Dataset Information

Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

ABSTRACT: Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), a member of the E3 ubiquitin-protein ligases, encoded by NEDD4L gene, was found to be involved in in salt sensitivity by regulating sodium reabsorption in salt-sensitive rats. The authors aimed to explore the associations of NEDD4L genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in Chinese adults. Participants from 124 families in Northern China in the Baoji Salt-Sensitive Study Cohort in 2004, who received the chronic salt intake intervention, including a 7-day low-salt diet (3.0 g/day) and a 7-day high-salt diet (18 g/day), were analyzed. Besides, the development of hypertension over 14 years was evaluated. NEDD4L single nucleotide polymorphism (SNP) rs74408486 was shown to be significantly associated with systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) responses to low-salt diet, while SNPs rs292449 and rs2288775 were significantly associated with pulse pressure (PP) response to high-salt diet. In addition, SNP rs4149605, rs73450471, and rs482805 were significantly associated with the longitudinal changes in SBP, DBP, MAP, or PP at 14 years of follow-up. SNP rs292449 was significantly associated with hypertension incidence over the 14-year follow-up. Finally, this gene-based analysis found that NEDD4L was significantly associated with longitudinal BP changes and the incidence of hypertension over the 14-year follow-up. This study indicated that gene polymorphism in NEDD4L serve an important function in salt sensitivity, longitudinal BP change and development of hypertension in the Chinese population.

SUBMITTER: Niu ZJ

PROVIDER: S-EPMC9581093 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

Niu Ze-Jiaxin ZJ Yao Shi S Zhang Xi X Mu Jian-Jun JJ Du Ming-Fei MF Zou Ting T Chu Chao C Liao Yue-Yuan YY Hu Gui-Lin GL Chen Chen C Wang Dan D Ma Qiong Q Yan Yu Y Jia Hao H Wang Ke-Ke KK Sun Yue Y Yan Rui-Chen RC Man Zi-Yue ZY Ren Dan-Feng DF Wang Lan L Gao Wei-Hua WH Li Hao H Wu Yong-Xing YX Li Chun-Hua CH Gao Ke K Zhang Jie J Yang Tie-Lin TL Wang Yang Y

Journal of clinical hypertension (Greenwich, Conn.) 20220830 10

Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), a member of the E3 ubiquitin-protein ligases, encoded by NEDD4L gene, was found to be involved in in salt sensitivity by regulating sodium reabsorption in salt-sensitive rats. The authors aimed to explore the associations of NEDD4L genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in Chinese adults. Participants from 124 families in Northern China in the Baoji Salt-Sensitiv ...[more]

PMID: 36039789

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Project description:Background and aimsIdentify novel metabolite associations with blood pressure (BP) salt-sensitivity and hypertension.Methods and resultsThe Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Replication study includes 698 Chinese participants who underwent a 3-day baseline examination followed by a 7-day low-sodium feeding and 7-day high-sodium feeding. Latent mixture models identified three trajectories of blood pressure (BP) responses to the sodium interventions. We selected 50 most highly salt-sensitive and 50 most salt-resistant participants for untargeted metabolomics profiling. Multivariable adjusted mixed logistic regression models tested the associations of baseline metabolites with BP salt-sensitivity. Multivariable adjusted mixed linear regression models tested the associations of BP salt-sensitivity with metabolite changes during the sodium interventions. Identified metabolites were tested for associations with hypertension among 1249 Bogalusa Heart Study (BHS) participants using multiple logistic regression. Fifteen salt-sensitivity metabolites were associated with hypertension in the BHS. Baseline values of serine, 2-methylbutyrylcarnitine and isoleucine directly associated with high salt-sensitivity. Among them, serine indirectly associated with hypertension while 2-methylbutyrylcarnitine and isoleucine directly associated with hypertension. Baseline salt-sensitivity status predicted changes in 14 metabolites when switching to low-sodium or high-sodium interventions. Among them, glutamate, 1-carboxyethylvaline, 2-methylbutyrylcarnitine, 3-methoxytyramine sulfate, glucose, alpha-ketoglutarate, hexanoylcarnitine, gamma-glutamylisoleucine, gamma-glutamylleucine, and gamma-glutamylphenylalanine directly associated with hypertension. Conversely, serine, histidine, threonate and 5-methyluridine indirectly associated with hypertension. Together, these metabolites explained an additional 7% of hypertension susceptibility when added to a model including traditional risk factors.ConclusionsOur findings contribute to the molecular characterization of BP response to sodium and provide novel biological insights into salt-sensitive hypertension.

Project description:ObjectiveRenalase, a novel secretory flavoprotein with amine oxidase activity, is secreted into the blood by the kidneys and is hypothesized to participate in blood pressure (BP) regulation. We investigated the associations of renalase with BP and the risk of hypertension by examining renalase single nucleopeptide polymorphism (SNPs), serum renalase levels, and renal expression of renalase in humans.Methods① Subjects (n = 514) from the original Baoji Salt-Sensitive Study cohort were genotyped to investigate the association of renalase SNPs with longitudinal BP changes and the risk of hypertension during 14 years of follow-up. ② Two thousand three hundred and ninety two participants from the Hanzhong Adolescent Hypertension Study cohort were used to examine the association of serum renalase levels with hypertension. Renalase expression in renal biopsy specimens from 193 patients were measured by immunohistochemistry. ③ Renalase expression was compared in hypertensive vs. normotensive patients.Results① SNP rs7922058 was associated with 14-year change in systolic BP, and rs10887800, rs796945, rs1935582, rs2296545, and rs2576178 were significantly associated with 14-year change in diastolic BP while rs1935582 and rs2576178 were associated with mean arterial pressure change over 14 years. In addition, SNPs rs796945, rs1935582, and rs2576178 were significantly associated with hypertension incidence. Gene-based analysis found that renalase gene was significantly associated with hypertension incidence over 14-year follow-up after adjustment for multiple measurements. ② Hypertensive subjects had higher serum renalase levels than normotensive subjects (27.2 ± 0.4 vs. 25.1 ± 0.2 μg/mL). Serum renalase levels and BPs showed a linear correlation. In addition, serum renalase was significantly associated with the risk of hypertension [OR = 1.018 (1.006-1.030)]. ③ The expression of renalase in human renal biopsy specimens significantly decreased in hypertensive patients compared to non-hypertensive patients (0.030 ± 0.001 vs. 0.038 ± 0.004).ConclusionsThese findings indicate that renalase may play an important role in BP progression and development of hypertension.

Dataset Information

Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

Publications

Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

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