How to assemble the cardiovascular system: instructions from the genome

心血管疾病是世界范围内导致死亡的主要原因。遗传的DNA序列变异在疾病风险中起作用。由于最近的技术进步，我们对与人类心血管疾病风险相关的基因位点的了解已经大大扩展。然而，到目前为止，只有一小部分遗传风险因素被确定和表征。一个主要的问题是，只有一小部分基因组，即由蛋白质编码基因占据的基因组，被理解为其功能。因此，我们只能预测在这个部分内发生的遗传变异的有害影响。然而，绝大多数与疾病相关的序列变异存在于基因组的其他地方。因此，非编码功能基因组（调控基因组）的发现和表征是至关重要的。该项目将使用最先进的技术来识别控制心脏流出道和大血管形成的功能性非编码人类基因组。然后，我们将确定的人类调节信息与已知的与心血管疾病风险相关的遗传变异以及我们的合作者在先天性心脏病（CHD）方面的可用数据联系起来。我们的结果将存储在一个可搜索的、开放访问的网络应用程序中，以方便临床翻译。我们期望该项目的结果将导致发现与先天性心脏病和临床表型疾病风险相关的遗传变异，并最终扩大诊断和治疗能力。

Cardiovascular disease is the leading cause of death worldwide. Inherited DNA sequence variants play a role in conferring risk for disease. Our knowledge of the genetic loci associated with risk of cardiovascular disease in humans has been greatly expanded by recent technological advancements. However, only a fraction of the genetic risk factors have been identified and characterized so far. A major problem is that only a small fraction of the genome, the one occupied by protein-coding genes, is understood in terms of its function. Therefore, we can only predict the harmful effects of genetic variations occurring within this fraction. However, the vast majority of sequence variants associated to disease reside elsewhere in the genome. Thus, it is crucial that the non-coding functional genome (regulatory genome) be discovered and characterized. This project will use state-of-the-art technologies to identify the functional, non-coding human genome that controls formation of the outflow tract of the heart and the great vessels. We will then link the identified human regulatory information to known genetic variations associated to cardiovascular disease risk, and to available data from our collaborators on congenital heart disease (CHD). Our results will be stored into a searchable, open-access web application to facilitate their clinical translation. We expect that the results of this project will lead to the discovery of genetic variants associated to congenital heart disease and clinical phenotypes disease risk, and will eventually expand diagnostic and therapeutic capacities.