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，对急性实验室应激的心血管反应性（CVR）是一种稳定的、可遗传的性状，可预测未来的血压（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血压对急性挑战的反应。 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的变异决定的，肾上腺素能受体介导了交感肾上腺对应激的反应。 越来越多的证据表明，这种心血管反应是由多种肾上腺素受体亚型的结构同源性。 迄今为止，已描述了9种同源肾上腺素能受体亚型。 只有一项研究发现CV疾病的基因-基因相互作用包含两种肾上腺素能受体亚型。 所有九种肾上腺素能受体亚型的遗传变异从未在一项研究中进行过研究。 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（单独或组合）对1048名健康青年人群CVR和其他定量心血管性状的影响。 受试者是黑人和白色双胞胎，作为格鲁吉亚心血管双胞胎研究（HL 56622）的一部分，已经进行了全面的表型分析。 肾上腺素受体基因效应的种族差异将受到特别关注，因为这种差异可能为黑人高血压的高患病率提供部分解释。 主要测量的是静息时和对两种行为应激源的反应时的收缩压。 次要指标为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来扩展该数据集，使我们能够进行（i）TDT（传递不平衡检验）和（ii）单倍型重建和分析。 在一个大组的黑人和白色双胞胎，包括TDT和单倍型分析的候选基因研究提供了一种创新的方法，以帮助识别个人在特定的风险，为发展高血压和改善选择的一级预防以及个性化治疗高血压（遗传药理学）。