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

描述（由申请人提供）：该项目的主要目的是鉴定导致心率变异性（HRV）的人类变异的基因，HRV是心脏副交感神经张力的非侵入性指标。八个关键基因参与乙酰胆碱的生物合成，运输，分解和受体结合将评估一个候选基因内的所有变异共同考虑的全基因的方法。最佳地利用最近扩大的人类群体遗传变异的公共数据库，这种方法，最好通过选择一组最小的标签SNP来实现，提供了基于基因的复制，并提供了一个有前途的解决方案，缺乏可复制性的关联研究。我们将使用来自格鲁吉亚心血管双胞胎研究的数据，该研究包括982名双胞胎受试者，其中黑人（219对）和白色（272对）美国青年和年轻成年人的数量大致相等，他们在休息时和三项急性行为应激任务中测量了心跳心率。我们计划通过使用免费提供的专用HRV软件来计算HRV的所有常用时域和频域参数。在最近的证据表明，影响HRV在休息时的基因的效果可能会更明显的行为压力下，我们的双胞胎设计，结合HRV在休息和压力下，将使我们能够定义最遗传的表型基因发现。该项目的具体目的是验证以下假设：（1）在暴露于行为应激期间，遗传对HRV的影响会增加，这是由相同基因的更大影响引起的，这些基因也是静息时HRV的基础，以及（2）参与副交感神经通路的8个关键基因的变异将解释HRV遗传性的重要部分。本项目的长期目标是了解心脏自主神经功能的遗传基础。这些发现可能会导致更准确地预测风险个体，提高主要干预措施的有效性，并有助于心血管疾病（药物遗传学）的个体化治疗的发展。简单总结：心率变异性（HRV）测量随时间推移的心跳心率波动，是心血管健康的指标。低HRV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.