Genetic Epidemiology of Blood Pressure Intervention

描述(由申请人提供)： 高血压是一种由遗传因素和环境因素及其相互作用共同决定的复杂疾病。这项拟议研究的总体目标是确定人类人群中高血压的易感基因。其具体目的是定位和识别与血压变化相关的新基因，这些基因与饮食钠摄入量低、饮食钠摄入量高、口服补钾和冷加压试验的血压反应有关。 这项拟议的研究将采用家庭干预研究设计。我们将从500个家庭中招募750个兄弟姐妹(n=1750个兄弟姐妹)和他们的父母(n=1250)，每个家庭由一个先证者确定，他们有未经治疗的正常高位血压或一期高血压(收缩压130~160 mm Hg，舒张压85~100 mm Hg)。我们将收集所有参与者的病史、生活方式危险因素、人体测量、血压和血液测量(肾素活性、血管紧张素转换酶、血管紧张素II、钠尿肽、葡萄糖、胰岛素和血脂)以及兄弟姐妹的饮食营养摄入量(三次24小时召回)和尿钠钾排泄(三次24小时)的基线信息。我们将在兄弟姐妹中进行以下干预：基线(第2天或第3天)的冷加压试验，为期1周的低钠喂养研究(第4-10天每天40 mmol钠)，1周的高钠喂养研究(第11-17天每天280 mmol钠)，以及1周的口服补钾(第18-24天每天90 mmol钾)。在每个干预期的最后3天，我们将测量血压和24小时尿钠钾排泄量。我们将为全基因组连锁扫描和所有兄弟姐妹及其父母的候选基因进行基因分型。BP对干预措施的反应将主要作为数量性状进行分析。初步分析包括连锁分析、传递/不平衡检验以及遗传标记与BP对干预措施的反应之间的关联分析。 我们的研究将确定与饮食钠钾摄入量或冷加压对血压的影响显著交互作用的新基因。这一信息有助于及早识别高血压的高危个体，并为高血压的一级预防制定有针对性的生活方式调整。这些信息也有助于设计量身定制的生活方式干预措施，以治疗个别患者的高血压。

DESCRIPTION (provided by applicant): Essential hypertension is a complex disease determined by both genetic and environmental factors and their interactions. The overall objective of the proposed study is to identify susceptibility genes for hypertension in human populations. The specific aims are to localize and identify novel genes related to variation in blood pressure (BP) responses to a low dietary sodium intake, a high dietary sodium intake, oral potassium supplementation, and cold pressor test. The proposed study will utilize a family intervention study design. We will recruit 750 sibships (n=1750 siblings) and their parents (n=1250) from 500 families, each family ascertained through a proband who has untreated high normal BP or stage-1 hypertension (systolic BP 130-160 mm Hg and diastolic BP 85-100 mm Hg) from rural China. We will collect baseline information on medical history, lifestyle risk factors, anthropometric measures, BP, and blood measures (renin activity, ACE, angiotensin II, natriuretic peptide, glucose, insulin, and lipids) in all participants, and dietary nutrient intake (three 24-hour recalls) and urinary sodium and potassium excretion (three 24-hour) in the siblings. We will conduct the following interventions in the siblings: a cold pressor test at baseline (day 2 or 3), a 1-week low sodium-feeding study (40 mmol sodium/day on days 4-10), a 1-week high sodium-feeding study (280 mmol sodium/day on days 11-17), and a 1-week oral potassium supplementation (90 mmol potassium/day on days 18-24). We will measure BP and 24-hour urinary sodium and potassium excretion during the last 3 days of each intervention period. We will perform genotyping for genome-wide linkage scans and for candidate genes in all siblings and their parents. BP responses to the interventions will be analyzed primarily as quantitative traits. The primary analyses include linkage analysis, transmission/disequilibrium test, and association analysis between genetic markers and BP responses to the interventions. Our study will identify novel genes that interact significantly with the effect of dietary sodium and potassium intake or cold pressor on BP. This information is useful for early identification of individuals at high risk for hypertension and for development of targeted lifestyle modification for the primary prevention of hypertension. This information is also useful for designing tailored lifestyle interventions for the treatment of hypertension among individual patients.