Sakowicz Agata, Pietrucha Tadeusz, Rybak-Krzyszkowska Magda, Huras Hubert, Gach Agnieszka, Sakowicz Bartosz, Banaszczyk Mateusz, Grzesiak Mariusz, Biesiada Lidia
Department of Medical Biotechnology, Medical University of Lodz, Lodz, Poland.
Department of Obstetrics and Perinatology, University Hospital in Krakow, Krakow, Poland.
PLoS One. 2017 Jun 27;12(6):e0180065. doi: 10.1371/journal.pone.0180065. eCollection 2017.
The precise etiology of preeclampsia is unknown. Family studies indicate that both genetic and environmental factors influence its development. One of these factors is NFkB, whose activation depends on NEMO (NFkB essential modulator. This is the first study to investigate the association between the existence of single nucleotide variant of the NEMO gene and the appearance of preeclampsia. A total of 151 women (72 preeclamptic women and 79 controls) and their children were examined. Sanger sequencing was performed to identify variants in the NEMO gene in the preeclamptic mothers. The maternal identified variants were then sought in the studied groups of children, and in the maternal and child controls, using RFLP-PCR. Real-time RT-PCR was performed to assess NEMO gene expression in maternal blood, umbilical cord blood and placentas. The sequencing process indicated the existence of two different variants in the 3'UTR region of the NEMO gene of preeclamptic women (IKBKG:c.*368C>A and IKBKG:c.*402C>T). The simultaneous occurrence of the TT genotype in the mother and the TT genotype in the daughter or a T allele in the son increased the risk of preeclampsia development 2.59 fold. Additionally, we found that the configuration of maternal/fetal genotypes (maternal TT/ daughter TT or maternal TT/son T) of IKBKG:c.*402C/T variant is associated with the level of NEMO gene expression. Our results showed that, the simultaneous occurrence of the maternal TT genotype (IKBKG:c.*402C>T variants) and TT genotype in the daughter or T allele in the son correlates with the level of NEMO gene expression and increases the risk of preeclampsia development. Our observations may offer a new insight into the genetic etiology and pathogenesis of preeclampsia.
子痫前期的确切病因尚不清楚。家族研究表明，遗传和环境因素均会影响其发展。其中一个因素是核因子κB（NFκB），其激活依赖于NFκB必需调节因子（NEMO）。这是第一项研究NEMO基因单核苷酸变异的存在与子痫前期出现之间关联的研究。共检查了151名女性（72名单纯子痫前期女性和79名对照）及其子女。采用桑格测序法鉴定子痫前期母亲NEMO基因中的变异。然后使用限制性片段长度多态性聚合酶链反应（RFLP-PCR）在研究的儿童组以及母婴对照组中寻找母亲鉴定出的变异。采用实时逆转录聚合酶链反应（Real-time RT-PCR）评估母亲血液、脐带血和胎盘组织中NEMO基因的表达。测序过程表明，子痫前期女性的NEMO基因3'非翻译区（UTR）存在两种不同的变异（IKBKG:c.*368C>A和IKBKG:c.*402C>T）。母亲为TT基因型且女儿为TT基因型或儿子为T等位基因同时出现会使子痫前期发展风险增加2.59倍。此外，我们发现IKBKG:c.*402C/T变异的母/胎基因型组合（母亲TT/女儿TT或母亲TT/儿子T）与NEMO基因表达水平相关。我们的结果表明，母亲TT基因型（IKBKG:c.*402C>T变异）与女儿TT基因型或儿子T等位基因同时出现与NEMO基因表达水平相关，并增加子痫前期发展风险。我们的观察结果可能为子痫前期的遗传病因和发病机制提供新的见解。
