Chen Shuheng, Guo Xiangli, He Yingchao, Wang Yinzhou
Department of Neurology, Fujian Provincial Hospital, Fuzhou, CHN.
Department of Medical Physics, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, CHN.
Cureus. 2025 Jun 20;17(6):e86453. doi: 10.7759/cureus.86453. eCollection 2025 Jun.
Background Hyperhomocysteinemia is a risk factor for ischemic stroke, but its role in hemorrhagic stroke remains unclear. Elevated homocysteine (Hcy) levels may promote endothelial dysfunction, oxidative stress, and extracellular matrix degradation, all of which can contribute to vessel wall fragility and susceptibility to rupture. This study aimed to investigate the causal relationship between plasma homocysteine level and spontaneous intracerebral hemorrhage (ICH). Method We used Mendelian randomization (MR) analysis with data from two independent groups to determine whether plasma homocysteine levels have a causal relationship with ICH. Genetic variants linked to homocysteine levels were taken from the largest available genome-wide association study (GWAS), which included 44,147 people of European ancestry. Data on primary (non-traumatic) spontaneous intracerebral hemorrhage were obtained from the FinnGen database, which comprised 7,763 cases and 412,105 controls, all of European ancestry. Primary Mendelian randomization estimates were calculated using the inverse-variance weighted method, with additional analyses conducted using alternative methods and multiple sensitivity tests. Result We found that genetic predisposition to higher plasma homocysteine levels was significantly associated with an increased risk of spontaneous ICH. Specifically, each one-unit increase in the natural logarithm of genetically predicted homocysteine levels was associated with 41% higher odds of ICH (odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.11-1.80, P = 0.0046), based on the inverse-variance weighted (IVW) method. This Mendelian randomization analysis involved 13 independent genetic variants (SNPs) as instrumental variables. No significant heterogeneity was observed among these SNPs (Cochran's Q test, P = 0.7818), indicating consistency across the genetic instruments used. Additionally, MR-Egger regression intercept analysis did not reveal evidence of horizontal pleiotropy (intercept = 0.0178, p = 0.3676), further supporting the robustness of our results. Visual inspection of scatter plots also did not identify obvious outliers or influential SNPs. Conclusions Total homocysteine levels were found to be associated with an increased risk of ICH. These findings suggest that homocysteine-lowering strategies may warrant further investigation as a potential approach to reduce the risk and progression of ICH, particularly in individuals with a genetic predisposition to elevated homocysteine levels.
高同型半胱氨酸血症是缺血性卒中的一个危险因素，但其在出血性卒中中的作用仍不明确。同型半胱氨酸（Hcy）水平升高可能会促进内皮功能障碍、氧化应激和细胞外基质降解，所有这些都可能导致血管壁脆弱性增加和易于破裂。本研究旨在探讨血浆同型半胱氨酸水平与自发性脑出血（ICH）之间的因果关系。
我们使用孟德尔随机化（MR）分析以及来自两个独立组的数据，以确定血浆同型半胱氨酸水平与ICH之间是否存在因果关系。与同型半胱氨酸水平相关的基因变异取自最大的全基因组关联研究（GWAS），该研究纳入了44147名欧洲血统的人。原发性（非创伤性）自发性脑出血的数据来自芬兰基因数据库，该数据库包含7763例病例和412105名对照，均为欧洲血统。使用逆方差加权法计算原发性孟德尔随机化估计值，并使用替代方法和多种敏感性检验进行额外分析。
我们发现，血浆同型半胱氨酸水平较高的遗传易感性与自发性ICH风险增加显著相关。具体而言，根据逆方差加权（IVW）法，遗传预测的同型半胱氨酸水平的自然对数每增加一个单位，ICH的几率就会增加41%（优势比[OR]=1.41，95%置信区间[CI]：1.11-1.80，P=0.0046）。这项孟德尔随机化分析涉及13个独立的基因变异（单核苷酸多态性）作为工具变量。在这些单核苷酸多态性中未观察到显著的异质性（ Cochr an Q检验，P=0.7818），表明所使用的遗传工具具有一致性。此外，MR-Egger回归截距分析未发现水平多效性的证据（截距=0.0178，p=0.3676），进一步支持了我们结果的稳健性。散点图的直观检查也未发现明显的异常值或有影响的单核苷酸多态性。
发现总同型半胱氨酸水平与ICH风险增加有关。这些发现表明，降低同型半胱氨酸水平的策略可能值得进一步研究，作为降低ICH风险和进展的一种潜在方法，特别是对于具有同型半胱氨酸水平升高遗传易感性的个体。
