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: 6893341
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893341
• 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）：我们和其他人表明，对急性实验室压力的心血管反应性（CVR）是一种稳定且可遗传的特征，可以预测未来血压（BP）水平（BP）水平和本质高血压（EH）。 交感神经系统（SNS）在BP调节和肾上腺素能受体亚型中具有重要作用，介导了BP对急性挑战的反应。 因此，我们的假设是，CVR中的个体差异部分取决于编码肾上腺素能受体的基因的变化，这些肾上腺素能受体介导了交感神经对压力的反应。 有越来越多的证据表明，这种心血管反应由具有结构同源性的多个肾上腺受体亚型调节。 迄今为止，已经描述了九种同源肾上腺素能受体亚型。 只有一项研究发现了伴有两个肾上腺素受体亚型的CV疾病的基因 - 基因相互作用。 在一项研究中，从未研究过所有9种肾上腺素能受体亚型的遗传变异。 该R-21的应用建议评估遗传变异在1048名健康青年人群中单独或组合在CVR和其他定量心血管性状特征上单独或组合的所有九种肾上腺素能受体亚型基因的影响。 受试者是黑白双胞胎，作为佐治亚州心血管双胞胎研究（HL56622）的一部分，已经对已经进行了全面表型。 肾上腺受体基因效应的种族差异将受到特别关注，因为这种差异可能会为黑人EH的较高患病率提供部分解释。 主要措施是静止时BP的收缩压，并响应两个行为应激源。 次要措施是舒张性BP，心脏输出和静止和应激源时的总周围电阻（TPR），左心室肿块（LVM），依赖内皮的动脉膨胀对反应性血症（EDAD），动脉僵硬和24小时的ABP AMBRORATY BP 。 我们建议通过从双胞胎的父母那里收集颊细胞DNA来扩展这些数据集，从而使我们能够执行（i）TDTS（传输不平衡测试）和（ii）单倍型的重建和分析。 这项在包括TDT和单倍型分析在内的大量黑白双胞胎中的候选基因研究提供了一种创新的方法，可以帮助识别具有EH发育和改善原发性预防和个性化治疗EH（药物遗传学）的特定风险的个人。