目的 采用两样本孟德尔(MR)方法,评估同型半胱氨酸(Hcy)与子痫前期的因果关联。方法 基于全基因组关联研究(GWAS)数据,正向分析以Hcy为暴露,以子痫前期为结局,选取与Hcy显著相关的遗传变异(SNP)作为工具变量,采用逆向方差加权法(IVW)作为主要分析方法,并辅以MR-Egger 回归进行敏感性分析。通过 Cochran’s Q及MR-Egger 截距检验分别检测异质性及水平多效性,采用留一法分析单个SNP的影响。反向分析以子痫前期为暴露,Hcy为结局进行上述评估。结果 遗传预测的Hcy水平升高与子痫前期发生风险之间存在因果关联,Hcy每增加1个单位,子痫前期发生风险显著升高(OR=3.92,P=2.97×10-6),无显著的异质性及水平多效性,研究结果具有稳健性。反向分析提示子痫前期易感性与Hcy水平呈负向关联,子痫前期遗传风险每增加1个标准差,Hcy降低约0.52个单位(β=-0.519,SE=0.103,P=4.75×10-7)。结论 基于遗传学数据,总体证据支持同型半胱氨酸与子痫前期具有正向因果关联,同型半胱氨酸具有潜在的病因学作用。
Abstract
Objective To evaluate the causal association between homocysteine(Hcy) and preeclampsia through two-sample Mendelian randomization (MR). Methods Based on the data from genome-wide association studies (GWAS), a forward analysis was conducted with Hcy as the exposure and preeclampsia as the outcome. Genetic variants significantly associated with Hcy(SNPs) were selected as instrumental variables, and the inverse variance weighted method (IVW) was used as the main analysis method, supplemented by MR-Egger regression for sensitivity analysis. Heterogeneity and horizontal pleiotropy were assessed using Cochran’s Q test and the MR-Egger intercept tests respectively, and the leave-one-out analysis was performed to examine the influence of individual SNPs. In the reverse-direction analysis, preeclampsia was treated as the exposure and Hcy as the outcome. Results Genetically predicted higher Hcy levels were causally associated with an increased risk of preeclampsia. Each 1-unit increase in Hcy was associated with significantly higher risk of preeclampsia (OR=3.92, P=2.97×10-6), with no significant heterogeneity or horizontal pleiotropy, supporting the robustness of the findings. The reverse-direction analysis showed a negative association between preeclampsia susceptibility and Hcy levels. For each 1 standard deviation increase in genetic risk of preeclampsia, Hcy decreased by approximately 0.52 units (β=-0.519, SE=0.103, P=4.75×10-7). Conclusions Based on genetic data, the overall evidence supports a positive causal association between homocysteine and preeclampsia, suggesting a potential etiological role for Hcy.
关键词
同型半胱氨酸 /
子痫前期 /
孟德尔随机化 /
因果关联 /
全基因组关联研究
Key words
homocysteine /
preeclampsia /
Mendelian randomization /
causal association /
genome-wide association study
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基金
国家自然青年科学基金(编号:62106160)
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