bluuebunny/crossref_metadata_2025_split huggingface dataset:
HUMAN RENAL RNA-SEQ IDENTIFIES RELATIONSHIP BETWEEN UMOD EXPRESSION AND MEDULLARY ION TRANSPORTERS
Authors: Fisher Simon , Molina Rafael Crespo , Graham Delyth , Mcbride Martin 
Published: April 2021

Objective:
Our previous genome wide association study (GWAS) highlighted a locus on the promoter of the human UMOD gene associated with hypertension. In this study, we sought to identify potential pathways which facilitate the association of UMOD with blood pressure through effects on gene expression.

Design and method:
From our bank of 98 human renal biopsy samples, we assessed UMOD and NKCC2 expression by qRT-PCR. Individuals were stratified by UMOD expression and RNA-sequencing using the NextSeq-500 system performed on a subset of high and low UMOD expression (n = 3/ group). Differential expression was assessed by DESeq2 to detect significant differences (p [adjusted] <0.05) in the transcriptome between high and low UMOD expressers and pathways visualised using Ingenuity Pathway Analysis (IPA).

Results:
RNA-Seq analysis identified 162 differentially expressed genes (138 protein coding genes,18 long non-coding RNAs and 8 additional transcriptomic elements), of these, 123 genes increased in expression with high UMOD expression. Using IPA, we detected enrichment for pathways related to immune system function, cell to cell communication and molecular ion transport. Notably, we show that an increase in UMOD expression associates with an increase in expression of the Na-K-Cl cotransporter (NKCC2) (p [adjusted] = 2.58e-9, fold-change = 10.89), the renal outer medullary potassium channel (ROMK) (p [adjusted] = 3.69e-2, fold-change = 2.79) and the gamma-subunit of the epithelial sodium channel (ENaC) (p [adjusted] = 1.83e-2, fold-change = 1.25). We further validated the relationship between UMOD and NKCC2, by Taqman qRT-PCR, showing a highly significant correlation of expression (p = 2.2e-16, R = 0.844) (n = 86). Using IPA we show this correlation may be facilitated by the transcription factor POU3F3, which can act at motifs found on promoters of both genes.

Conclusions:
Of several pathways identified by IPA, association of UMOD expression with expression of these three ion channels (NKCC2, ROMK and ENaC) may explain previously observed relationship between UMOD and blood pressure. These data suggest the UMOD: ion-transport pathway may be a drug target in the treatment of hypertension.
CORRELATION BETWEEN PEANUT SKIN PHENOLIC COMPOUNDS AND THEIR EFFECTS ON DYSLIPIDEMIA IN SWISS MICE
Authors: De Melo Kamilla Correia , Lins Lais Pinheiro , Costa Danilo José De Almeida , Rocha Aline Tavares , Neto Inácio De Barros Melo , Da Silva Joelmir L. Veiga , Pereira Schirley Almeida C. , Costa Lorena De Farias Pimentel , Gomes Felippe Barbosa , Silva Jose Sergio N. , Oliveira Thárcia Kiara Beserra De 
Published: April 2021

Objective:
To characterize the secondary metabolites of aqueous peanut extract (EAAsp) plus 1% of skin (EAAcp) and its effects combined with a hyperlipidic diet in male Swiss mice, analyzing serum concentrations of biochemical analysis.

Design and method:
The pulp extract was prepared at a 1:8 ratio to obtain a final concentration of 1.25 mg/mL and added 1% peanut skin to the total volume. Polyphenols and flavonoids quantifications were used following official methodologies. The experiment was performed divided into groups (n = 10): GI - received hypercholesterolemic diet plus 0.5 mL of EAAsp daily; GII - received hypercholesterolemic diet plus 0.5 ml EAAcp. Diet time was 12 weeks. Animal weights were evaluated weekly and at the end of the experiment biochemical analyzes were performed. The difference into mean was analyzed by Tukey test, when values of p < 0.05 were considered significant.

