单基因高血压相关致病基因与子痫前期的关联  

Association of monogenic hypertension related pathogenic genes with preeclampsia

作　　者：王欢[1] 梁丹[1,3] 苏灿峰 林靓 林晶[2] 陈慧[1] WANG Huan;LIANG Dan;SU Can-feng;LIN Liang;LIN Jing;CHEN Hui(Cardiovascular Department,Shengli Clinical Medical College of Fujian Medical University,Fuzhou,Fujian 350001,China;Obstetrical Department,Shengli Clinical Medical College of Fujian Medical University,Fuzhou,Fujian 350001,China)

机构地区：[1]福建医科大学省立临床医学院心血管内科,福建福州350001 [2]福建医科大学省立临床医学院产科,福建福州350001 [3]龙岩市第一医院 [4]厦门大学附属翔安医院

出　　处：《中华高血压杂志》2022年第3期236-243,共8页Chinese Journal of Hypertension

基　　金：国家青年科学基金项目(81800363);福建省科技厅青年创新课题项目(20GJ05136);福建省卫健委中青年骨干人才培养项目(2018-ZQN-24);福建省医学创新课题项目(2018-CX-4);福建省立医院高水平医院建设项目(2017-GSP-4)。

摘　　要：目的研究41个单基因高血压相关致病基因与子痫前期的关联,观察基因变异对子痫前期患者胎盘微血管生成和外周T细胞亚型的影响。方法收集入选志愿者外周血并记录临床资料,采用相关致病基因Panel对2016年9月至2019年4月住院的109例子痫前期患者和47例因非患病原因需剖宫产的产妇(对照组)进行基因谱分析;用免疫组化检测部分子痫前期患者(29例)及对照产妇(27例)胎盘组织血管内皮生长因子(VEGF)表达和计数胎盘微血管密度(MVD),用流式细胞仪检测外周血T细胞亚型。结果与对照组比,子痫前期组磷酸二酯酶3A(PDE3A)基因变异频率低(0.9%比8.5%,χ^(2)=6.103,P=0.029),磷酸二酯酶11A(PDE11A)和赖氨酸缺陷蛋白激酶1(WNK1)基因变异频率高(25.5%比6.4%,χ^(2)=7.148,P=0.008;19.3%比4.3%,χ^(2)=5.887,P=0.015)。29例子痫前期患者的PDE11A基因9个外显子位点变异为:c.1825G>T、c.755C>T、c.604C>T、c.2071G>A、c.1921A>G、c.2599C>G、c.305G>T、c.935T>A和c.2757-2758insTCC。21例子痫前期患者的WNK1基因7个外显子位点变异为:c.4564G>A、c.446C>T、c.6707C>T、c.1922A>T、c.1748-1749insA、c.2220-2221insC和c.2175-2176insC,经多重评分软件检测,这些变异大多存在致病性。WNK1野生型对照(n=29)、WNK1野生型子痫前期(n=17)和WNK1变异型子痫前期(n=10)三组胎盘MVD比较显示,WNK1变异型子痫前期组比野生型子痫前期和对照组都低(均P<0.05),野生型子痫前期组和对照组间的差异无统计学意义。二元logistic回归分析显示,在调整了年龄、血压、糖尿病、肥胖、胎龄和胎儿体质量因素后,胎盘MVD与WNK1基因变异负相关(OR=0.86,95%CI 0.75~0.99,P=0.04);三组胎盘VEGF阳性率比较显示,WNK1变异型子痫前期组低于对照组(70%比100%,χ^(2)=8.815,P=0.017),而对照组与野生型子痫前期组对比差异无统计学意义(100%比94.7%,χ^(2)=1.453,P=0.858)。PDE11A基因变异与子痫前期组T细胞亚型变化关系不明确。结论Objective To investigate the relationship between 41 pathogenic genetic variations related to monogenic hypertension and preeclampsia(PE),and to explore the effects of related gene mutations on placental micro-angiogenesis and on the peripheral blood T lymphocyte subsets in PE patients.Methods The peripheral blood of the selected volunteers was collected and the clinical data were recorded.The related pathogenic gene panel was used to analyze gene profile in 109 patients with preeclampsia who were hospitalized from September 2016 to April 2019 and 47 puerperae who required cesarean section for non-disease reasons(control group);immunohistochemistry was used to detect the expression of vascular endothelial growth factor(VEGF)in placental tissue of some preeclampsia patients(n=29)and control group(n=27),the placental microvessel density(MVD)was counted,and flow cytometry was used to detect peripheral blood T cells subtype.Results Compared with the control group,the phosphodiesterase 3 A(PDE3A)gene mutation frequency was lower(0.9%vs 8.5%,χ^(2)=6.103,P=0.029),while the phosphodiesterase 11 A(PDE11A)and WNK1 gene mutation frequencies were higher(25.5%vs 6.4%,χ^(2)=7.148,P=0.008;19.3%vs 4.3%,χ^(2)=5.887,P=0.015)in the PE group.The eight exons variants of PDE11A gene were c.1825 G>T,c.755 C>T,c.604 C>T,c.2071 G>A,c.1921 A>G,c.2599 C>G,c.305 G>T,c.935 T>A and c.2757-2758 insTCC.The seven exons variants of WNK1 gene were c.4564 G>A,C.446 C>T,c.6707 C>T,c.1922 A>T,c.1748-1749 insA,c.2220-2221 insC and c.2175-2176 insC.Most of these variants were predicted to be pathogenic using multiple scoring software.The placental MVD in the WNK1 variant PE group(n=10)was lower than that in the wild-type PE(n=17)and the control group(n=29,both P<0.05),and there was no significant difference between the wild-type PE group and the control group.Binary logistic regression analysis showed that after adjusted for blood pressure,diabetes,obesity,gestational age and fetal weight,placental MVD was negatively correlated with the mutation of

关 键 词：子痫前期 单基因高血压 基因变异 T细胞亚型 胎盘微血管密度 血管内皮生长因子 

分 类 号：R714.244[医药卫生—妇产科学] R544.1[医药卫生—临床医学]