASs). Among these, castor zinc finger 1(CASZ1) is considered to be involved in the pathophysiology of hypertension via modulation of aldosterone action. In 2021, using a biochemical approach with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we identified CASZ1b, an isoform of CASZ1, as a novel mineralocorticoid receptor (MR) coregulator. Our further analysis revealed that CASZ1b is coexpressed with MR in MR targets such as kidney tubule cells, and that a decrease in CASZ1 protein levels promotes aldosterone-dependent transcriptional activity of MR. Further, a recent study of GWAS on PA identified CASZ1 to be a PA-related gene and demonstrated that overexpression of CASZ1 suppresses aldosterone biosynthesis in adrenal cells. These results suggest CASZ1 plays a pivotal role in the pathophysiology of hypertension and PA via dual mechanisms: aldosterone biosynthesis and transcriptional activity of MR., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Mineralocorticoid receptor (MR) and its ligand aldosterone play a central role in controlling blood pressure by promoting sodium reabsorption in the kidney. Coregulators are recruited to regulate the activation of steroid hormone receptors. In our previous study, we identified several new candidates for MR coregulators through liquid chromatography-tandem mass spectrometry analysis using a biochemical approach. Lysine-specific demethylase 1 (LSD1) was identified as a candidate. The relationship between LSD1 and salt-sensitive hypertension has been reported; however, the role of MR in this condition is largely unknown. Here, we investigated the functions of LSD1 as a coregulator of MR. First, a coimmunoprecipitation assay using HEK293F cells showed specific interactions between MR and LSD1. A chromatin immunoprecipitation study demonstrated LSD1 recruitment to the gene promoter of epithelial Na + channel (ENaC), a target gene of MR. Reduced LSD1 expression by treatment with shRNA potentiated the hormonal activation of ENaC and serum/glucocorticoid-regulated kinase 1, another target gene of MR, indicating that LSD1 is a corepressor of MR. In an animal study, mice with kidney-specific LSD1 knockout (LSD1 flox/flox KSP-Cre mice) developed hypertension after a high-salt diet without elevation of aldosterone levels, which was counteracted by cotreatment with spironolactone, an MR antagonist. In conclusion, our in vitro and in vivo studies demonstrated that LSD1 is a newly identified corepressor of MR., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

A genetic influence on blood pressure was demonstrated more than 100 years ago and a simple Mendelian inheritance was initially presumed. Platt and Pickering conducted a lively debate on this topic. Platt favored the idea that a single gene or only a few genes were responsible for high blood pressure. Pickering presented research results, which supported the assumption that many genes exerted an influence on blood pressure. This was all in a period when it was not even known what genes were. Genome-wide association studies (GWAS) according to the Pickering model have identified > 500 blood pressure relevant gene loci, which are distributed over the whole genome. Each individual gene exerts only a small effect on blood pressure. The dark horses of hypertension research are the secondary causes. In pheochromocytoma, primary aldosteronism, Cushing's syndrome and even fibromuscular dysplasia (renovascular hypertension) the results indicate that a genetic cause regularly underlies secondary hypertension. This would therefore also partially confirm Platt's theory. In the meantime, a multitude of forms of hypertension have been described with a genetic inheritance according to Mendel. Each of these genetic variants exerts a considerable influence on blood pressure. A multitude of novel physiological mechanisms were explained by this. These findings will become therapeutically important. Therefore, it is incumbent upon clinicians to be optimally informed about these research results.

Background: Genomic variants of the disease are often discovered nowadays through population-based genome-wide association studies (GWAS). Identifying genomic variations potentially underlying a phenotype, such as hypertension, in an individual is important for designing personalized treatment; however, population-level models, such as GWAS, may not capture all the important, individualized factors well. In addition, GWAS typically requires a large sample size to detect the association of low-frequency genomic variants with sufficient power. Here, we report an individualized Bayesian inference (IBI) algorithm for estimating the genomic variants that influence complex traits, such as hypertension, at the level of an individual (e.g., a patient). By modeling at the level of the individual, IBI seeks to find genomic variants observed in the individual’s genome that provide a strong explanation of the phenotype observed in this individual. Results: We applied the IBI algorithm to the data from the Framingham Heart Study to explore the genomic influences of hypertension. Among the top-ranking variants identified by IBI and GWAS, there is a significant number of shared variants (intersection); the unique variants identified only by IBI tend to have relatively lower minor allele frequency than those identified by GWAS. In addition, IBI discovered more individualized and diverse variants that explain hypertension patients better than GWAS. Furthermore, IBI found several well-known low-frequency variants as well as genes related to blood pressure that GWAS missed in the same cohort. Finally, IBI identified top-ranked variants that predicted hypertension better than GWAS, according to the area under the ROC curve. Conclusions: The results support IBI as a promising approach for complementing GWAS, especially in detecting low-frequency genomic variants as well as learning personalized genomic variants of clinical traits and disease, such as the complex trait of hypertension, to help advance precision medicine. [ABSTRACT FROM AUTHOR]

Objectives: This study assessed the CVD risk factors among Filipino women (FW) in Korea and compared them with FW in the Philippines and women in Korea (KW). Methods: A cohort of 504 women from the Filipino Women's Health and Diet Study (FiLWHEL) aged 20–57 years old were age-matched (1:1 ratio) with women from the 2013 National Nutrition Survey in the Philippines and the 2013–2015 Korean National Health and Nutrition Examination Survey. Anthropometric data, blood pressure (BP), lipid and glucose levels were compared across the four populations by calculating the odds ratio (OR)s and 95% confidence interval (CI)s using conditional logistic regression models. Results: Compared to KW, FW in Korea and FW in the Philippines were more than 2 and 3 times higher odds of having obesity for BMI ≥ 30 kg/m2 and waist circumference ≥ 88 cm, respectively. However, FW in Korea had the highest odds (OR 5.51, 95% CI 3.18–9.56) of having hypertension compared to KW. FW in the Philippines had the highest odds of having dyslipidemia (compared to KW, total cholesterol ≥ 200 mg/dL: OR 8.83, 95% CI 5.30–14.71; LDL-C ≥ 130 mg/dL: OR 3.25, 95% CI 2.13–4.98; and triglyceride ≥ 150 mg/dL: OR 2.59, 95% CI 1.59–4.22), but FW in Korea and KW had similar prevalence of dyslipidemia. Conclusions: FW in Korea had higher prevalence of obesity and hypertension, with similar prevalence of dyslipidemia compared to KW in this sample. FW in the Philippines had higher prevalence of dyslipidemia compared to FW in Korea. Further prospective studies are warranted to examine the CVD risk factors among continental and native-born Filipino women. [ABSTRACT FROM AUTHOR]

