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

描述（由申请人提供）：本项目的主要目的是鉴定导致人类心率变异性（HRV）变异的基因，HRV是心脏副交感神经张力的无创指标。参与乙酰胆碱生物合成、转运、分解和受体结合的8个关键基因将通过基因全范围方法进行评估，同时考虑候选基因内的所有变体。优化利用最近扩大的人类群体遗传变异公共数据库，这种方法最好通过选择最小的标记snp集来实现，提供了基于基因的复制，并为缺乏可复制性的关联研究提供了一个有希望的解决方案。我们将使用来自乔治亚心血管双胞胎研究的数据，这是一项982名双胞胎受试者的队列研究，其中包括大致相同数量的黑人（219对）和美国白人（272对）青年和年轻人，他们在休息和三个急性行为压力任务期间测量了心跳速率。我们计划使用免费的HRV专用软件来计算所有常用的HRV时频域参数。最近有证据表明，在行为压力下，基因对静止HRV的影响可能更为明显，我们的双胞胎设计结合了静止HRV和压力HRV，将使我们能够确定基因发现中最具遗传性的表型。该项目的具体目的是验证以下假设：(1)在暴露于行为压力时，对HRV的遗传影响会增加，这是由于在静止状态下HRV的相同基因的更大影响造成的；(2)参与副交感神经通路的8个关键基因的变异将解释HRV的遗传能力的重要部分。该项目的长期目标是了解心脏自主神经功能的遗传基础。研究结果可能导致更准确地预测高危个体，提高初级干预措施的有效性，并有助于心血管疾病个体化治疗的发展（药物遗传学）。摘要：心率变异性（HRV）测量的是每搏心率随时间的波动，是心血管健康的一个指标。低HRV会增加患心血管疾病的风险。我们将寻找参与HRV调节的基因变异，看看它们是否解释了人群中观察到的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.