Results:
Regarding phenolic compounds, lower values for EAAsp (3.3 mg EAG/g) were found when compared to the EAAcp formulation (5.7 mg EAG/g), demonstrating a high polyphenols potential for the skin enriched extract. For flavonoids, values of 1.78 + 0.001 for EAAsp and 4.30 + 0.001 for EAAcp were obtained with an average difference of 2.52 mg/100 g. The incorporation of peanut skin in the EAA resulted in the increasing of phenolic compounds concentration that contribute to antioxidant activity. In vivo, the extracts decreased LDL-cholesterol levels (GI-56 ± 2.2 x GII-9.8 ± 1.0), however EAAcp was more efficacy (p < 0.05) as well as the total cholesterol levels (GI-126 ± 12.7 x GII-90 ± 10.5). Both extracts decreased CRP (C-reactive protein) values in a similar manner (GI-0.96 ± 0.2 x GII-0.93 ± 0.23). Reduction in LDL-cholesterol levels could be attributed to the chemical composition of peanut skin that may promote reduced risk of cardiovascular disease.

Conclusions:
The peanut skin enriched the extract as antioxidant potential that probable greater efficacy in the reducing blood lipid levels, but it preserved the decreasing CRP levels.
SEX AND SALT-RESPONSIVE CONJUGATION OF BILE ACIDS BY THE HOLOBIONT REGULATES HYPERTENSION
Authors: Chakraborty Saroj Chakrabort , Lulla Anju , Cheng Xi , Mccarthy Cameron G , Yeo Ji-Youn , Alimadadi Ahmad , Mandal Juthika , Saha Piu , Yeoh Beng San , Louis Evangelina F , Mell Blair , Jia Wei , Wenceslau Camilla F , Vijay-Kumar Matam , Meyer Katie , Joe Bina 
Published: April 2021

Objective:
Men and women are differently prone to cardiovascular diseases. Salt-sensitive women are more likely to develop aggravated hypertension in response to an overloaded salt diet than men. Men and women also differ in gut microbiota, which regulates both bile acid composition and hypertension; however, whether sex may differentially influence the gut microbial production of bile acids, with attendant effects on hypertension, is not known. We hypothesized that reshaping of gut microbiota by dietary salt is sex-dependent and adversely affects bile acids to promote hypertension.

Design and method:
To test this hypothesis, groups of male and female salt-sensitive hypertensive (Dahl S) and salt-resistant normotensive (Dahl R) rats (n = 6/gp) on low (0.3% NaCl) or high (2% NaCl) diets were profiled for fecal microbiota by 16S sequencing and serum bile acids by targeted GC-TOF-MS metabolomics.

Results:
Hierarchical clustering analysis of bile acids with microbiotal profiles revealed that glycine- and taurine-conjugated bile acids were prominently negatively correlated with blood pressure (BP) in female rats, while only taurine-conjugated bile acids were negatively correlated with BP in male rats. These observations were corroborated by microbiotal and bile acid metabolomic profiling of human hypertensive samples from a population-based cohort (CARDIA). Next, to test whether hypertension can be prevented by supplementing substrates for bile acid conjugation, high salt fed S rats were administered with either taurine (3% v/v in drinking water) or glycine (1% v/v in drinking water) in drinking water, monitored for BP by telemetry, and profiled for bile acid metabolites. Both taurine and glycine feeding prevented hypertension in females (Systolic BP: taurine:176 ± 7∗, glycine: 182 ± 4∗, control: 197 ± 4 mmHg, n = 6–9/gp, ∗p < 0.05) likely by rescuing levels of levels of respective conjugated bile acids, whereas only taurine, but not glycine, prevented hypertension in males (Systolic BP: taurine: 166 ± 2∗, glycine:184 ± 5, control: 184 ± 8 mmHg, n = 5–6/gp, ∗p < 0.05).