Objective: To identify risk factors for impaired glucose regulation (IGR) and assess their impact on community residents, this study used a questionnaire to conduct cross-sectional surveys and analysis. Methods: Overall, 774 residents of an urban community in northern China (Jian city) participated in this study. Trained investigators conducted surveys using questionnaires. Based on their medical history, respondents were divided into three glucose status groups as follows: normal (NGT), IGR, and diabetes mellitus (DM). Statistical analysis of survey data was performed using SPSS v. 22.0. Results: Age, hypertension, family history of diabetes (FHD), dyslipidemia, obesity, and cardiovascular and cerebral disease (CVD) were positively correlated with IGR in men and women. IGR was negatively correlated with a sedentary lifestyle in men and positively correlated with being overweight in women. The number of type 2 diabetes mellitus (T2D) risk factors per subject was positively correlated with age in the NGT group. Glucose status deteriorated with increasing age and the number of risk factors. FHD was the strongest risk factor in both men and women. Conclusions: Prevention of IGR includes weight control, physical activity, and prevention of hypertension and dyslipidemia, especially in subjects with FHD. [ABSTRACT FROM AUTHOR]

Elevated serum uric acid (UA) level has been shown to be influenced by multiple genetic variants, but it remains uncertain how UA‐associated variants differ in their influence on hyperuricemia risk in people taking antihypertensive drugs. We examined a total of 43 UA‐related variants at 29 genes in 1840 patients with hypertension from a community‐based longitudinal cohort during a median 2.25‐year follow‐up (including 1031 participants with normal UA, 440 prevalent hyperuricemia at baseline, and 369 new‐onset hyperuricemia). Compared with the wild‐type genotypes, patients carrying the SLC2A9 rs3775948G allele or the rs13129697G allele had decreased risk of hyperuricemia, while patients carrying the SLC2A9 rs11722228T allele had increased risk of hyperuricemia, after adjustment for cardiovascular risk factors and correction for multiple comparisons; moreover, these associations were modified by the use of diuretics, β‐blockers, or angiotensin converting enzyme inhibitors. The rs10821905A allele of A1CF gene was associated with increased risk of hyperuricemia, and this risk was enhanced by diuretics use. The studied variants were not observed to confer risk for incident cardiovascular events during the follow‐up. In conclusion, the genes SLC2A9 and A1CF may serve as potential genetic markers for hyperuricemia risk in relation to antihypertensive drugs therapy in Chinese hypertensive patients. [ABSTRACT FROM AUTHOR]

Introduction: Hypertension is one of the most important risk factors for cardiovascular disease, and its control rates remain low worldwide. The most effective strategy is that patients with hypertension should be diagnosed and treated early. Preliminary studies showed that the Bushen Jiangya granule (BSJY) could suppress ventricular hypertrophy and inflammatory responses, lower blood pressure, and protect the target organs of hypertension. We designed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of BSJY in patients with low-to-medium risk hypertension.Methods and Analysis: This trial is a one-center, randomized, double-blind, placebo-controlled study. A total of 260 participants will be randomized in a 1:1 ratio to an experimental group (BSJY plus amlodipine) and a control group (placebo plus amlodipine). The trial cycle will last 8 weeks. The primary outcome is the change in 24-h average systolic and diastolic blood pressure. The secondary outcomes include heart rate variability, pharmacogenomic evaluation, improvement in TCM syndrome, and serum pro-inflammatory/anti-inflammatory cytokines between the two groups. The safety of medication will also be evaluated. All the data will be recorded in electronic case report forms and analyzed by SPSS V.22.0.Ethics and Dissemination: This study has been approved by the Research Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences in Beijing, China (No. 2019-186-KY-01). The participants are volunteers, understand the process of this trial, and sign an informed consent. The results of this study will be disseminated to the public through peer-reviewed journals and academic conferences.Discussion: We hypothesize that patients with low-to-medium-risk hypertension will benefit from BSJY. If successful, this study will provide evidence-based recommendations for clinicians.Trial Registration: Chinese Clinical Trial Registry ChiMCTR1900002876. Registered in November 2019. [ABSTRACT FROM AUTHOR]

Background: Association between blood pressure (BP) and kidney function among the middle and old aged general population without hypertension remains unclear.Methods: Participants aged ≥ 45 years, with complete data in 2011 and 2015 interviews of the China Health and Retirement Longitudinal Study(CHARLS), and without pre-existing hypertension were included. Systolic BP (SBP) was categorized as low (< 120 mmHg), medium (120-129 mmHg), and high (120-139 mmHg). Diastolic BP (DBP) was categorized as low (< 60 mmHg), medium (60-74 mmHg), and high (75-89 mmHg). Pulse pressure (PP) was categorized as normal (< 60 mmHg) and high (≥ 60 mmHg). The outcome was defined as rapid decline of estimated glomerular filtration rate(eGFR, decline ≥ 4 ml/min/1.73 m2/year). BP combination was designed according to the category of SBP and PP. The association between BP components, types of BP combination, and the risk of rapid decline of eGFR was analyzed using multivariate logistic regression models, respectively. Age-stratified analyses were conducted.Results: Of 4,534 participants included, 695(15.3%) individuals were recognized as having rapid decline of eGFR. High PP[odds ratio(OR) = 1.34, 95%confidence interval(CI) 1.02-1.75], low SBP (OR = 1.28, 95%CI 1.03-1.59), and high SBP (OR = 1.32, 95% CI 1.02-1.71) were significantly associated with the risk of eGFR decline. Low SBP were associated with 65% increment of the risk of eGFR decline among participants aged < 55 years. The combination of high SBP and high PP (OR = 1.79, 95% CI 1.27-2.54) and the combination of low SBP and high PP (OR = 3.07, 95% CI 1.24-7.58) were associated with the increased risk of eGFR decline among the middle and old aged general population.Conclusion: Single and combination of high PP and high SBP could be the risk indicators of eGFR decline among the middle and old aged general population. [ABSTRACT FROM AUTHOR]

