From the Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Amsterdam, The Netherlands (C.C.V., S.P., R.T., E.M.L., I.M., L.B., A.A.M.W., R.C., A.O.V., C.A.R., C.R.B.); Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute, Canada (R.T.); Université de Montréal, Canada (R.T.); Department of Medical Biology, Academic Medical Center, Amsterdam, The Netherlands (B.d.J., R.W., B.J.B., A.O.V.); INSERM, CNRS, Université de Nantes, L'institut du Thorax, Nantes, France (J.B.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia (A.A.M.W.); and Electrophysiology and Heart Modeling Institute LIRYC, Université de Bordeaux, France (R.C.).
Circ Res. 2017 Aug 18;121(5):537-548. doi: 10.1161/CIRCRESAHA.117.310959. Epub 2017 Jun 21.
Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near ) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved.
We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in ( heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome.
We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for -expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and expression (β=+0.159; =0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for , which uncovered , encoding the β-subunit of the channel underlying the transient outward current (), as the transcript most robustly correlating with expression (β=+1.47; =2×10). Transcript abundance of and the subunits and , assessed by quantitative reverse transcription-polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in mice compared with wild type. Surface ECG measurements showed less prominent J waves in mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower V in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher and a lower sodium current () density in subepicardium versus subendocardium. These transmural differences were diminished in mice because of changes in subepicardial cardiomyocytes.
This study uncovers a role of in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a -dependent alteration of ion channel expression across the cardiac ventricular wall.
全基因组关联研究先前确定了染色体 6q22.3（靠近）上的 rs9388451 与 Brugada 综合征之间的关联。因果基因和潜在机制仍未解决。
我们使用一种综合方法，包括人类心脏的转录组研究和（杂合子敲除）小鼠的电生理研究，以剖析 6q22.31 与 Brugada 综合征关联的基础。
我们在基因型组织表达联盟获得的 190 个人类左心室样本的表达数量性状基因座数据中查询了 rs9388451 的 -表达数量性状基因座效应，结果显示 Brugada 综合征风险等位基因剂量与 表达之间存在关联（β=+0.159；=0.0036）。在相同的转录组数据中，我们对 进行了全基因组共表达分析，发现编码瞬时外向电流（）通道β亚基的 （β=+1.47；=2×10）是与 表达最密切相关的转录本。通过定量逆转录聚合酶链反应评估的 和 亚基 和 的转录本丰度，在左、右心室的心外膜与心内膜相比均较高，而 小鼠与野生型相比则较低。与野生型相比， 小鼠的体表心电图测量显示 J 波不那么明显。在野生型小鼠中，右心室心肌细胞的膜片钳电生理研究显示，与心内膜心肌细胞相比，心外膜的动作电位持续时间更短，V 更低，而心外膜与心内膜相比， 更高，钠电流（）密度更低。由于心外膜心肌细胞的变化，这些穿壁差异在 小鼠中减小。
本研究揭示了 在心室正常穿壁电生理梯度中的作用，并提供了令人信服的证据，表明 6q22.31（rs9388451）上的遗传变异通过改变心脏心室壁上的离子通道表达与 Brugada 综合征相关。