Conclusions:
Our results connect sex-specific differences in salt-sensitive hypertension to the gut-liver axis and suggests that nutritional restoration of host taurine- or glycine-conjugated bile acids for women and host taurine-conjugated bile acids for men as potential therapeutics for salt-sensitive hypertension.
SCREENING FOR GENETIC MUTATIONS IN LDLR GENE WITH FAMILIAL HYPERCHOLESTEROLEMIA IN THE MONGOLIAN POPULATION
Authors: Unurjargal Tsolmon , Byambatsogt Bolortuul , Sodovsuren Naranchimeg , Lhagvasuren Sodnomtsogt 
Published: April 2021

Abstract

Objective:
The objective of this study was to characterize LDLR (low density lipoprotein receptor) gene mutation in patients with familial hypercholesterolemia.

Design and method:
Methods: This cross-sectional study was included subjects aged from 20 to 64 years, with a clinical diagnosis of familial hypercholesterolemia. Clinical diagnosis of familial hypercholesterolemia was based on Dutch Lipid Clinic Network diagnostic criteria. Possible and probable familial hypercholesterolemia were defined as a total score was 3–5 and 6–8 points. Ten ml of venous blood samples were collected from all the subjects and used for biochemical and genetic analysis. Deoxyribonucleic acid was isolated from peripheral blood samples and precise primers were designed for LDLR gene which includes 18 exons. Polymerize chain reaction test was followed by deoxyribonucleic acid sequence analysis.

Results:
Results: A total of 89 subjects included in the study of which, 32 (36%) were men and 57 (64%) were women. The mean age of the participants was 46.5 ± 7.8 years. In our study, we found the following 3 LDLR mutations: S265R mutation in Exon-6, C308Y mutation Exon-8 and V502 M mutation in Exon-10.

Conclusions:
Conclusion: This was the first study to identify genetic mutations in LDLR gene in Mongolia. We conclude that screening of family hypercholesterolemia among the Mongolian population is very important to identify individuals who are prone to develop the atherosclerotic cardiovascular disease.
THE VARIETY OF GENETIC DEFECTS EXPLAINS THE PHENOTYPIC HETEROGENEITY AND THE MODE OF TRANSMISSION OF FAMILIAL HYPERKALEMIC HYPERTENSION
Authors: Hureaux Marguerite , Marzukiewicz Stephanie , Vargas-Poussou Rosa , Jeunemaitre Xavier 
Published: April 2021

Abstract

Objective:
Familial Hyperkalemic Hypertension (FHHt) is a rare inherited form of arterial hypertension. Four genes are responsible for this disease, interacting together in the regulation of ion transport in the distal renal tubule. Whether the type of variants and mutated gene explains the large phenotypic heterogeneity and the different modes of transmission in FHHt has not been explored yet.
We report herein the experience of a referral centre based on 151 molecularly proven FHHt cases (82 probands, 69 relatives).

Design and method:
Patients with persistent hyperkalemia without renal failure, associated with metabolic acidosis, were genetically explored by Sanger sequencing and by new generation sequencing (NGS)Identified variants were confirmed and classified according to the American College of medical Genetics.
Clinical and biological data were analyzed based on “questionnaires” filled out by the prescribing physicians. Statistical analyzes were done using Kruskal-Wallis test and post hoc Dunn's multiple comparison tests using Prism V6.

Results:
We identified 16 families with 12 different CUL3 splice-site variants, 48 families with 37KLHL3 variants (13 in recessive form, 24 in dominant form), 4 families with 4 different WNK1 intron 1 deletions, 11 families with 6 variants in the WNK1 acidic motif and 4 families with 4 different variants in the WNK4 acidic and basic motifs (figure 1). De novo cases were mainly observed in the CUL3-related cases (9 out of 16), recessive cases were only observed in few KLHL3-related cases (13 out 48), whereas all others variants were transmitted in an autosomal dominant manner. The more severe and earlier cases were caused by KLHL3 homozygous variants and CUL3 heterozygous variants in this case associated with growth retardation. Patients with WNK1 acidic motif variants had a typical biological phenotype without hypertension conversely to WNK4 mutations affecting the same motif. Molecular familial screening of relatives allowed us to detect 69 positive cases. Whatever the causing gene, administration of hydrochlorothiazide was effective.

