Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.
Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.
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肉瘤蛋白滴定中的罕见截断变体与家族性和早期心房颤动相关。
DOI：
10.1038/s41467-018-06618-y
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发表时间：
2018-10-17
影响因子：
16.6
通讯作者：
Olesen MS
中科院分区：
文献类型：
--
作者：
Ahlberg G;Refsgaard L;Lundegaard PR;Andreasen L;Ranthe MF;Linscheid N;Nielsen JB;Melbye M;Haunsø S;Sajadieh A;Camp L;Olesen SP;Rasmussen S;Lundby A;Ellinor PT;Holst AG;Svendsen JH;Olesen MS
心房颤动的家族史构成了发生该疾病的重大风险，然而，这种复杂疾病的发病机制尚不清楚。我们对24个至少有3个家庭成员被诊断为房颤（AF）的家庭进行了全外显子组测序，发现titin-truncating变异体（TTNtv）在这些患者中显著富集（P = 1.76 × 10−6）。这一发现在早发性单发房颤患者的独立队列中得到了重复（n = 399；优势比= 36.8;P = 4.13 × 10−6）。利用携带titin截断变体的CRISPR/Cas9修饰的斑马鱼来研究TTNtv在心房发育中的作用。我们观察到心房和心室肌节的受损，PR间期较长，杂合的成年斑马鱼心房纤维化程度较高，表明TTNtv是房颤的重要危险因素。这与疾病的早期发病一致，并为了解房颤的分子易感性增加了重要的层面。结构蛋白中常见的遗传变异有助于房颤（AF）的风险。在这里，作者使用全外显子组测序，鉴定出TTN中罕见的截断变异，这些变异与家族性和早发性房颤有关，并显示TTN中心肌肌节组装存在缺陷。2-mutant斑马鱼。
A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10−6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10−6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF. Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2-mutant zebrafish.
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使用组织特异性定量相互作用蛋白质组学对全基因组关联研究中的基因座进行注释。
影响因子：
48
作者：
Lundby, Alicia;Rossin, Elizabeth J.;Steffensen, Annette B.;Acha, Moshe Ray;Newton-Cheh, Christopher;Pfeufer, Arne;Lyneh, Stacey N.;Olesen, Soren-Peter;Brunak, Soren;Ellinor, Patrick T.;Jukema, J. Wouter;Trompet, Stella;Ford, Ian;Macfarlane, Peter W.;Krijthe, Bouwe P.;Hofman, Albert;Uitterlinden, Andre G.;Stricker, Bruno H.;Nathoe, Hendrik M.;Spiering, Wilko;Daly, Mark J.;Asselbergs, Ikea W.;van der Harst, Pim;Milan, David J.;de Bakker, Paul I. W.;Lage, Kasper;Olsen, Jesper V.
通讯作者：
Olsen, Jesper V.
影响因子：
2.1
作者：
Conomos MP;Miller MB;Thornton TA
通讯作者：
Thornton TA
DOI：
10.1161/circoutcomes.110.958165
发表时间：
2011-05-01
影响因子：
6.9
作者：
Kim, Michael H.;Johnston, Stephen S.;Schulman, Kathy L.
通讯作者：
Schulman, Kathy L.
影响因子：
37.8
作者：
Chugh SS;Havmoeller R;Narayanan K;Singh D;Rienstra M;Benjamin EJ;Gillum RF;Kim YH;McAnulty JH Jr;Zheng ZJ;Forouzanfar MH;Naghavi M;Mensah GA;Ezzati M;Murray CJ
通讯作者：
Murray CJ
影响因子：
24
作者：
Israel, CW;Grönefeld, G;Hohnloser, SH
通讯作者：
Hohnloser, SH