Smith J Gustav, Newton-Cheh Christopher
Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
J Mol Cell Cardiol. 2015 Jun;83:131-41. doi: 10.1016/j.yjmcc.2015.04.004. Epub 2015 Apr 11.
Human genetics is a powerful tool for discovering causal mediators of human disease and physiology. Cardiovascular diseases with late onset in the lifecourse have historically not been considered genetic diseases, but in recent years the contribution of a heritable factor has been established. More importantly, over the last decade genome-wide association studies (GWASs) have identified many loci associated with late-onset cardiovascular diseases including coronary artery disease, carotid artery disease, ischemic stroke, aortic aneurysm, peripheral vascular disease, atrial fibrillation, valvular disease and correlates of vascular and myocardial function. Here we review findings from GWASs considered statistically robust with regard to multiple testing (p<5×10(-8)) for late-onset cardiovascular diseases and traits. Although for only a handful of the 92 genetic loci described here have the mechanisms underlying disease association been established, new and previously unsuspected pathways have been implicated for several conditions. Examples include a role for NO signaling in myocardial repolarization and sudden cardiac death and a role for the protein sortilin in lipid metabolism and coronary artery disease. Genetic loci with multiple trait associations have also provided novel biological insights. For example, of the 46 genetic loci associated with coronary artery disease, only 16 are also associated with conventional risk factors for cardiovascular disease whereas the remaining two thirds may reflect novel pathways. Much work remains to functionally characterize genetic loci and for clinical utility, but accruing insights into the biological basis of cardiovascular aging in human populations promise to point to novel therapeutic and preventive strategies. This article is part of a Special Issue entitled 'SI:CV Aging'.
人类遗传学是发现人类疾病和生理过程因果介质的有力工具。在生命历程中发病较晚的心血管疾病，在历史上一直未被视为遗传性疾病，但近年来已证实存在遗传因素的作用。更重要的是，在过去十年中，全基因组关联研究（GWAS）已确定了许多与晚发性心血管疾病相关的基因座，包括冠状动脉疾病、颈动脉疾病、缺血性中风、主动脉瘤、外周血管疾病、心房颤动、瓣膜疾病以及血管和心肌功能的相关指标。在此，我们回顾GWAS的研究结果，这些结果在针对晚发性心血管疾病和性状的多重检验（p<5×10(-8)）方面具有统计学稳健性。尽管在此描述的92个基因座中只有少数几个的疾病关联潜在机制已被确定，但对于几种疾病已涉及新的和先前未被怀疑的途径。例如，NO信号在心肌复极化和心源性猝死中的作用，以及sortilin蛋白在脂质代谢和冠状动脉疾病中的作用。具有多种性状关联的基因座也提供了新的生物学见解。例如，在与冠状动脉疾病相关的46个基因座中，只有16个也与心血管疾病的传统危险因素相关，而其余三分之二可能反映了新的途径。在功能上表征基因座以及将其用于临床应用方面仍有许多工作要做，但对人类群体中心血管衰老生物学基础的不断深入了解有望指向新的治疗和预防策略。本文是名为“SI:CV Aging”特刊的一部分。
