结合LGALS13（胎盘蛋白13）启动子变体-98A/C、黑人种族、既往子痫前期病史、肥胖和产妇年龄预测孕早期发生子痫前期的风险。
Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age.
作者信息
Madar-Shapiro Liora, Karady Ido, Trahtenherts Alla, Syngelaki Argryo, Akolekar Ranjit, Poon Liona, Cohen Ruth, Sharabi-Nov Adi, Huppertz Berthold, Sammar Marei, Juhasz Kata, Than Nandor Gabor, Papp Zoltan, Romero Roberto, Nicolaides Kypros H, Meiri Hamutal
机构信息
Hy Laboratories, Rehovot, Israel.
出版信息
Fetal Diagn Ther. 2018;43(4):250-265. doi: 10.1159/000477933. Epub 2017 Jul 21.
BACKGROUND
LGALS13 (placental protein 13 [PP13]) promoter DNA polymorphisms was evaluated in predicting preeclampsia (PE), given PP13's effects on hypotension, angiogenesis, and immune tolerance.
METHODS
First-trimester plasma samples (49 term and 18 intermediate) of PE cases matched with 196 controls were collected from King's College Hospital, London, repository. Cell-free DNA was extracted and the LGALS13 exons were sequenced after PCR amplification. Expression of LGALS13 promoter reporter constructs was determined in BeWo trophoblast-like cells with luciferase assays. Adjusted odds ratio (OR) was calculated for the A/A genotype combined with maternal risk factors.
RESULTS
The A/A, A/C, and C/C genotypes in the -98 promoter position were in Hardy-Weinberg equilibrium in the control but not in the PE group (p < 0.036). The dominant A/A genotype had higher frequency in the PE group (p < 0.001). The A/C and C/C genotypes protected from PE (p < 0.032). The ORs to develop term and all PE, calculated for the A/A genotype, previous PE, body mass index (BMI) >35, black ethnicity, and maternal age >40 were 15.6 and 11.0, respectively (p < 0.001). In luciferase assays, the "-98A" promoter variant had lower expression than the "-98C" variant in non-differentiated (-13%, p = 0.04) and differentiated (-26%, p < 0.001) BeWo cells. Forskolin-induced differentiation led to a larger expression increase in the "-98C" variant than in the "-98A" variant (4.55-fold vs. 3.85-fold, p < 0.001).
CONCLUSION
Lower LGALS13 (PP13) expression with the "A" nucleotide in the -98 promoter region position (compared to "C") and high OR calculated for the A/A genotype in the -98A/C promoter region position, history of previous PE, BMI >35, advanced maternal age >40, and black ethnicity could serve to aid in PE prediction in the first trimester.
背景
鉴于PP13对低血压、血管生成和免疫耐受的影响，评估了LGALS13（胎盘蛋白13 [PP13]）启动子DNA多态性在预测子痫前期（PE）中的作用。
方法
从伦敦国王学院医院的储存库中收集了与196名对照匹配的PE病例的孕早期血浆样本（49例足月样本和18例中期样本）。提取游离DNA，并在PCR扩增后对LGALS13外显子进行测序。通过荧光素酶测定法测定BeWo滋养层样细胞中LGALS13启动子报告基因构建体的表达。计算A/A基因型与母亲风险因素相结合的调整优势比（OR）。
结果
-98启动子位置的A/A、A/C和C/C基因型在对照组中处于哈迪-温伯格平衡，但在PE组中并非如此（p < 0.036）。显性A/A基因型在PE组中的频率更高（p < 0.001）。A/C和C/C基因型可预防PE（p < 0.032）。针对A/A基因型、既往PE史、体重指数（BMI）>35、黑人种族和母亲年龄>40计算的足月和所有PE发生的OR分别为15.6和11.0（p < 0.001）。在荧光素酶测定中，“-98A”启动子变体在未分化的BeWo细胞（-13%，p = 0.04）和分化的BeWo细胞（-26%，p < 0.001）中的表达低于“-98C”变体。福斯可林诱导的分化导致“-98C”变体的表达增加幅度大于“-98A”变体（4.55倍对3.85倍，p < 0.001）。
结论
-98启动子区域位置的“A”核苷酸（与“C”相比）导致LGALS13（PP13）表达降低，以及-98A/C启动子区域位置的A/A基因型、既往PE史、BMI >35、母亲年龄>40和黑人种族的高OR，可有助于在孕早期预测PE。
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