Conclusions:
This study reinforces the interest of a genetic screening in case of suspicion of FHHt to better orientate the medical care of the patient and his family
SEX DIFFERENCES IN THE GENETIC RISK FOR HYPERTENSION
Authors: Aittokallio Jenni , Kauko Anni , Vaura Felix , Suvila Karri , Cheng Susan , Niiranen Teemu 
Published: April 2021

Abstract

Objective:
The development of hypertension differs markedly between men and women. The genetic drivers of this difference have not been fully studied. Genome-wide polygenic risk scores (PRSs), consisting of data from up to 6 M single nucleotide polymorphisms have been shown to considerably improve hypertension risk prediction, particularly in early-onset disease. However, the sex differences in the ability of PRSs to predict hypertension has not been studied previously.
Figure Survival curves from Cox proportional hazards models illustrate the cumulative risk of hypertension by systolic blood pressure PRS categories in FinnGen for women and men. We observed 123 579 women and 95 213 men with 27 804 and 28 113 cases of incident hypertension, respectively.

Design and method:
Our study sample comprised 218792 FinnGen Study participants with lifetime register-based follow-up for incident hypertension (56% women, mean age 58 years). We used publicly available genome-wide association results from UK Biobank to compute sex-specific PRSs for systolic blood pressure. We categorized SBP PRS into five bins according to percentiles (<2.5, 2.5–20, 20–80, 80–97.5, > 97.5) and used middle bin as the reference. We used multivariable-adjusted Cox proportional hazards models to measure the association between the PRSs and incident hypertension.

Results:
The PRS was more strongly associated with incident hypertension in women than in men (Figure). The hazard ratios (HR) per 1 SD increase in PRSs were 1.42 (95% CI, 1.40–1.44) for women and 1.27 (95% CI, 1.26–1.29) with an interaction P-value of 4x10–29. The difference between women (HR, 1.56; 95% CI, 1.53–1.58) and men (HR, 1.35; 95% CI, 1.32–1.37) was even greater for early-onset hypertension (onset at age < 55 years). Men and women in the top 2.5 PRS percentile had 2.1-fold (95% CI, 2.0–2.3) and 1.8-fold (95% CI, 1.7–1.9) greater risks of developing hypertension than the reference group.

Conclusions:
The genetic risk of hypertension appears to be more distinctive in women than in men, which may reflect physiological differences starting already at an early age. These results emphasize the use of sex-specific PRSs in clinical prediction of hypertension.
ACCEPTABILITY AND FEASIBILITY OF USING DIETARY NITRATE AND FOLATE SUPPLEMENTATION FOR THE TREATMENT OF HYPERTENSION IN A RURAL TANZANIAN POPULATION
Authors: Prabhakar Meghna , Kandhari Navneet , Mmbaga Blandina , Rogathi Jane , Gray William , Paddick Stella-Maria , Walker Richard , Siervo Mario 
Published: April 2021

Objective:
There is a substantial and growing burden of hypertension and hypertensive related disease in Tanzania. Low-cost and effective interventions are urgently needed. Little evidence is available on the use of inorganic nitrate and folate for treating hypertension in Africans. This study aims to assess the acceptability and feasibility of using nitrate supplementation in the form of beetroot juice and folate as a combined dietary intervention in a hypertensive Tanzanian population.

Design and method:
A three-arm, parallel, placebo controlled randomised clinical trial was conducted. Acceptability was assessed by one-to-one interviews, compliance and study retention rate. Trial assessments included clinic and ambulatory blood pressure measurements, electrocardiography, salivary samples, and blood samples.

