围产期心肌病和扩张型心肌病的共同遗传易感性。
Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.
作者信息
Ware James S, Li Jian, Mazaika Erica, Yasso Christopher M, DeSouza Tiffany, Cappola Thomas P, Tsai Emily J, Hilfiker-Kleiner Denise, Kamiya Chizuko A, Mazzarotto Francesco, Cook Stuart A, Halder Indrani, Prasad Sanjay K, Pisarcik Jessica, Hanley-Yanez Karen, Alharethi Rami, Damp Julie, Hsich Eileen, Elkayam Uri, Sheppard Richard, Kealey Angela, Alexis Jeffrey, Ramani Gautam, Safirstein Jordan, Boehmer John, Pauly Daniel F, Wittstein Ilan S, Thohan Vinay, Zucker Mark J, Liu Peter, Gorcsan John, McNamara Dennis M, Seidman Christine E, Seidman Jonathan G, Arany Zoltan
机构信息
From the Department of Genetics, Harvard Medical School (J.S.W., E.M., C.M.Y., C.E.S., J.G.S.), the Howard Hughes Medical Institute (C.E.S.), and the Cardiovascular Division, Brigham and Women's Hospital (J.S.W., E.M., C.E.S., J.G.S.) - all in Boston; the Cardiovascular Institute and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (J.L., T.D., T.P.C., Z.A.), the Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh (I.H., J.P., K.H.-Y., J.G., D.M.M.), and Penn State Hershey Medical Center, Hershey (J.B.) - all in Pennsylvania; the National Institute for Health Research Royal Brompton Cardiovascular Biomedical Research Unit (J.S.W., F.M., S.K.P.) and the National Heart and Lung Institute (J.S.W., F.M., S.A.C., S.K.P.), Imperial College London, London; the Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York (E.J.T.), and the University of Rochester, Rochester (J.A.) - both in New York; the Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (D.H.-K.); the Department of Perinatology and Gynecology, the National Cerebral and Cardiovascular Center, Osaka, Japan (C.A.K.); the National Heart Center and Duke-National University of Singapore, Singapore (S.A.C.); the Intermountain Medical Center, Murray, Utah (R.A.); Vanderbilt University, Nashville (J.D.); Cleveland Clinic, Cleveland (E.H.); University of Southern California, Los Angeles (U.E.); McGill University and Jewish General Hospital, Montreal (R.S.), University of Calgary, Calgary, AB (A.K.), and University of Toronto, Toronto (P.L.) - all in Canada; University of Maryland, College Park (G.R.), and Johns Hopkins Hospital, Baltimore (I.S.W.) - both in Maryland; Morristown Hospital, Morristown (J.S.), and Newark Beth Israel Medical Center, Newark (M.J.Z.) - both in New Jersey; Truman Medical Center, University of Missouri, Kansas City (D.F.P.); and Wa
出版信息
N Engl J Med. 2016 Jan 21;374(3):233-41. doi: 10.1056/NEJMoa1505517. Epub 2016 Jan 6.
Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.
背景
围产期心肌病与特发性扩张型心肌病有一些共同的临床特征，特发性扩张型心肌病是一种由40多个基因的突变引起的疾病，包括编码肌节蛋白肌联蛋白的TTN基因。方法：在172例围产期心肌病女性中，我们对43个与扩张型心肌病相关的变异基因进行了测序。我们比较了这些女性中不同变异类型（无义、移码和剪接）的患病率与扩张型心肌病患者及人群对照组中此类变异的患病率。结果：我们在围产期心肌病女性中鉴定出8个基因中的26个不同的罕见截断变异。截断变异的患病率（172例中有26例[15%]）显著高于60706人的参考人群（4.7%，P = 1.3×10⁻⁷），但与扩张型心肌病患者队列（332例患者中有55例[17%]，P = 0.81）相似。三分之二的已鉴定截断变异位于TTN基因，在10%的患者和1.4%的参考人群中可见（P = 2.7×10⁻¹⁰）；几乎所有TTN变异都位于肌联蛋白A带。7个TTN截断变异先前在特发性扩张型心肌病患者中已有报道。在83例临床特征明确的围产期心肌病女性队列中，TTN截断变异的存在与1年随访时较低的射血分数显著相关（P = 0.005）。结论：在一大系列围产期心肌病女性中，截断变异的分布与特发性扩张型心肌病患者中发现的分布非常相似。TTN截断变异是每种疾病中最常见的遗传易感性因素。
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