Fetal Microsatellite in the Heme Oxygenase 1 Promoter Is Associated With Severe and Early-Onset Preeclampsia
Fetal Microsatellite in the Heme Oxygenase 1 Promoter Is Associated With Severe and Early-Onset Preeclampsia
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DOI：
10.1161/hypertensionaha.117.10425
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发表时间：
2018-01-01
期刊：
影响因子：
8.3
通讯作者：
Laivuori, Hannele
中科院分区：
文献类型：
--
作者：
Kaartokallio, Tea;Utge, Siddheshwar;Laivuori, Hannele
子痫前期是一种血管性妊娠疾病，通常涉及胎盘发育受损。HO-1（血红素加氧酶1，由HMOX1编码）是一种应激反应酶，对内皮和胎盘功能至关重要。HMOX1启动子中鸟嘌呤-胸腺嘧啶（GT(n)）微卫星的长版本会降低HO-1的表达，而母体重复序列的长版本与晚发性子痫前期有关。我们的目的是研究胎儿重复序列的长度是否与母体子痫前期有关，胎儿和母体重复序列的长度是否影响胎盘和母体血清中的HO-1水平，以及HO-1水平是否在子痫前期发生改变。我们对609名子痫前期和745名非子痫前期新生儿脐带血中的重复序列进行了基因分型。采用酶联免疫吸附法测定36份胎盘样本、第一份（222例/243例对照）和第三份（176例/53例对照）妊娠三个月血清样本的HO-1水平。长胎儿GT(n)重复序列与子痫前期及其严重和早发亚型相关。交互作用分析表明母胎效应是独立的。胎盘或血清HO-1水平在子痫前期未发生改变，可能反映了子痫前期的异质性。携带长重复序列的胎儿和母体分别具有较低的胎盘和血清HO-1水平，为这种关联提供了功能证据。我们的结论是，长胎儿GT(n)重复可能增加母亲的风险，特别是严重和早发性先兆子痫。胎儿和母亲的风险等位基因可能易患不同的疾病亚型。
Preeclampsia is a vascular pregnancy disorder that often involves impaired placental development. HO-1 (heme oxygenase 1, encoded by HMOX1) is a stress response enzyme crucial for endothelial and placental function. Long version of the guanine-thymine (GT(n)) microsatellite in the HMOX1 promoter decreases HO-1 expression, and the long maternal repeat is associated with late-onset preeclampsia. Our aim was to study whether the length of fetal repeat is associated with mother's preeclampsia, whether the length of fetal and maternal repeats affect HO-1 levels in placenta and maternal serum, and whether HO-1 levels are altered in preeclampsia. We genotyped the repeat in the cord blood of 609 preeclamptic and 745 nonpreeclamptic neonates. HO-1 levels were measured in 36 placental samples, and in the first (222 cases/243 controls) and third (176 cases/53 controls) pregnancy trimester serum samples using enzyme-linked immunosorbent assay. The long fetal GT(n) repeat was associated with preeclampsia and its severe and early-onset subtypes. Interaction analysis suggested the maternal and fetal effects to be independent. Placental or serum HO-1 levels were not altered in preeclamptics, possibly reflecting heterogeneity of preeclampsia. Carriers of the long fetal and maternal repeats had lower placental and serum HO-1 levels, respectively, providing functional evidence for the association. We conclude that the long fetal GT(n) repeat may increase mother's risk for especially severe and early-onset preeclampsia. The fetal and maternal risk alleles likely predispose to different disease subtypes.