Results:
Forty-eight participants were randomised for intervention. Forty-six participants completed the feasibility questionnaire. Twenty-six (57%) did not know what hypertension was and 37 (80%) had never heard of beetroot. Forty-two (91%) participants were happy to have the ambulatory blood pressure measurements repeated. All participants reported to have a >90% compliance to the dietary supplements.

Conclusions:
Awareness and knowledge of hypertension and the dietary interventions were low. Despite this, the interventions and protocol were well tolerated. This pilot shows that a dietary intervention of this nature is acceptable to this population, and that our study protocol can be feasibly used for a future trial in this setting.
NITRATE-RICH BEETROOT JUICE ALONE OR IN COMBINATION WITH FOLIC ACID REDUCES BLOOD PRESSURE IN HYPERTENSIVE TANZANIAN ADULTS: A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL
Authors: Prabhakar Meghna , Kandhari Navneet , Shannon Oliver , Fostier William , Koehl Christina , Rogathi Jane , Temu Gloria , Stephan Blossam , Gray William , Paddick Stella Maria , Haule Irene , Mmbaga Blandina , Walker Richard , Siervo Mario 
Published: April 2021

Objective:
In Sub-Saharan Africa, current management strategies are struggling to control the burgeoning hypertension epidemic. Dietary interventions such as inorganic nitrate and folate could represent alternative strategies for reducing blood pressure in this setting. This study aims to explore the effects of dietary inorganic nitrate supplementation alone or in combination with folic acid supplementation on blood pressure in a group of adult individuals with elevated blood pressure in Tanzania.

Design and method:
A placebo-controlled, double blind, randomized controlled trial (RCT) was conducted. Forty seven participants were randomly assigned to three conditions for a period of 60 days: 1) high-nitrate beetroot juice (∼400 mg nitrate) and folic acid (∼5 mg folate), 2) high-nitrate beetroot juice and placebo, 3) nitrate-depleted beetroot juice and placebo. Clinic and 24-hour ambulatory blood pressure, markers of nitric oxide production, and measurements of intervention compliance were obtained prior to and following the intervention period.

Results:
Resting clinic-based systolic blood pressure was significantly lower after 60 days of nitrate supplementation alone (p = 0.01). Both alone and combined nitrate + folate interventions had a significant effect on 24-Hour systolic blood pressure. After 60 days systolic blood pressure dropped by −10.8 ± 9.8 mmHg (p < 0.001) and −6.1 ± 13.2 mmHg (p = 0.03) in the nitrate alone and nitrate + folate groups, respectively. There was a significant decrease in 24-hour diastolic blood pressure in the nitrate alone group (−5.4 ± 5.0 mmHg, p = 0.04).

Conclusions:
Dietary inorganic nitrate, alone or in combination with folic acid, represents a potential nutritional strategy to lessen the hypertension epidemic in Sub-Saharan Africa. These findings support the rationale for future long-term investigations exploring the efficacy of dietary nitrate for lowering blood pressure and attenuating CVD risk in this setting.
PROVINCIAL-LEVEL CARDIOVASCULAR AND ALL-CAUSE MORTALITY BURDEN ATTRIBUTABLE TO HYPERTENSION IN CHINA
Authors: Kang Yuting , Wang Zengwu , Chen Zuo , Zhang Linfeng , Wang Xin , Zheng Congyi , Jiang Linlin , Shao Lan , Tian Ye 
Published: April 2021

Objective:
Understanding disparities in the burden of cardiovascular and all-cause mortality attributable to hypertension is crucial to inform and improve hypertension control measures. In this report, we estimate the population attributable fraction (PAF) of cardiovascular mortality attributable to hypertension at the national and provincial levels in China.

Design and method:
The multivariable-adjusted RRs by cox regression using cohort study with more than 30,000 individuals, along with the national BP level from national study, were used to calculate the population attributable fractions (PAF). China Hypertension Survey, involving 458,273 participants from 262 selected counties by stratified multistage random sampling method was used to calculate the prevalence of different BP level. CVD events were defined as the incidence of fatal and non-fatal stroke, fatal and non-fatal coronary heart disease (CHD), heart failure, and other causes from CVD.