Objective: Hypertension is more prevalent in African Americans (AA) than other ethnic groups. Genome-wide association studies (GWAS) have identified loci associated with hypertension and other cardio-metabolic traits like type 2 diabetes, coronary artery disease, and body mass index (BMI), however the AA population is underrepresented in these studies. In this study, we examined a large AA cohort for the generalizability of 14 Metabochip array SNPs with previously reported European hypertension associations. Methods: To evaluate associations, we analyzed genotype data of 14 SNPs for their associations with a diagnosis of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in a case-control study of an AA population (N = 9,534). We also performed an age-stratified analysis (>30, 30≥59 and ≥60 years) following the hypertension definition described by the 8th Joint National Committee (JNC). Associations were adjusted for BMI, age, age2, sex, clinical confounders, and genetic ancestry using multivariable regression models to estimate odds ratios (ORs) and beta-coefficients. Analyses stratified by sex were also conducted. Meta-analyses (including both BioVU and COGENT-BP cohorts) were performed using a random-effects model. Results: We found rs880315 to be associated with systolic hypertension (SBP≥140 mmHg) in the entire cohort (OR = 1.14, p = 0.003) and within women only (OR = 1.16, p = 0.012). Variant rs17080093 associated with lower SBP and DBP (β = -2.99, p = 0.0352 and - β = 1.69, p = 0.0184) among younger individuals, particularly in younger women (β = -3.92, p = 0.0025 and β = -1.87, p = 0.0241 for SBP and DBP respectively). SNP rs1530440 associated with higher SBP and DBP measurements (younger individuals β = 4.1, p = 0.039 and β = 2.5, p = 0.043 for SBP and DBP; (younger women β = 4.5, p = 0.025 and β = 2.9, p = 0.028 for SBP and DBP), and hypertension risk in older women (OR = 1.4, p = 0.050). rs16948048 increases hypertension risk in younger individuals (OR = 1.31, p = 0.011). Among mid-age women rs880315 associated with higher risk of hypertension (OR = 1.20, p = 0.027). rs1361831 associated with DBP (β = -1.96, p = 0.02) among individuals older than 60 years. rs3096277 increases hypertension risk among older individuals (OR = 1.26 p = 0.0015), however, this variant also reduces SBP among younger women (β = -2.63, p = 0.0102). Conclusion: These findings suggest that European-descent and AA populations share genetic loci that contribute to blood pressure traits and hypertension. However, the OR and beta-coefficient estimates differ, and some are age-dependent. Additional genetic studies of hypertension in AA are warranted to identify new loci associated with hypertension and blood pressure traits in this population. [ABSTRACT FROM AUTHOR]

Background High blood pressure is common and comorbid with type 2 diabetes (T2D). Almost 50% of patients with T2D have high blood pressure. Patients with both conditions of hypertension (HTN) and T2D are at risk for cardiovascular diseases and mortality. The study aim was to investigate genetic risk factors for HTN in T2D patients. Methods This study included 999 T2D (cohort 1) patients for the first genome scan stage and 922 T2D (cohort 2) patients for the replication stage. Here, we investigated the genetic susceptibility and cumulative weighted genetic risk score for HTN in T2D patients of Han Chinese descent in Taiwan. Results Thirty novel genetic single nucleotide polymorphisms (SNPs) were associated with HTN in T2D after adjusting for age and body mass index (P value <1 × 10−4). Eight blood pressure-related and/or HTN-related genetic SNPs were associated with HTN in T2D after adjusting for age and body mass index (P value <0.05). Linkage disequilibrium and cumulative weighted genetic risk score analyses showed that 14 of the 38 SNPs were associated with risk of HTN in a dose-dependent manner in T2D (Cochran–Armitage trend test: P value <0.0001). The 14-SNP cumulative weighted genetic risk score was also associated with increased regression tendency of systolic blood pressure in T2D (SBP = 122.05 + 0.8 × weighted genetic risk score; P value = 0.0001). Conclusions A cumulative weighted genetic risk score composed of 14 SNPs is important for HTN, increased tendency of systolic blood pressure, and may contribute to HTN risk in T2D in Taiwan. [ABSTRACT FROM AUTHOR]

Background: Hypertension (HTN) is one of the major cardiovascular risk factors, which contributes to increasing target organ damages and cardiovascular morbidity and mortality worldwide. Isolated systolic HTN (ISH) and isolated diastolic HTN (IDH) are two important subtypes of HTN. Previous researches have demonstrated the alteration of fecal bacteria in HTN, but not down to these two sub-types. In order to identify whether the composition of bacterial taxa and functional modules shift in ISH and IDH, we performed a metagenomic sequencing analysis of fecal samples from 15 controls, 14 ISH, and 11 IDH. Results: Compared with control and ISH, IDH patients showed decreased gene number, bacterial richness, and evenness, although the bacterial alterations did not reach statistical significance in the Shannon index. Also, at the genus level, the β-diversity for intestinal flora in IDH was distinguishable from those with ISH. Furthermore, the taxonomic composition of ISH or IDH was different from that of healthy control at genus and species levels. Patients with IDH or ISH were confirmed to be enriched with Rothia mucilaginosa, along with reduced Clostridium sp. ASBs410. Lastly, the altered KEGG modules were significantly decreased in IDH compared with the control group, such as sodium transport system; while for ISH, functions relevant to biotin biosynthesis were decreased. Conclusions: Overall, our results showed the disordered fecal bacteria profiles in subjects with ISH and especially IDH, emphasizing the significance of early intervention for IDH. [ABSTRACT FROM AUTHOR]

Genetic studies of DNA have been unable to explain a significant portion of the variance of the estimated heritability of blood pressure (BP). Epigenetic mechanisms, particularly DNA methylation, have helped explain additional biological processes linked to BP phenotypes and diseases. Candidate gene methylation studies and genome-wide methylation studies of BP have highlighted impactful cytosine-phosphate-guanine (CpG) markers across different ethnicities. Furthermore, many of these BP-related CpG sites are also linked to metabolism-related phenotypes. Integrating epigenome-wide association study data with other layers of molecular data such as genotype data (from single nucleotide polymorphism arrays or sequencing), other epigenetic data, and/or transcriptome data can provide additional information about the significance and complexity of these relationships. Recent data suggest that epigenetic changes can be consequences rather than causes of BP variation. Finally, these data can give insight into downstream effects of long-standing high BP (due to target organ damage (TOD)). The current review provides a literature overview of epigenetic modifications in BP and TOD. Recent studies strongly support the importance of epigenetic modifications, such as DNA methylation, in BP and TOD for relevant biological insights, reliable biomarkers, and possible future therapeutics. [ABSTRACT FROM AUTHOR]

