From the Human Genetics Research Group, Institute of Biomedicine and Translational Medicine (T.K., R.I., K. Ratnik, K. Rull, M.L.), University of Tartu, Tartu, Estonia.
SYNLAB Estonia OÜ, Tallinn, Estonia (K. Ratnik).
Hypertension. 2020 Sep;76(3):884-891. doi: 10.1161/HYPERTENSIONAHA.120.15346. Epub 2020 Aug 3.
The variant rs4769613 T/C within the enhancer element near , an acknowledged gene in preeclampsia, was previously identified as a risk factor for preeclampsia in the genome-wide association study (GWAS) targeting placental genotypes. We aimed to test the robustness of this association in 2 Estonian cohorts. Both placental sample sets HAPPY PREGNANCY (Development of novel non-invasive biomarkers for fertility and healthy pregnancy; preeclampsia, n=44 versus nonpreeclampsia, n=1724) and REPROMETA (REPROgrammed fetal and/or maternal METAbolism; 52/277) exhibited suggestive association between rs4769613[C] variant and preeclampsia (logistic regression adjusted for gestational age and fetal sex, nominal <0.05). Meta-analysis across 2 samples (96/2001) replicated the genome-wide association study outcome (Bonferroni corrected =4×10; odds ratio, 1.75 [95% CI, 1.23-2.49]). No association was detected with gestational diabetes mellitus, preterm birth, and newborn parameters. Also, neither maternal nor paternal rs4769613 genotypes predisposed to preeclampsia. The exact role of placental rs4769613 genotype in the preeclampsia pathogenesis is to be clarified as no effect was detected on maternal baseline serum sFlt-1 (soluble fms-related receptor tyrosine kinase 1) levels. However, when placental gene expression and maternal serum sFlt-1 measurements were stratified by placental rs4769613 genotypes, significantly higher transcript and biomarker levels were detected in preeclampsia versus nonpreeclampsia cases in the CC- and CT- (Student test, ≤0.02), but not in the TT-genotype subgroup. We suggest that rs4769613 represents a conditional expression Quantitative Trait Locus, whereby only the enhancer with the C-allele reacts to promote the expression in unfavorable placental conditions. The study highlighted that the placental rs4769613 C-allele is a preeclampsia-specific risk factor. It may contribute to early identification of high-risk women, for example, when genotyped in the cffDNA available in maternal blood plasma.
位于基因附近增强子元件中的变体 rs4769613T/C 是子痫前期的公认基因，先前在针对胎盘基因型的全基因组关联研究 (GWAS) 中被确定为子痫前期的风险因素。我们旨在检验该关联在 2 个爱沙尼亚队列中的稳健性。HAPPY PREGNANCY（生育和健康妊娠的新型非侵入性生物标志物的发展；子痫前期，n=44 与非子痫前期，n=1724）和 REPROMETA（REPROgrammed fetal and/or maternal METAbolism；52/277）两个胎盘样本组均显示 rs4769613[C]变体与子痫前期之间存在提示性关联（调整了孕龄和胎儿性别后的逻辑回归，名义 <0.05）。2 个样本（96/2001）的荟萃分析复制了全基因组关联研究的结果（Bonferroni 校正=4×10；优势比，1.75[95%CI，1.23-2.49]）。未检测到与妊娠糖尿病、早产和新生儿参数的关联。此外，母体和父本 rs4769613 基因型均未导致子痫前期。由于未检测到对母体基线血清 sFlt-1（可溶性 fms 相关受体酪氨酸激酶 1）水平的影响，因此需要进一步阐明胎盘 rs4769613 基因型在子痫前期发病机制中的确切作用。然而，当根据胎盘 rs4769613 基因型对胎盘基因表达和母体血清 sFlt-1 测量进行分层时，与非子痫前期病例相比，CC-和 CT-（Student 检验，≤0.02）中观察到显著更高的转录物和生物标志物水平，但 TT 基因型亚组中则没有。我们认为 rs4769613 代表了一个条件表达数量性状基因座，只有带有 C-等位基因的增强子会反应并在不利的胎盘条件下促进基因表达。该研究强调了胎盘 rs4769613 C-等位基因是子痫前期的特异性风险因素。它可能有助于早期识别高危女性，例如，当在母体血浆中可用的 cffDNA 中进行基因分型时。
