SCN5A基因测序鉴定出与心脏传导相关的罕见和常见变异：基因组流行病学心脏与衰老研究队列（CHARGE）联盟。
Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
作者信息
Magnani Jared W, Brody Jennifer A, Prins Bram P, Arking Dan E, Lin Honghuang, Yin Xiaoyan, Liu Ching-Ti, Morrison Alanna C, Zhang Feng, Spector Tim D, Alonso Alvaro, Bis Joshua C, Heckbert Susan R, Lumley Thomas, Sitlani Colleen M, Cupples L Adrienne, Lubitz Steven A, Soliman Elsayed Z, Pulit Sara L, Newton-Cheh Christopher, O'Donnell Christopher J, Ellinor Patrick T, Benjamin Emelia J, Muzny Donna M, Gibbs Richard A, Santibanez Jireh, Taylor Herman A, Rotter Jerome I, Lange Leslie A, Psaty Bruce M, Jackson Rebecca, Rich Stephen S, Boerwinkle Eric, Jamshidi Yalda, Sotoodehnia Nona
出版信息
Circ Cardiovasc Genet. 2014 Jun;7(3):365-73. doi: 10.1161/CIRCGENETICS.113.000098.
BACKGROUND
The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.
METHODS AND RESULTS
In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).
CONCLUSIONS
By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
背景
心脏钠通道SCN5A调节房室传导和心室传导。该基因的遗传变异与PR间期和QRS间期相关。我们试图进一步明确SCN5A中罕见和常见编码变异对心脏传导的影响。
方法与结果
在基因组流行病学心脏与衰老研究队列（CHARGE）联盟靶向测序研究中，我们对SCN5A进行了靶向外显子测序（n = 3699，欧洲血统个体），并鉴定出4个常见变异（次要等位基因频率>1%）和157个罕见变异。通过对来自CHARGE、美国国立心肺血液研究所外显子测序项目（n = 607）以及UK10K（n = 1275）的欧洲血统参与者进行荟萃分析，并检测外显子测序项目中的非洲血统参与者（n = 972），研究常见和罕见的SCN5A编码变异与PR间期和QRS间期的关联。总体而言，罕见的SCN5A编码变异与欧洲和非洲血统参与者的PR间期相关（P = 1.3×10⁻³）。在欧洲血统参与者中，有3个常见变异与PR和QRS间期时长相关，在非洲血统参与者中有1个相关。其中包括2个著名的错义变异：rs1805124（H558R）与欧洲血统参与者的PR和QRS间期缩短相关（分别为P = 6.25×10⁻⁴和P = 5.2×10⁻³），rs7626962（S1102Y）与非洲血统参与者的PR间期缩短相关（P = 2.82×10⁻³）。在欧洲血统参与者中，2个新的同义变异rs1805126和rs6599230与心脏传导相关。我们最显著的信号rs1805126与PR和QRS间期延长相关（分别为P = 3.35×10⁻⁷和P = 2.69×10⁻⁴），rs6599230与PR间期缩短相关（P = 2.67×10⁻⁵）。
结论
通过对SCN5A进行测序，我们鉴定出了与心脏传导相关的新的常见和罕见编码变异。
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