BACKGROUND Maternal hypertension has been associated with congenital heart defect occurrence in several studies. We assessed whether maternal genotypes associated with this condition were also associated with congenital heart defect occurrence. METHODS We used data from the National Birth Defects Prevention Study to identify non-Hispanic white (NHW) and Hispanic women with (cases) and without (controls) a pregnancy in which a select simple, isolated heart defect was present between 1999 and 2011. We genotyped 29 hypertension-related single nucleotide polymorphisms (SNPs). We conducted logistic regression analyses separately by race/ethnicity to assess the relationship between the presence of any congenital heart defect and each SNP and an overall blood pressure genetic risk score (GRS). All analyses were then repeated to assess 4 separate congenital heart defect subtypes. RESULTS Four hypertension-related variants were associated with congenital heart defects among NHW women (N = 1,568 with affected pregnancies). For example, 1 intronic variant in ARHGAP2 , rs633185, was associated with conotruncal defects (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1–1.6). Additionally, 2 variants were associated with congenital heart defects among Hispanic women (N = 489 with affected pregnancies). The GRS had a significant association with septal defects (OR: 2.1, 95% CI: 1.2–3.5) among NHW women. CONCLUSIONS We replicated a previously reported association between rs633185 and conotruncal defects. Although additional hypertension-related SNPs were also associated with congenital heart defects, more work is needed to better understand the relationship between genetic risk for maternal hypertension and congenital heart defects occurrence. [ABSTRACT FROM AUTHOR]

Hypertension is a common condition that is often seen in patients with diabetes. Both diseases increase the risk of morbidity and mortality from CV events and kidney disease progression. Factors that influence blood pressure (BP) control in diabetes include the persons' genetic background for hypertension and kidney disease, level of obesity and insulin resistance, the magnitude of preexisting kidney disease, and lifestyle factors, such as level of sodium and potassium intake, sleep quality and exercise effort all of which can affect levels of sympathetic nerve activity and contribute to increased BP variability. Lifestyle intervention is a key component to the effective management of diabetes and hypertension and can markedly reduce event rates of both heart and kidney outcomes. The approach to pharmacologic treatment of BP in diabetes is crucial since certain classes of agents for both BP and diabetes confer significant benefits to reduce cardiorenal outcomes. [ABSTRACT FROM AUTHOR]

Key points: The roles of the Na+/HCO3– cotransporters NBCn1 and NBCn2 as well as their activators IRBIT and L‐IRBIT in the regulation of the mTAL transport of NH4+, HCO3–, and NaCl are investigated.Dietary challenges of NH4Cl, NaHCO3 or NaCl all increase the abundance of NBCn1 and NBCn2 in the outer medulla.The three challenges generally produce parallel increases in the abundance of IRBIT and L‐IRBIT in the outer medulla.Both IRBIT and L‐IRBIT powerfully stimulate the activities of the mTAL isoforms of NBCn1 and NBCn2 as expressed in Xenopus oocytes.Our findings support the hypothesis that NBCn1, NBCn2, IRBIT and L‐IRBIT appropriately promote NH4+ shunting but oppose HCO3– and NaCl reabsorption in the mTAL, and thus are at the nexus of the regulation pathways for multiple renal transport processes. The medullary thick ascending limb (mTAL) plays a key role in urinary acid and NaCl excretion. NBCn1 and NBCn2 are present in the basolateral mTAL, where NBCn1 promotes NH4+ shunting. IRBIT and L‐IRBIT (the IRBITs) are two powerful activators of certain acid‐base transporters. Here we use western blotting and immunofluorescence to examine the effects of multiple acid‐base and electrolyte disturbances on expression of NBCn1, NBCn2 and the IRBITs in rat kidney. We also use electrophysiology to examine the functional effects of IRBITs on NBCn1 and NBCn2 in Xenopus oocytes. NH4Cl‐induced metabolic acidosis (MAc) substantially increases protein expression of NBCn1 and NBCn2 in the outer medulla (OM) of rat kidney. Surprisingly, NaHCO3‐induced metabolic alkalosis (MAlk) and high‐salt diet (HSD) also increase expression of NBCn1 and NBCn2 (effect of NaHCO3 > HSD). Moreover, all three challenges generally increase OM expression of the IRBITs. In Xenopus oocytes, the IRBITs substantially increase the activities of NBCn1 and NBCn2. We propose that upregulation of basolateral NBCn1 and NBCn2 plus the IRBITs in the mTAL: (1) promotes NH4+ shunting by increasing basolateral HCO3– uptake to neutralize apical NH4+ uptake during MAc; (2) inhibits HCO3– reabsorption during MAlk by opposing HCO3− efflux via the basolateral anion exchanger AE2; and (3) inhibits NaCl reabsorption by mediating (with AE2) net NaCl backflux into the mTAL cell during HSD. Thus, NBCn1, NBCn2 and the IRBITs are at the nexus of the regulatory pathways for multiple renal transport processes. Key points: The roles of the Na+/HCO3– cotransporters NBCn1 and NBCn2 as well as their activators IRBIT and L‐IRBIT in the regulation of the mTAL transport of NH4+, HCO3–, and NaCl are investigated.Dietary challenges of NH4Cl, NaHCO3 or NaCl all increase the abundance of NBCn1 and NBCn2 in the outer medulla.The three challenges generally produce parallel increases in the abundance of IRBIT and L‐IRBIT in the outer medulla.Both IRBIT and L‐IRBIT powerfully stimulate the activities of the mTAL isoforms of NBCn1 and NBCn2 as expressed in Xenopus oocytes.Our findings support the hypothesis that NBCn1, NBCn2, IRBIT and L‐IRBIT appropriately promote NH4+ shunting but oppose HCO3– and NaCl reabsorption in the mTAL, and thus are at the nexus of the regulation pathways for multiple renal transport processes. [ABSTRACT FROM AUTHOR]

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = − 0.76, 95% CI − 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = − 0.06, 95% CI − 0.93 to 0.87 mmHg), or pulse pressure (β = − 0.65, 95% CI − 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses. [ABSTRACT FROM AUTHOR]

