Genetics and cardiovascular reactivity in young twins

年轻双胞胎的遗传学和心血管反应性

• 批准号: 6768263
• 负责人: Yanbin Dong
• 金额: $ 14.3万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6768263
• 关键词: African American; adolescence (12-20); adrenergic receptor; blood pressure; cardiac output; cardiovascular stress test; caucasian American; clinical research; essential hypertension; family genetics; gene mutation; genetic polymorphism; genetic susceptibility; human genetic material tag; human subject; linkage disequilibriums; pathologic process; physiologic stressor; protein isoforms; psychological stressor; racial /ethnic difference; twin /multiplet; vascular resistance; vasodilation

DESCRIPTION (provided by applicant): We and others have shown that cardiovascular reactivity (CVR) to acute laboratory stress is a stable and heritable trait and predictive of future blood pressure (BP) levels and essential hypertension (EH). The sympathetic nervous system (SNS) has a major role in BP regulation and adrenergic receptor subtypes mediate BP responses to acute challenges. As such, our hypothesis is that individual differences in CVR are partly determined by variation in genes encoding for adrenergic receptors mediating the sympathoadrenal response to stress. There is increasing evidence that this cardiovascular response is regulated by multiple adrenoceptor subtypes with structural homology. To date, nine homologous adrenergic receptor subtypes have been described. Only one study has found a gene-gene interaction upon CV disease incorporating two adrenergic receptor subtypes. Genetic variants in all the nine adrenergic receptor subtypes have never been investigated in a single study. This R-21 application proposes to evaluate the effects of genetic variants in all of the nine adrenergic receptor subtype genes, alone or in combination, on CVR and other quantitative cardiovascular traits in a population of 1048 healthy youth. Subjects are Black and White twins that have already been comprehensively phenotyped as part of the Georgia Cardiovascular Twin Study (HL56622). Racial differences in adrenoceptor gene effects will receive special attention, because such differences may offer a partial explanation for the higher prevalence of EH in Blacks. Primary measures are systolic BP at rest and in response to two behavioral stressors. Secondary measures are diastolic BP, cardiac output and total peripheral resistance (TPR) at rest and in response to the stressors, left ventricular mass (LVM), endothelium dependent arterial dilation to reactive hyperemia (EDAD), arterial stiffness and 24-hour ambulatory BP. We propose to expand this data set through collection of buccal cell DNA from the parents of the twins, enabling us to perform (i) TDTs (transmission disequilibrium tests) and (ii) haplotype reconstruction and analyses. This candidate gene study in a large group of Black and White twins including TDT and haplotype analyses provides an innovative approach to help identify individuals at particular risk for the development of EH and improve options for primary prevention as well as individualized therapy of EH (pharmacogenetics).

描述（由申请人提供）：我们和其他人已经证明，心血管反应性（CVR）对急性实验室应激是一种稳定的、可遗传的特征，可以预测未来血压（BP）水平和原发性高血压（EH）。交感神经系统（SNS）在血压调节中起主要作用，肾上腺素能受体亚型介导急性应激下的血压反应。因此，我们的假设是，CVR的个体差异部分是由编码肾上腺素能受体的基因变异决定的，这些受体介导肾上腺交感神经对压力的反应。越来越多的证据表明，这种心血管反应是由多种具有结构同源性的肾上腺素能受体亚型调节的。迄今为止，已经描述了九种同源的肾上腺素能受体亚型。只有一项研究发现两种肾上腺素能受体亚型在心血管疾病中存在基因-基因相互作用。所有九种肾上腺素能受体亚型的遗传变异从未在单一研究中被调查过。这项R-21申请旨在评估所有9种肾上腺素能受体亚型基因的遗传变异（单独或联合）对1048名健康青年人群中CVR和其他定量心血管特征的影响。受试者为黑白双胞胎，已作为Georgia心血管双胞胎研究（HL56622）的一部分进行了全面表型分析。肾上腺素能受体基因作用的种族差异将受到特别关注，因为这种差异可能为黑人中较高的EH患病率提供部分解释。主要测量是静息时的收缩压和对两种行为应激源的反应。次要测量是静息和应激时的舒张压、心输出量和总外周阻力（TPR）、左心室质量（LVM）、内皮依赖性动脉扩张至反应性充血（EDAD）、动脉僵硬度和24小时动态血压。我们建议通过收集双胞胎父母的颊细胞DNA来扩展这一数据集，使我们能够进行(i) tdt（传递不平衡测试）和（ii）单倍型重建和分析。这项在一大群黑人和白人双胞胎中进行的候选基因研究，包括TDT和单倍型分析，提供了一种创新的方法，帮助识别具有EH发展特殊风险的个体，并改善初级预防选择以及EH的个性化治疗（药物遗传学）。