Results:
Of more than 30,000 individuals aged 35 years or older in the current study, over a mean of 4.8 years of follow up (143,314.6 person-years), we documented 571 cardiovascular events. Comparing with normal BP, prehypertension and hypertension increased more than 50% and 170% risk for CVD events. Nationally, the CVD events attributable to prehypertension, hypertension and elevated BP were 17.30%, 28.74% and 37.99%, respectively. The PAFs for elevated BP ranged from 44.06% in Tianjin to 31.59% in Qinghai, however. In 2016, about 687.68 thousand (95%CI: 670.89, 705.15) and 1.14 (95%CI: 1.11, 1.17) million cardiovascular deaths were derived from prehypertension and hypertension, respectively. The province with high socio-demographic Index (SDI), such as Shanghai, Beijing and Tianjin, all had relative lower CVD death numbers for hypertension, with less than 15 thousands CVD deaths attributable to hypertension. More than 17 thousands CVD deaths could been derived from controlled hypertension in Shandong, Henna and Hebei provinces.

Conclusions:
Elevated BP were related with excess CVD deaths. Geography heterogeneity exited among 31 provinces, with lower excess CVD deaths in high SDI provinces. Additional attention should be taken to reduce prehypertension, which are preferable to attend universal health.
DIFFERENCES IN HYPERTENSION PHENOTYPES BETWEEN AFRICANS AND EUROPEANS: ROLES OF INHERITANCE AND ENVIRONMENT
Authors: Faconti Luca , McNally Ryan , Farukh Bushra , Adeyemib Olusoji , Cruickshankc J. Kennedy , Wilkinson Ian , Chowienczyk Philip , Ojji Dike 
Published: April 2021

Objective:
Hypertension phenotypes differ in Africans and white Europeans, with a greater prevalence of low renin salt-sensitive hypertension and greater predisposition to adverse cardiac remodelling in Africans.
We aim to elucidate roles of inheritance and environment in determining hypertension phenotypes in Africans born and resident in Nigeria (AA), sub-Saharan Africans living in the UK (AE) and white Europeans in the UK (EE).

Design and method:
469 hypertensive subjects in the UK and Nigeria were enrolled. Biochemistry, blood pressure, left ventricular structure (echocardiography) and 24 h urinary collections of sodium and potassium were measured

Results:
24-hour urinary sodium and potassium excretion were similar in AE and EE but lower in AA with a proportionately greater excretion of potassium compared to sodium in Africans resident in Europe compared to those in Africa (sodium excretion 46.9% greater in AE compared to AA and potassium excretion 109.8% greater in AE compared to AA, both P < 0.01) so that the ratio of sodium to potassium in the urine was higher in AA compared to both AE and EE. Plasma renin was lower in Africans irrespective of residency compared to white Europeans, but aldosterone was higher in Africans in Europe compared to those in Africa (466.15 ± 32.95 pmol/L vs 258.60 ± 17.42 pmol/L, P < 0.001). Left ventricular mass index adjusted for blood pressure was greatest in Africans in Europe (103.27 ± 2.32 g/m2) compared to those in Africa (89.28 ± 1.98 g/m2, P < 0.01) or white Europeans (86.77 ± 2.63 g/m2, P < 0.01). The difference between AE and AA was largely driven by a greater LV cavity size in AE compared to AA (difference in end diastolic diameter, 0.45 ± 0.056 cm, P < 0.001). Consequently, the RWT showed a trend to “eccentricity” moving from AA to AE.

Conclusions:
Both genetic and environmental differences contribute to phenotypic differences between Africans in Europe and white Europeans. A low renin state is predominantly genetically determined whereas higher aldosterone, related to higher potassium intake or another environmental factor, may contribute to greater LV mass in Africans in Europe.