Purpose: Cortisol secretion, peripheral activation, and sensitivity seem to be associated with hypertension (HY), type 2 diabetes (T2D), and fragility fractures (FX) even in eucortisolemic subjects. The aim of the present study was to determine the cutoff(s) of the parameters of cortisol secretion and peripheral activation for predicting the presence of HY, T2D, and FX (comorbidities). Methods: In 206 postmenopausal females (157 with ≥1 comorbidities and 49 without any), we assessed the ratio between 24-h urinary free cortisol and cortisone (R-UFF/UFE, cortisol activation index), cortisol after 1 mg-overnight-dexamethasone (F-1mgDST, cortisol secretion index), and the GC receptor N363S single-nucleotide polymorphism (N363S-SNP, cortisol sensitivity index). Results: The cutoffs for F-1mgDST and R-UFF/UFE were set at 0.9 μg/dL (area under the curve, AUC 0.634 ± 0.43, p = 0.005) and 0.17 (AUC 0.624 ± 0.5, p = 0.017), respectively, predicted the presence of ≥1 comorbidities. The presence of F-1mgDST > 0.9 μg/dL plus R-UFF/UFE > 0.17 showed 82.1% specificity for predicting the presence of ≥1 comorbidities, while the simultaneous presence of F-1mgDST ≤ 0.9 μg/dL and R-UFF/UFE ≤ 0.17 showed 88% sensitivity for predicting the absence of comorbidities. The F-1mgDST > 0.9 μg/dL or R-UFF/UFE > 0.17 was associated with 2.8 and 2.1-fold increased risk of having ≥1 comorbidities, respectively. The F-1mgDST ≤ 0.9 μg/dL plus R-UFF/UFE ≤ 0.17 or F-1mgDST > 0.9 μg/dL plus R-UFF/UFE > 0.17 was associated with 2.8-fold reduced or 4.9-fold increased risk of having ≥1 comorbidities regardless of age, BMI, and N363S-SNP. Conclusions: F-1mgDST > 0.9 μg/dL and R-UFF/UFE > 0.17 may be used for predicting the presence of ≥1 among HY, T2D, and fragility FX. [ABSTRACT FROM AUTHOR]

Background: The ABCG2 rs2231142 single nucleotide polymorphism (SNP) is one of the most significant genetic variants associated with hyperuricemia (HUA) in Asian populations. However, the risk of ABCG2 rs2231142 variants for HUA could interact with other important HUA risk variants and cardiovascular factors. This study investigated the effects of the combined association among ABCG2 rs2231142 and multiple HUA genetic variants or cardiovascular risk factors on HUA risk and serum uric acid (sUA) levels in an elderly Chinese population. Methods: A total of 1206 participants over 65 years old were enrolled in this study. Physical and laboratory examinations were performed for all participants. The ABCG2 rs2231142, SLC2A9 rs3733591, and SLC22A12 rs893006 SNPs were assayed using a standardized protocol. Logistic regression analysis and liner regression were adjusted respectively to account for the association between ABCG2 rs2231142 and other genetic variants, as well as between cardiovascular risk factors and HUA risk and sUA levels. Results: The prevalence of HUA was 14.71% in the elderly community-dwelling population. The ABCG2 rs2231142 risk T allele was associated with HUA risk (odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.27–2.11; p = 1.65 × 10− 4) and with increased sUA levels (Beta = 0.16, p = 6.75 × 10− 9) in the whole study population. Linear regression analysis showed that the mean sUA level increased linearly with the number of risk alleles of the three candidate genetic variants (Beta = 0.18, p = 1.94 × 10− 12) The joint effect of the ABCG2 rs2231142 T allele and cardiovascular risk factors (obesity, hypertension and dyslipidemia) was also associated with increased HUA risk and sUA levels. Each copy of the risk T allele was significantly associated with enhanced HUA risk in patients with hypertriglyceridemia (OR = 2.52, 95% CI: 1.33–4.60; p = 0.003) compared to controls. Conclusion: Our findings reinforce the importance of the ABCG2 rs2231143 variant as a crucial genetic locus for HUA in Chinese populations and demonstrated the combined effects of multiple genetic risk variants and cardiovascular risk exposures on HUA risk and increased sUA level. [ABSTRACT FROM AUTHOR]

Objective: The pathogenesis for hypertension is complicated. Except environmental factors, genetic variations are a large part of reasons account for hypertension. With the rapid development of sequencing techniques, genome wide association study (GWAS) provide an effective method for understanding the complicated genetic backgroundof multifactorial diseases. More than 150 genes associated with essential hypertension were knew today, of which, ATP2B1 is most prominent. Whether in Europe or in East Asia, the association between essential hypertension and ATP2B1 is statistically significant in different people with different genetic background. Here we reviewed the relationship between genetic polymorphisms of ATP2B1 and essential hypertension. [ABSTRACT FROM AUTHOR]

No risk assessment tools for the efficacy of folic acid treatment for hyperhomocysteinaemia (HHcy) have been developed. We aimed to use two common genetic risk score (GRS) methods to construct prediction models for the efficacy of folic acid therapy on HHcy, and the best gene–environment prediction model was screened out. A prospective cohort study enrolling 638 HHcy patients was performed. We used a logistic regression model to estimate the associations of two GRS methods with the efficacy. Performances were compared using area under the receiver operating characteristic curve (AUC). The simple count genetic risk score (SC-GRS) and weighted genetic risk score (wGRS) were found to be independently associated with the efficacy of folic acid treatment for HHcy. Using the SC-GRS, per risk allele increased with a 1·46-fold increased failure risk (P < 0·001) after adjustment for traditional risk factors, including age, sex, BMI, smoking, alcohol consumption, history of diabetes, history of hypertension, history of hyperlipidaemia, history of stroke and history of CHD. When used the wGRS, the association was strengthened (OR = 2·08, P < 0·001). Addition of the SC-GRS and wGRS to the traditional risk model significantly improved the predictive ability by AUC (0·859). A precise gene–environment predictive model with good performance was developed for predicting the treatment failure rate of folic acid therapy for HHcy. [ABSTRACT FROM AUTHOR]

Periodontitis has been reported to relate to metabolic syndrome traits such as obesity, blood pressure, and so on. However, the relation between periodontitis and metabolic syndrome remains unclear. The present study aimed to confirm common genetic factors between periodontitis and metabolic traits using Candidate gene association study (CGAS) in the Korean population. Based on the analysis of CGAS, this study performed linear regression analyses to examine the single-nucleotide polymorphisms (SNPs) between periodontitis and metabolic syndrome traits. Among the analyzed SNPs, 2649 SNPs in five genes (TENM2, LDLRAD4, SLC9C2, MFSD1, and A2BP1) showed a statistical significance at p < 0.05. Interestingly, A2BP1 and TENM2 were related to obesity. Also, elevated levels of LDLRAD4, SLC9C2, and MFSD1 were observed in the patients with high blood pressure. Taken together, the present study suggests that some of the SNPs are related to periodontitis. Therefore, if any of TENM2, A2BP1, LDLRAD4, SLC9C2, and MFSD1 is detected in the patients with periodontitis, obesity and blood pressure have to be treated simultaneously. [ABSTRACT FROM AUTHOR]

