Identifying genes related to heart rate variability at rest and during stress

描述(申请人提供)：该项目的主要目标是确定导致人类心率变异性(HRV)变异的基因，心率变异性是心脏副交感神经张力的非侵入性指标。涉及乙酰胆碱的生物合成、运输、分解和受体结合的八个关键基因将通过一种全基因的方法进行评估，候选基因中的所有变体都将被联合考虑。这种方法最好地利用了最近扩大的人类群体遗传变异公共数据库，最好是通过选择最小的一组标记SNPs来实现，提供了基于基因的复制，并为缺乏相关性研究的可复制性提供了一种有前途的解决方案。我们将使用佐治亚州心血管双胞胎研究的数据，该队列由982名双胞胎受试者组成，其中包括数量大致相同的黑人(219对)和美国白人(272对)青年和年轻人，他们在休息时和在三项急性行为应激任务中测量了心率。我们计划使用免费的专用HRV软件来计算HRV的所有常用的时域和频域参数。鉴于最近的证据表明，在行为应激状态下，影响安静状态下心率变异性的基因的作用可能更加明显，我们的双胞胎设计结合了安静状态和应激状态下的心率变异性，将使我们能够定义最易遗传的表型，用于基因发现。这个项目的具体目的是检验这样的假设：(1)在暴露于行为应激期间，遗传对HRV的影响会增加，这是因为相同的基因在静息状态下对HRV的影响更大，(2)副交感神经通路中涉及的8个关键基因的变异将解释HRV的很大一部分遗传性。该项目的长期目标是了解心脏自主神经功能的遗传基础。研究结果可能导致对处于危险中的个体进行更准确的预测，提高主要干预措施的有效性，并有助于开发心血管疾病的个体化治疗(药物遗传学)。综述：心率变异性(HRV)测量心率随时间的波动是心血管健康的一个指标。心率变异性低会增加心血管疾病的风险。我们将寻找参与调节HRV的基因的变异，看看它们是否解释了在人群中观察到的HRV的个体差异。

DESCRIPTION (provided by applicant): The main objective of this project is to identify genes contributing to human variation in heart rate variability (HRV), a noninvasive index of cardiac parasympathetic tone. Eight key genes involved in biosynthesis, transport, breakdown and receptor binding of acetylcholine will be assessed by a gene-wide approach with all variants within a candidate gene considered jointly. Making optimal use of the recently enlarged public databases of genetic variants in human populations, such an approach, best achieved through selection of a minimal set of tagging SNPs, affords gene-based replication and offers a promising solution to the lack of replicability of association studies. We will use the data from the Georgia Cardiovascular Twin Study, a cohort of 982 twin subjects including roughly equal numbers of black (219 pairs) and white American (272 pairs) youth and young adults who had beat-to-beat heart rate measured both at rest and during three acute behavioral stress tasks. We plan to calculate all the commonly used time and frequency-domain parameters of HRV by using freely available dedicated HRV software. In context of recent evidence suggesting that the effect of genes influencing HRV at rest may be more pronounced under behavioral stress, our twin design incorporating both HRV at rest and under stress, will enable us to define the most heritable phenotype for gene finding. The specific aims of this project are to test the hypotheses that: (1) genetic influence on HRV will increase during exposure to behavioral stress caused by a larger effect of the same genes that also underlie HRV at rest, and (2) variants in 8 key genes involved in the parasympathetic pathway will explain a significant part of the heritability of HRV. The long term objective of this project is to understand the genetic basis of cardiac autonomic function. Findings may lead to a more accurate prediction of individuals at risk and improve the effectiveness of primary interventions and contribute to the development of individualized therapy for cardiovascular disease (pharmacogenetics). Lay summary: Heart rate variability (HRV) measuring the beat-to-beat heart rate fluctuations over time is an indicator of cardiovascular health. Low HRV increases the risk of cardiovascular disease. We will look for variants in the genes involved in the regulation of HRV to see if they explain individual differences in HRV observed in the population.