Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
PLoS One. 2012;7(7):e41032. doi: 10.1371/journal.pone.0041032. Epub 2012 Jul 31.
β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.
β-受体阻滞剂和β-激动剂主要用于治疗心血管疾病。人们已经充分认识到，个体对这两类药物的反应存在差异，但涉及的遗传因素的性质和相对贡献仍知之甚少。本研究是首次针对选择性β1-受体阻滞剂阿替洛尔（ate）和β-激动剂异丙肾上腺素（iso）对心血管相关特征的作用和易感性进行的全基因组关联研究（GWAS）。表型数据集包含 27 个高度遗传的特征，每个特征在 22 个近交系小鼠和 4 种药理学条件下进行测量。基因型面板包括 79922 个来自小鼠 HapMap 资源的信息 SNP。通过高效混合模型关联（EMMA）进行关联映射，该方法纠正了各种品系的群体结构和遗传相关性。总共分析了 205 个独立的全基因组扫描。最显著的结果包括与心脏和体重相关的三个候选基因座，三个心电图（ECG）值相关的基因座，两个心房重量指数对 iso 易感性的基因座，四个与β-肾上腺素能系统扰动时收缩压（SBP）易感性相关的基因座，以及一个对 QTc 反应性的基因座（p<10(-8)）。另外 60 个基因座对 27 个特征中的一个或另一个具有提示性，而另外 46 个基因座对一种或另一种药物作用具有提示性（p<10(-6)）。大多数结果标记了意想不到的区域，但至少有两个 SBP 对β-肾上腺素能药物易感性的基因座指向了下丘脑-垂体-甲状腺轴的成员。与心脏相关的特征基因座在心脏表达的基因中优先富集，而可测试基因座的 23%可以通过 Mouse Phenome Database（MPD）数据集进行复制。总的来说，这些数据和验证测试表明，所映射的基因座与研究的特征和反应相关。
