Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.
Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.
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DOI：
10.1038/ncomms15481
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发表时间：
2017-05-25
影响因子：
16.6
通讯作者：
Willer CJ
中科院分区：
文献类型：
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作者：
Yang B;Zhou W;Jiao J;Nielsen JB;Mathis MR;Heydarpour M;Lettre G;Folkersen L;Prakash S;Schurmann C;Fritsche L;Farnum GA;Lin M;Othman M;Hornsby W;Driscoll A;Levasseur A;Thomas M;Farhat L;Dubé MP;Isselbacher EM;Franco-Cereceda A;Guo DC;Bottinger EP;Deeb GM;Booher A;Kheterpal S;Chen YE;Kang HM;Kitzman J;Cordell HJ;Keavney BD;Goodship JA;Ganesh SK;Abecasis G;Eagle KA;Boyle AP;Loos RJF;Eriksson P;Tardif JC;Brummett CM;Milewicz DM;Body SC;Willer CJ
二叶主动脉瓣（BAV）是一种遗传性先天性心脏病，也是瓣膜病和主动脉病的重要危险因素。在这里，我们报告了466例BAV病例和4，660例年龄，性别和种族匹配的对照的全基因组关联扫描，其中1，326例病例和8，103例对照重复。我们确定了与编码心脏特异性转录因子GATA 4的基因的非编码变体151 kb的关联，以及GATA 4中p.Ser377Gly的近显著性。在来自健康供体的诱导多能干细胞中，GATA 4被CRISPR-Cas9中断。GATA 4的破坏显著损害了从内皮细胞向间充质细胞的转化，这是心脏瓣膜发育的关键步骤。二叶式主动脉瓣（BAV）是人类最常见的先天性心血管畸形。在这里，作者对BAV进行了全基因组关联研究，并确定了心脏特异性转录因子GATA 4基因区域的风险变体，并暗示GATA 4与心脏瓣膜发育有关。
Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development. Bicuspid aortic valve (BAV) is the most common human congenital cardiovascular malformation. Here, the authors perform a genome-wide association study for BAV and identify risk variants in the gene region of cardiac-specific transcription factor GATA4 and implicate GATA4 in heart valve development.