Wellcome Trust Sanger Institute, Cambridge, UK.
deCODE Genetics/Amgen, Reykjavik, Iceland.
Nat Genet. 2017 Aug;49(8):1255-1260. doi: 10.1038/ng.3895. Epub 2017 Jun 19.
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) 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.
子痫前期影响约 5%的妊娠，是孕产妇和围产儿死亡的主要原因。子痫前期的病因仍不清楚，但有遗传易感性的证据。全基因组关联研究（GWAS）尚未确定在独立数据集复制的具有全基因组意义的母体序列变异。我们报告了首例子痫前期妊娠后代的全基因组关联研究，并在 4380 例病例和 310238 例对照中发现了第一个全基因组显著易感位点（rs4769613；P=5.4×10）。该位点位于编码 Fms 样酪氨酸激酶 1 的 FLT1 基因附近，为这种蛋白质的胎盘同工型（sFlt-1）参与子痫前期病理学提供了生物学支持。该关联在子痫前期发生于妊娠晚期的病例和出生体重超过第十个百分位数的后代中最强。另一个附近的变体 rs12050029 与 rs4769613 无关，与子痫前期独立相关。新发现的基因座可能有助于更好地理解子痫前期及其亚型的病理生理学。