Background: Plasma renin activity is involved in the regulation of body salt content and blood pressure. However, there is a paucity of data regarding the association between low or high plasma renin activity and the development of hypertension. Method: We investigated the relation of baseline plasma renin activity to increases in blood pressure and the incidence of hypertension after four years in 2,146 non-hypertensive individuals from a community-based Korean population (mean age, 50 years), 58% of whom were women. We defined an "increase in blood pressure" as an increment of systolic blood-pressure ≥ 10 mmHg or initiation of antihypertensive drugs and defined "hypertension" as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or the use of antihypertensive medications. Results: After 4 years, the increase in blood pressure had increased in 27.9% of the participants, and hypertension had developed in 17.9%. After adjustment, the lowest sex-specific tertile of plasma renin activity was an independent risk factor of an elevation in blood pressure (Adjusted Odds Ratio 1.37, 95% confidence interval 1.07–1.74, p = 0.011) and hypertension (Adjusted Odds Ratio 1.84, 95% confidence interval 1.36–2.50, p < 0.001) compared to the highest sex-specific tertile. The associations between the plasma renin activity and blood-pressure outcomes were evident in adults with especially high urine sodium excretion. Conclusion: Low plasma renin activity was associated with the development of hypertension in the middle-aged Asian population, especially in peoples with high sodium intake. [ABSTRACT FROM AUTHOR]

Background and aims: Genetic factors play an important role in the cervico-cerebral large-artery atherosclerotic stenosis (LAS), and ATP2B1 gene has been associated with the process of atherosclerosis disorders, such as coronary artery disease and arterial stiffness. But there is little information about the relationship between ATP2B1 gene and atherosclerosis in the intracranial arteries. We hereby investigated the association of common variants in ATP2B1 gene with LAS in asymptomatic Chinese hypertension patients. Methods: The stenosis of intracranial and extracranial arteries were evaluated in 899 subjects through computerized tomography angiography from the aortic arch to the skull base. A total of 11 ATP2B1 common variants were genotyped. Multivariate logistic regression was carried out in a dominant model with confounding factors adjusted. Results: rs17249754-A (OR = 0.43, p = 0.0002) and rs1401982-G (OR = 0.47, p = 0.0007) were associated with decreased susceptibility of concurrent extra and intracranial stenosis even after Bonferroni correction. These two minor alleles were also significantly associated with less stenotic arteries and moderate-to-severe stenosis. Conclusion: rs17249754 and rs1401982 were associated with asymptomatic LAS in stroke-free Chinese hypertension patients and might benefit early recognition of LAS patients in clinical practice. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) is a complex trait that is regulated by multiple physiological pathways and include but is not limited to extracellular fluid volume homeostasis, cardiac contractility, and vascular tone through renal, neural, or endocrine systems. Uncontrolled hypertension (HTN) has been associated with an increased mortality risk. Therefore, understanding the genetics that underpins and influence BP regulation will have a major impact on public health. Moreover, uncontrolled HTN has been linked to inter-individual variation in the drugs' response and this has been associated with an individual's genetics architecture. However, the identification of candidate genes that underpin the genetic basis of HTN remains a major challenge. To date, few variants associated with inter-individual BP regulation have been identified and replicated. Research in this field has accelerated over the past 5 years as a direct result of on-going genome-wide association studies (GWAS) and the progress in the identification of rare gene variants and mutations, epigenetic markers, and the regulatory pathways involved in the pathophysiology of BP. In this review we describe and enhance our current understanding of how genetic variants account for the observed variability in BP response in patients on first-line antihypertensive drugs, amlodipine and hydrochlorothiazide. [ABSTRACT FROM AUTHOR]

Background: Hypertension is dramatically increasing in Africa with evidence of increased severity and resistance to treatment. Although angiotensin converting enzyme gene polymorphism is associated with higher prevalence of hypertension, the evidence is inconclusive on its influence on the emerging pattern in Africa. This meta-analysis is conducted to pool the available evidence to inform future research and interventions. Methods: Articles published through May 2018 were systematically searched in PubMed, Scopus and EMBASE databases. Studies were assessed for inclusion by two independent researchers. Six models were used to assess the effect of angiotensin converting enzyme deletion-insertion gene polymorphism. Heterogeneity and publication bias were tested and sensitivity analysis was carried out. Odds ratio and 95% confidence intervals were measured for pooled effect. Both random effect and fixed effect models were used, whilst the frequency of DD, II and DI genotypes were computed and compared. Result: Patients with D allele were 1.49 times more likely to develop essential hypertension compared with patients who carry the I allele (OR:1.49; CI:1.07, 2.07). Similarly, patients who had homozygous co-dominance genotype DD (i.e., DD vs II) were at a 2.17 times higher risk of essential hypertension compared to the co-dominant genotype II (OR:2.17, CI:1.79, 3.18), dominant model (I.e., DD+ID vs II) (OR:1.48; CI:1.03, 2.12), and recessive model (OR:1.64; CI:1.03, 2.61). On subgroup analysis, participants from Sub-Saharan Africa were more genetically susceptible to hypertension compared to their North Africa counterparts. There was no publication bias found, but there was high to moderate heterogeneity. Conclusion: ACE I/D polymorphism is associated with essential hypertension in Africa in the allele contrast model, as well as the dominant, recessive and homozygous codominance model. On subgroup analysis, ACE I/D was associated with essential hypertension in patients from Sub-Saharan Africa but not in North Africa. A future large scale study, which includes different ethnic groups, is recommended. [ABSTRACT FROM AUTHOR]

The article offers the authors' insight regarding the association between single nucleotide polymorphisms (SNPs) and hypertension. Topics discussed include the genome-wide association studies (GWAS) which examine the incidence of SNPs, the recognition of autoimmunity and immunity as important elements in determining the patophysiology of hypertension, and the sympathetic nervous system (SNS) and central nervous system (CNS) stimulation.

