Department of Obstetrics and Gynecology, Changzhou maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, NO.16 Dingxiang Road, Changzhou, Jiangsu Province, 213000, China.
Medical Research Center, Changzhou maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, NO.16 Dingxiang Road, Changzhou, Jiangsu Province, 213000, China.
BMC Womens Health. 2024 Apr 5;24(1):223. doi: 10.1186/s12905-024-03000-7.
Observational studies have revealed that metabolic disorders are closely related to the development of preeclampsia (PE). However, there is still a research gap on the causal role of metabolites in promoting or preventing PE. We aimed to systematically explore the causal association between circulating metabolites and PE.
Single nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) of 486 blood metabolites (7,824 participants) were extracted as instrumental variables (P < 1 × 10), GWAS summary statistics for PE were obtained from FinnGen consortium (7,212 cases and 194,266 controls) as outcome, and a two-sample Mendelian randomization (MR) analysis was conducted. Inverse variance weighted (IVW) was set as the primary method, with MR-Egger and weighted median as auxiliary methods; the instrumental variable strength and confounding factors were also assessed. Sensitivity analyses including MR-Egger, Cochran's Q test, MR-PRESSO and leave-one-out analysis were performed to test the robustness of the MR results. For significant associations, repeated MR and meta-analysis were performed by another metabolite GWAS (8,299 participants). Furthermore, significantly associated metabolites were subjected to a metabolic pathway analysis.
The instrumental variables for the metabolites ranged from 3 to 493. Primary analysis revealed a total of 12 known (e.g., phenol sulfate, citrulline, lactate and gamma-glutamylglutamine) and 11 unknown metabolites were associated with PE. Heterogeneity and pleiotropy tests verified the robustness of the MR results. Validation with another metabolite GWAS dataset revealed consistency trends in 6 of the known metabolites with preliminary analysis, particularly the finding that genetic susceptibility to low levels of arachidonate (20:4n6) and citrulline were risk factors for PE. The pathway analysis revealed glycolysis/gluconeogenesis and arginine biosynthesis involved in the pathogenesis of PE.
This study identifies a causal relationship between some circulating metabolites and PE. Our study presented new perspectives on the pathogenesis of PE by integrating metabolomics with genomics, which opens up avenues for more accurate understanding and management of the disease, providing new potential candidate metabolic molecular markers for the prevention, diagnosis and treatment of PE. Considering the limitations of MR studies, further research is needed to confirm the causality and underlying mechanisms of these findings.
观察性研究表明，代谢紊乱与子痫前期（PE）的发生密切相关。然而，代谢物在促进或预防 PE 中的因果作用仍存在研究空白。我们旨在系统探索循环代谢物与 PE 之间的因果关系。
从 486 项血液代谢物的全基因组关联研究（GWAS）中提取单核苷酸多态性（SNP）作为工具变量（P < 1×10），从芬兰人群遗传研究联盟（FinnGen）获得 PE 的 GWAS 汇总统计数据（7212 例病例和 194266 例对照）作为结局，并进行两样本 Mendelian 随机化（MR）分析。以逆方差加权（IVW）作为主要方法，以 MR-Egger 和加权中位数作为辅助方法；还评估了工具变量的强度和混杂因素。进行了 MR-Egger、Cochran's Q 检验、MR-PRESSO 和单样本剔除分析等敏感性分析，以检验 MR 结果的稳健性。对于有意义的关联，通过另一项代谢物 GWAS（8299 名参与者）进行了重复 MR 和荟萃分析。此外，对显著相关的代谢物进行了代谢途径分析。
代谢物的工具变量范围为 3 至 493。初步分析共发现 12 种已知（如对苯二酚硫酸盐、瓜氨酸、乳酸和γ-谷氨酰谷氨酰胺）和 11 种未知代谢物与 PE 相关。异质性和多效性检验验证了 MR 结果的稳健性。使用另一项代谢物 GWAS 数据集进行验证，在初步分析中发现，6 种已知代谢物与前瞻性分析的一致性趋势一致，特别是遗传易感性低水平的花生四烯酸（20:4n6）和瓜氨酸是 PE 的危险因素。通路分析显示，糖酵解/糖异生和精氨酸生物合成与 PE 的发病机制有关。
本研究确定了一些循环代谢物与 PE 之间的因果关系。本研究通过整合代谢组学和基因组学，为 PE 的发病机制提供了新的视角，为更准确地理解和管理该疾病开辟了道路，为 PE 的预防、诊断和治疗提供了新的潜在候选代谢分子标志物。考虑到 MR 研究的局限性，需要进一步研究来确认这些发现的因果关系和潜在机制。
