Chen Xiaoyan, Liu Zhaoming, Cui Jingen, Chen Xiaolan, Xiong Jing, Zhou Wei
Department of Obstetrics, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
Front Genet. 2022 Aug 22;13:935757. doi: 10.3389/fgene.2022.935757. eCollection 2022.
Several observational studies have demonstrated that significantly rising circulating adipokine levels are pervasive in preeclampsia or eclampsia disorder (or preeclampsia toxemia (PET)). However, it remains unclear whether this relationship is causal. In this study, we sought to elucidate the causal effects of circulating adipokine levels on PET. Summary-level data and independent genetic variants strongly associated with common adipokine molecule (adiponectin, leptin, resistin, sOB-R, and PAI-1) levels were drawn from public genome-wide association study (GWASs). Additionally, the corresponding effects between instrumental variables and PET outcomes were acquired from the FinnGen consortium, including 4,743 cases and 136,325 controls of European ancestry. Subsequently, an inverse-variance weighted (IVW) approach was applied for the principal two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Various complementary sensitivity analyses were then carried out to determine the robustness of our models. The results of the IVW method did not reveal any causal relationship shared across genetically predisposed adipokine levels and PET risk (for adiponectin, OR = 0.86, 95% CI: 0.65-1.13, = 0.274). Additionally, no significant associations were identified after taking into account five circulating adipokines in MVMR research. Complementary sensitivity analysis also supported no significant associations between them. In the reverse MR analysis, genetically predicted PET risk showed a suggestive association with elevating PAI-1 levels by the IVW method (Beta = 0.120, 95% CI: 0.014, 0.227, = 0.026). Furthermore, there were no strong correlations between genetic liability to PET and other adipokine levels ( > 0.05). Our MR study did not provide robust evidence supporting the causal role of common circulating adipokine levels in PET, whereas genetically predicted PET may instrumentally affect PAI-1 levels. These findings suggest that PAI-1 may be a useful biomarker for monitoring the diagnosis or therapy of PET rather than a therapeutic target for PET.
多项观察性研究表明，循环中脂肪因子水平显著升高在先兆子痫或子痫疾病（或先兆子痫毒血症（PET））中普遍存在。然而，这种关系是否具有因果性仍不清楚。在本研究中，我们试图阐明循环脂肪因子水平对PET的因果效应。汇总水平数据和与常见脂肪因子分子（脂联素、瘦素、抵抗素、可溶性瘦素受体和纤溶酶原激活物抑制剂-1）水平密切相关的独立基因变异来自公开的全基因组关联研究（GWAS）。此外，工具变量与PET结局之间的相应效应取自芬兰基因联盟，包括4743例病例和136325例欧洲血统对照。随后，采用逆方差加权（IVW）方法进行主要的两样本孟德尔随机化（MR）和多变量MR（MVMR）分析。然后进行各种补充敏感性分析以确定我们模型的稳健性。IVW方法的结果未揭示遗传易感性脂肪因子水平与PET风险之间存在任何因果关系（脂联素的比值比=0.86，95%可信区间：0.65-1.13，P=0.274）。此外，在MVMR研究中考虑五种循环脂肪因子后，未发现显著关联。补充敏感性分析也支持它们之间无显著关联。在反向MR分析中，基因预测的PET风险通过IVW方法显示与PAI-1水平升高存在提示性关联（β=0.120，95%可信区间：0.014，0.227，P=0.026）。此外，PET的遗传易感性与其他脂肪因子水平之间无强相关性（P>0.05）。我们的MR研究未提供有力证据支持常见循环脂肪因子水平在PET中的因果作用，而基因预测的PET可能会对PAI-1水平产生工具性影响。这些发现表明PAI-1可能是监测PET诊断或治疗的有用生物标志物，而不是PET的治疗靶点。
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