Clinical trial NCT04471389: Longitudinal Follow-up Study in Two Chinese Hypertension Cohorts
Official title: Effect of the Interaction Between Environmental Factors and Salt-sensitive Genomics on Long-term Blood Pressure in Chinese Population
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Hypertension
Keywords: blood pressure
Salt-sensitive
Left Ventricular Hypertrophy
Vascular Stiffness
Carotid Artery Diseases
Lead sponsor: First Affiliated Hospital Xi'an Jiaotong University
Sponsor class: OTHER
First posted: 2020-07-15
Enrollment: 5611
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: In March and April 1987, investigators established the cohort of Hanzhong Adolescent Hypertension Study. A total of 4,623 adolescents aged 6-15 years old in over 20 schools of three towns (Qili, Laojun and Shayan) in Hanzhong, Shaanxi, China were recruited. In 2003-2004, investigators established the cohort of Mei county adult salt-sensitive hypertension Study. This study was a family-based dietary intervention study conducted in a Han Chinese population from rural areas of northern China. A total of 675 subjects from 126 families were recruited in this cohort.

Brief summary: Essential hypertension is a complex trait that results from interaction between environmental factors and genetic factors. Salt sensitivity is the genetic susceptibility of blood pressure to salt, and it is an intermediate genetic phenotype of essential hypertension. This study aims to investigate the effects of interaction between salt sensitivity genomics and environmental factors on long-term blood pressure (BP) and target organ damage based on two established cohorts including "the cohort of Hanzhong adolescent hypertension study" and "the cohort of Mei county adult salt-sensitive hypertension study". Firstly, the Hanzhong cohort-based follow-up study is designed to observe the track of BP from childhood, and to explore the effects of many risk factors (such as salt-sensitivity, obesity et al) on long-term BP changes and the occurrence of TODs. In addition, by using DNA samples collected from subjects of "Mei county adult salt-sensitive hypertension study" in which all participants had completed a chronic salt loading and potassium intervention trial, investigators attempt to carry out whole-exome sequencing (WES), whole-genome DNA methylation and transcriptome detection, and analyze the relationship between salt sensitivity genomics and BP responses to dietary sodium/potassium intervention, long-term BP change, the risk of target organ damages. Investigators aim to explore the role of risk factors, including salt sensitivity, in the development of hypertension, and to illustrate the effects of interaction between salt sensitivity genomics and environmental factors on hypertension and target organ damage. This study would enable the investigators to further explore the genetic mechanism of essential hypertension, to identify new genetic markers for predicting early hypertension and target organ damage as well as to provide the basis for the prevention, targeted treatment, and new drugs development of hypertension in the future.

Detailed description: This study is a longitudinal cohort follow-up study. The main contents include:

(1) Questionnaire design: the questionnaire is designed according to the research contents and purposes. The standard questionnaires will be used to collect the general information, dietary habits, lifestyle, medical history, and family history etc. (2) Anthropometric measurements: blood pressure, pulse, height, body weight, waist and hip circumference will be acquired by medical practitioners who received professional training based on World Health Organization (WHO) standards, and passed relevant examinations. (3) Blood and urine samples collection: morning fasting blood, nocturia, and 24-hour urine specimen will be collected by medical staffs, and blind tubes will be set up according to 5% of the total samples. Blood biochemistries including serum total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, fasting glucose, creatinine and hsCRP can be measured using automatic biochemical analyzer. The sodium and potassium concentrations in the urine will be measured by flame photometry. The total sodium and potassium excretions in urine in 24h were calculated by multiplying the concentration and 24-h volume of urine. (4) Auxiliary examinations: Auxiliary examinations including carotid intima-media thickness, endothelium-dependent vasodilation (FMD), measurements of brachial-ankle pulse wave velocity (baPWV) and electrocardiographic parameters. The measurement will be done in hospitals by medical practitioners who received professional trainings and passed relevant examinations. (5) Whole-exome sequencing: Genomic DNA will be isolated from blood samples and subjected to exome capture, followed by next-generation sequencing on the Roche NimbleGen system. (6) Whole-genome DNA methylation analysis: levels of DNA methylation will be quantified using the Illumina Infinium HumanMethylation450K Beadchip array (HM450K). (7) Transcriptome sequencing: cDNA libraries will be sequenced via the Illumina HiSeqTM 2500 platform. (8) Data processing and statistics: investigators should input the data to the database, and utilize software such as Access, SPSS, STATA, CASAVA, MutSigCV, and Genome MuSic to analyze. (9) Quality control: ① Questionnaire is strictly designed and amended by epidemiologists and clinical experts. ② A standardized "Investigator Handbook" will be stipulated according to the guidelines. ③ Staff members are required to do a rigorous training and pass the exam. ④ The investigation process will be strictly supervised by the principal investigator. ⑤ Data entry uses the parallel double-entry method. ⑥ During laboratory testing, blank control and blind detection are applied to ensure the quality. ⑦ Data analysis is performed by 2-3 postgraduates, inconsistent data need to be double-checked.

