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Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.
Nature Genetics ( IF 30.8 ) Pub Date : 2017-Aug-01 , DOI: 10.1038/ng.3895
Ralph McGinnis , , Valgerdur Steinthorsdottir , Nicholas O Williams , Gudmar Thorleifsson , Scott Shooter , Sigrun Hjartardottir , Suzannah Bumpstead , Lilja Stefansdottir , Lucy Hildyard , Jon K Sigurdsson , John P Kemp , Gabriela B Silva , Liv Cecilie V Thomsen , Tiina Jääskeläinen , Eero Kajantie , Sally Chappell , Noor Kalsheker , Ashley Moffett , Susan Hiby , Wai Kwong Lee , Sandosh Padmanabhan , Nigel A B Simpson , Vivien A Dolby , Eleonora Staines-Urias , Stephanie M Engel , Anita Haugan , Lill Trogstad , Gulnara Svyatova , Nodira Zakhidova , Dilbar Najmutdinova , Anna F Dominiczak , Håkon K Gjessing , Juan P Casas , Frank Dudbridge , James J Walker , Fiona Broughton Pipkin , Unnur Thorsteinsdottir , Reynir T Geirsson , Debbie A Lawlor , Ann-Charlotte Iversen , Per Magnus , Hannele Laivuori , Kari Stefansson , Linda Morgan ,

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

中文翻译:

胎儿基因组中FLT1附近的变异与先兆子痫的风险有关。

子痫前期约占孕妇的5%,是孕产妇和围产期死亡的主要原因。先兆子痫的病因尚不清楚,但是有证据表明遗传易感性。全基因组关联研究(GWAS)尚未鉴定出可在独立数据集中复制的具有全基因组意义的母体序列变异体。我们报告了先兆子痫先兆后代的第一个GWAS,并发现了第一个全基因组范围内的显着易感基因座(rs4769613; P = 5.4×10 -11)在4,380个案例和310,238个控件中。该基因座靠近编码Fms样酪氨酸激酶1的FLT1基因,提供了生物学支持,因为该蛋白(sFlt-1)的胎盘同工型与先兆子痫的病理学有关。这种关联在妊娠的子孙中最为强烈,在妊娠后期,先兆子痫在此发生,子孙的出生体重超过了十分之一。另一个邻近变体rs12050029与先兆子痫相关,独立于rs4769613。新发现的基因座可增强对先兆子痫及其亚型的病理生理学的理解。
更新日期:2017-07-28
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