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and genetargeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND Hypertension affects 33% of Americans while type 2 diabetes and Alzheimer's disease (AD) affect 10% of Americans, respectively. Ryanodine receptor 3 gene (RYR3) codes for the RYR which functions to release stored endoplasmic reticulum calcium ions (Ca2+) to increase intracellular Ca2+ concentration. Increasing studies demonstrate that altered levels of intracellular Ca2+ affect cardiac contraction, insulin secretion, and neurodegeneration. In this study, we investigated associations of the RYR3 genetic variants with hypertension, AD, and diabetes. METHODS Family data sets were used to explore association of RYR3 polymorphisms with risk and age at onset (AAO) of hypertension, diabetes, and AD. RESULTS Family-based association tests using generalized estimating equations (FBAT--GEE) showed several unique or shared disease-1 associated variants in the RYR3 gene. Three single nuclear polymorphisms (SNPs; rs2033610, rs2596164, and rs2278317) are significantly associated with risk for hypertension, diabetes, and AD. Two SNPs (rs4780174 and rs7498093) are significantly associated with AAO of the 3 diseases. CONCLUSIONS RYR3 variants are associated with hypertension, diabetes, and AD. Replication of these results of this gene in these 3 complex traits may help to better understand the genetic basis of calcium-signaling gene, RYR3 in association with risk and AAO of these diseases. [ABSTRACT FROM AUTHOR]

BACKGROUND Poor mental health status is more prevalent in women and may be related to poor hypertension outcomes and increased hospital inpatient visits. This study aims to find the association between mental health status and hypertension in women and the combined effect of mental health status and hypertension on hospital inpatient visits in women in the United States. METHODS The household component of 2014 Medical Expenditure Panel Surveys (MEPS) was analyzed (N = 9,137). Kessler (K6) scale for mental health status (poor, good/excellent), hypertension (yes, no), and hospital inpatient visits (yes, no) were examined. A combined effect variable for mental health status and hypertension was created. Multiple logistic regression analysis was conducted and adjusted odds ratios (AORs) with corresponding 95% confidence intervals (CIs) were calculated. RESULTS After adjusting for confounders, women who reported poor mental health had significantly higher odds of hypertension compared to women who reported good/excellent mental health (AOR = 1.39, 95% CI = 1.16, 1.68). Further, women who reported hypertension coupled with poor mental health had higher odds of having hospital inpatient visits compared to women who reported no hypertension coupled with good/excellent mental health in the adjusted analysis (AOR = 3.03, 95% CI = 1.96, 4.69). CONCLUSIONS There is a significant association between mental health status and hypertension in women. Further, poor mental health status coupled with hypertension leads to increase hospital inpatient visits for women. It is important that health professionals focus on utilizing available screening tools to assess mental health status of women for early detection and to manage the disorder. [ABSTRACT FROM AUTHOR]

Hypertension, or elevated blood pressure, constitutes a major public health burden that affects more than 1 billion people worldwide and contributes to ~9 million deaths annually. Hereditary factors are thought to contribute to up to 50% of interindividual blood pressure variability. Blood pressure in the general population approximately shows a normal distribution and is thought to be a polygenic trait. In rare cases, early-onset hypertension or hypotension are inherited as Mendelian traits. The identification of the underlying Mendelian genes and variants has contributed to our understanding of the physiology of blood pressure regulation, emphasizing renal salt handling and the renin angiotensin aldosterone system as players in the determination of blood pressure. Genome-wide association studies (GWAS) have revealed more than 100 variants that are associated with blood pressure, typically with small effect sizes, which cumulatively explain ~3.5% of blood pressure trait variability. Several GWAS associations point to a role of the vasculature in the pathogenesis of hypertension. Despite these advances, the majority of the genetic contributors to blood pressure regulation are currently unknown; whether large-scale exome or genome sequencing studies will unravel these factors remains to be determined. [ABSTRACT FROM AUTHOR]

Introduction Genetic variation may play explain some of the disparity in prevalence and control of hypertension across Sub-Saharan Africa. However, there have been very few studies to characterize genetic variation of blood pressure traits. Aim To determine whether a set of blood pressure-associated genetic loci can be replicated among samples East African samples. Methods Twenty-seven blood pressures ( BP)-related single nucleotide polymorphisms ( SNPs) were genotyped among 2881 samples from participants in the Medical Education Partnership Initiative for Cardiovascular Disease ( MEPI-CVD) survey. Associations with known BP variants were evaluated for systolic blood pressure ( SBP), diastolic blood pressure ( DBP) and pulse pressure ( PP) as continuous variables and for hypertension ( HTN) as a binary variable. Results Eleven SNPS were associated with at least 1 BP trait ( P < .05). Four SNPs; rs2004776, rs7726475, rs11837544 and rs2681492, whose nearest genes are AGT, NPR3/ SUB1, PLXNC1 and ATP2B1, respectively, were associated with SBP. Six SNPs, rs2004776, rs11977526, rs11191548, rs381815, rs2681492 and rs1327235, close to AGT, IGFBP3, CYP17A1, PLEKHA7, ATP2B1 and JAG, respectively, were associated with DBP while 2 SNPs located within AGT and IGFBP-3 genes associated with HTN. For PP, 4 variants rs1458038, rs11725861, rs7726475 and rs11953630 whose corresponding genes are FGF5, CHIC2, SUB1/ NPR3 and EBF1 reached significance ( P < .05). Eight SNPs were replicated in the same effect direction as the parent studies. Risk scores defined using published effect sizes were significantly associated with both SBP ( P = .0026) and DBP ( P = .0214). Conclusion The replication of multiple BP variants among East Africans suggests that these variants may have universal effects across ethnic populations. [ABSTRACT FROM AUTHOR]

Background: Several single nucleotide polymorphisms (SNPs) have been implicated in the predisposition to chronic kidney disease (CKD). Atherosclerotic disease is deeply involved in the incidence of CKD; however, whether SNPs related to arteriosclerosis are involved in CKD remains unclear. This study aimed to identify SNPs associated with CKD and to examine whether risk allele accumulation is associated with CKD. Methods: We conducted a cross-sectional study using data of 4814 male workers to examine the association between estimated glomerular filtration rate (eGFR) and 59 candidate polymorphisms (17 CKD, 42 atherosclerotic diseases). We defined the genetic risk score (GRS) as the total number of risk alleles that showed a significant association in this analysis and examined the relationship with CKD (eGFR < 60 ml/min/1.73m2). Multivariate logistic regression, discrimination by area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), and category-free net reclassification improvement (cNRI) were evaluated. Results: In total, 432 participants were categorized as having CKD. We found eight candidate SNPs with P value < 0.05 (CX3CR1 rs3732379, SHROOM3 rs17319721, MTP rs1800591, PIP5K1B rs4744712, APOA5 rs662799, BRAP rs3782886, SPATA5L1 rs2467853, and MCP1 rs1024611) in the multivariate linear regression adjusted for age, body mass index, systolic blood pressure, and fasting blood glucose. Among these eight SNPs, BRAP rs3782886 and SPATA5L1 rs2467853 were significantly associated with eGFR (false discovery rate < 0.05). GRS was significantly associated with CKD (odds ratio, 1.17; 95% confidence interval, 1.09–1.26). C-statisics improved from 0.775 to 0.780 but showed no statistical significance. However, adding GRS significantly improved IDI and cNRI (0.0057, P = 0.0028, and 0.212, P < 0.001, respectively). Conclusions: After adjustment for clinical factors, kidney function was associated with BRAP rs3782886 and SPATA5L1 rs2467853 and the GRS for CKD that we developed was associated CKD. [ABSTRACT FROM AUTHOR]

