The genomic architecture of sporadic heart failure.
The genomic architecture of sporadic heart failure.
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DOI：
10.1161/circresaha.110.229260
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发表时间：
2011-05-13
影响因子：
20.1
通讯作者：
Dorn GW 2nd
中科院分区：
文献类型：
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作者：
Dorn GW 2nd
常见或散发性收缩期心力衰竭（心衰）是由心肌疾病引起的前向心输出量不足的临床综合征。大多数心力衰竭是由缺血性或特发性心肌病引起的。心衰有明显的家族性易感性，遗传因素估计占总风险的20%至30%。该综合征的多因素病因学使其遗传基础的鉴定变得复杂。直到最近，几乎所有关于心力衰竭的遗传研究都是根据共同疾病-共同变异假说设计和部署的，在这种假说中，个体风险等位基因会产生微小的积极或消极影响，而总体遗传风险是所有功能性遗传变异的累积影响。早期研究采用候选基因方法，主要关注影响心力衰竭进展的肾上腺素能和肾素-血管紧张素途径中的因素，这些因素是标准药物治疗的目标。许多报道的与心力衰竭相关的等位基因尚未得到证实。然而，多数数据支持β1-肾上腺素能受体Arg389Gly多态性和血管紧张素转换酶内含子16 in/del多态性的风险修饰因子效应。最近使用全基因组单核苷酸多态性（SNP）微阵列进行的无偏倚研究显示，与这些平台应用于高血压、心肌梗死或糖尿病相比，阳性结果较少，这可能反映了心力衰竭的复杂病因。一个新的以心血管基因为中心的亚基因组SNP阵列在多个独立队列中发现了1p36的常见热衰竭风险等位基因，但这种关联的生物学机制仍然不确定。常见的基因多态性可能只占个体遗传心力衰竭风险的一小部分，未来使用深度重测序的研究可能会发现具有更大生物学效应的罕见基因变异。
Common or sporadic systolic heart failure (heart failure) is the clinical syndrome of insufficient forward cardiac output resulting from myocardial disease. Most heart failure is the consequence of ischemic or idiopathic cardiomyopathy. There is a clear familial predisposition to heart failure, with a genetic component estimated to confer between 20 and 30% of overall risk. The multifactorial etiology of this syndrome has complicated identification of its genetic underpinnings. Until recently, almost all genetic studies of heart failure were designed and deployed according to the common disease-common variant hypothesis, in which individual risk alleles impart a small positive or negative effect and overall genetic risk is the cumulative impact of all functional genetic variations. Early studies employed a candidate gene approach, focused mainly on factors within adrenergic and renin-angiotensin pathways that affect heart failure progression and are targeted by standard pharmacotherapeutics. Many of these reported allelic associations with heart failure have not been replicated. However, the preponderance of data support risk-modifier effects for the Arg389Gly polymorphism of β1-adrenergic receptors and the intron 16 in/del polymorphism of angiotensin converting enzyme. Recent unbiased studies using genome-wide single nucleotide polymorphism (SNP) microarrays have shown fewer positive results than when these platforms were applied to hypertension, myocardial infarction, or diabetes, possibly reflecting the complex etiology of heart failure. A new cardiovascular gene-centric sub-genome SNP array identified a common heat failure risk allele at 1p36 in multiple independent cohorts, but the biological mechanism for this association is still uncertain. It is likely that common gene polymorphisms account for only a fraction of individual genetic heart failure risk, and future studies using deep resequencing are likely to identify rare gene variants with larger biological effects.