Eligibility criteria: Inclusion Criteria:

1. Hanzhong cohort of Adolescent Hypertension Study:

   • adolescents aged 6-15 years old in over 20 schools of three towns (Qili, Laojun and Shayan) in Hanzhong, Shaanxi, China.
2. Mei county cohort of adult salt-sensitive hypertension study:

   * Han individuals in rural northern China
   * adults aged 18-60 years
   * individuals who had a mean systolic BP (SBP) between 130-160 mmHg and/or a diastolic BP (DBP) between 85-100 mmHg and no use of antihypertensive medications were identified as the proband
   * the probands'parents, siblings, spouses, and offspring were recruited for the study.

Exclusion Criteria:

* Secondary hypertension
* a history of severe cardiovascular disease
* chronic kidney disease or liver disease
* unable to complete the examination
* unable/refuse to sign the informed consent form

Primary outcomes:
measure: blood pressure value(mmHg)
timeFrame: First day of the three-day follow-up period
Secondary outcomes:
measure: Left ventricular hypertrophy (g/m^2)
timeFrame: During the three-day follow-up period
measure: Increased arterial stiffness (mm/s)
timeFrame: During the three-day follow-up period
measure: Carotid artery wall thickening (mm)
timeFrame: During the three-day follow-up period
measure: Microalbuminuria (mg/24h)
timeFrame: Second day of the three-day follow-up period
measure: whole exome sequencing
timeFrame: the whole year after the follow-up period
measure: whole genome DNA methylation detection
timeFrame: the whole year after the follow-up period
measure: whole-genome transcriptome sequencing
timeFrame: the whole year after the follow-up period
Other outcomes:
Locations:
city: Xi'an
country: China
facility: First Affiliated Hospital of Xi'an Jiaotong University
state: Shaanxi
Study officials:
affiliation: First Affiliated Hospital Xi'an Jiaotong University
name: Jianjun Mu, doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zheng W, Mu J, Chu C, Hu J, Yan Y, Ma Q, Lv Y, Xu X, Wang K, Wang Y, Deng Y, Yan B, Yang R, Yang J, Ren Y, Yuan Z. Association of Blood Pressure Trajectories in Early Life with Subclinical Renal Damage in Middle Age. J Am Soc Nephrol. 2018 Dec;29(12):2835-2846. doi: 10.1681/ASN.2018030263. Epub 2018 Nov 12.
citation: Fang Y, Mu JJ, He LC, Wang SC, Liu ZQ. Salt loading on plasma asymmetrical dimethylarginine and the protective role of potassium supplement in normotensive salt-sensitive asians. Hypertension. 2006 Oct;48(4):724-9. doi: 10.1161/01.HYP.0000238159.19614.ce. Epub 2006 Sep 11.