Hypertension is a well-established risk factor for adverse cardiovascular events, and older age is a risk factor for the development of hypertension. Genomewide association studies have linked ATP2B1, the gene for the plasma membrane calcium ATPase 1 ( PMCA1), to blood pressure ( BP) and hypertension. Here, we present the effects of reduction in the expression of PMCA1 on BP and small artery structure and function when combined with advancing age. Heterozygous PMCA1 null mice ( PMCA1Ht) were generated and conscious BP was measured at 6 to 18 months of age. Passive and active properties of isolated small mesenteric arteries were examined by pressure myography. PMCA1Ht mice exhibited normal BP at 6 and 9 months of age but developed significantly elevated BP when compared to age-matched wild-type controls at ≥12 months of age. Decreased lumen diameter, increased wall thickness and increased wall:lumen ratio were observed in small mesenteric arteries from animals 9 months of age and older, indicative of eutrophic remodelling. Increases in mesenteric artery intrinsic tone and global intracellular calcium were evident in animals at both 6 and 18 months of age. Thus, decreased expression of PMCA1 is associated with increased BP when combined with advancing age. Changes in arterial structure precede the elevation of BP. Pathways involving PMCA1 may be a novel target for BP regulation in the elderly. [ABSTRACT FROM AUTHOR]

Multiple GWAS studies have reported strong association of cardiac QT-interval to a region on HSA17. Interestingly, a rat locus homologous to this region is also linked to QT-intervals. The high resolution positional mapping study located the rat QT-interval locus to a <42.5kb region on RNO10. This region contained no variants in protein-coding sequences, but a prominent contiguous 19bp indel polymorphism was noted within a novel predicted long non-coding RNA (lncRNA), which we named as Rffl-lnc1. To assess the candidacy of this novel lncRNA on QT-interval, targeted CRISPR/Cas9 based genome-engineering approaches were applied on the rat strains used to map this locus. Targeted disruption of the rat Rffl-lnc1 locus caused aberrant, short QT-intervals and elevated blood pressure. Further, to specifically examine the significance of the 19bp polymorphism within the Rffl-lnc1 locus, a CRISPR/Cas9 based targeted knock-in rescue model was constructed by inserting the 19bp into the strain which contained the deletion polymorphism. The knock-in alleles successfully rescued the aberrant QT-interval and blood pressure phenotypes. Further studies revealed that the 19bp polymorphism was necessary and sufficient to recapitulate the phenotypic effect of the previously mapped <42.5kb rat locus. To our knowledge, this study is the first demonstration of a combination of both CRISPR/Cas9 based targeted disruption as well as CRISPR/Cas9 based targeted knock-in rescue approaches applied for a mammalian positional cloning study, which defines the quantitative trait nucleotides (QTNs) within a rat long non-coding RNA as being important for the pleiotropic regulation of both cardiac QT-intervals and blood pressure. [ABSTRACT FROM AUTHOR]

Aims Parental hypertension is known to predict high blood pressure (BP) in children. However, the extent to which risk for hypertension is conferred across multiple generations, notwithstanding the impact of environmental factors, is unclear. Our objective was therefore to evaluate the degree to which risk for hypertension extends across multiple generations of individuals in the community. Methods and results We studied three generations of Framingham Heart Study participants with standardized blood pressure measurements performed at serial examinations spanning 5 decades (1948 through 2005): First Generation (n = 1809), Second Generation (n = 2631), and Third Generation (n = 3608, mean age 39 years, 53% women). To capture a more precise estimate of conferrable risk, we defined early-onset hypertension (age <55 years) as the primary exposure. In multinomial logistic regression models adjusting for standard risk factors as well as physical activity and daily intake of dietary sodium, risk for hypertension in the Third Generation was conferred simultaneously by presence of early-onset hypertension in parents [OR 2.10 (95% CI, 1.66-2.67), P < 0.001] as well as in grandparents [OR 1.33 (95% CI, 1.12-1.58), P < 0.01]. Conclusion Early-onset hypertension in grandparents raises the risk for hypertension in grandchildren, even after adjusting for early-onset hypertension in parents and lifestyle factors. These results suggest that a substantial familial predisposition for hypertension exists, and this predisposition is not identical when assessed from one generation to the next. Additional studies are needed to elucidate the mechanisms underlying transgenerational risk for hypertension and its clinical implications. [ABSTRACT FROM AUTHOR]

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension. [ABSTRACT FROM AUTHOR]

Background and objective: Several studies have been conducted to examine the association between aldehyde dehydrogenase 2 family (ALDH2) rs671 polymorphism and essential hypertension (EH). However, the results remain inconsistent. This study aimed to clarify the association between ALDH2 rs671 polymorphism and EH susceptibility. Methods: One thousand and ninety-four cases and 1236 controls who were ethnic Han Chinese were collected for this population-based case-control study. A meta-analysis was performed to calculate the pooled odds ratio and 95% confidence interval, using allele contrast, dominant, recessive, and co-dominant models using fixed or random-effect models. Results: Significant differences were observed between EH cases and controls at the level of both genotype (χ2 = 6.656, P<0.05) and alleles (χ2 = 6.314, P<0.05). An additional meta-analysis using 4204 cases and 5435 controls established that rs671 was significantly associated with EH (P<0.00001). Conclusion: The results of our case-control study and meta-analysis showed that there is a significant association between ALDH2 rs671 polymorphism and EH susceptibility. In addition, the results of the breakdown analysis by gender suggest a male-specific association between the ALDH2 rs671 polymorphism and EH. [ABSTRACT FROM AUTHOR]