Zhou Futao, He Yue, Xie Xinhua, Guo Ning, Chen Wanjiao, Zhao Yushi
School of Basic Medicine, Gannan Medical University, Ganzhou City, Jiangxi Province, China.
School of Basic Medicine, Gannan Medical University, Ganzhou City, Jiangxi Province, China.
Adv Nutr. 2025 Jun;16(6):100434. doi: 10.1016/j.advnut.2025.100434. Epub 2025 Apr 25.
Elevated levels of homocysteine (Hcy) are associated with various health outcomes. We aimed to systematically assess the credibility and certainty of evidence of associations of Hcy and Hcy-lowering therapies with various health outcomes. We retrieved observational meta-analyses examining the associations between Hcy and health outcomes, interventional meta-analyses investigating health outcomes related to Hcy-lowering treatments, and Mendelian randomization (MR) studies exploring the causal associations of Hcy with health outcomes to perform an umbrella review. A total of 135 observational meta-analyses, 106 MR studies, and 26 interventional meta-analyses were included. Among observational studies, 10 associations of diseases/outcomes were classified as highly suggestive; only 1 outcome (digestive tract cancer) was supported by convincing evidence (class I; odd ratio = 1.27, 95% confidence interval = 1.16, 1.40; P = 6.79 × 10; I = 0, 95% prediction interval excluding null, >1000 cases; P > 0.1 for tests of both small-study effects and excess significance bias). In MR studies, 5 outcomes associated with Hcy presented robust evidence (P < 0.01, power >80%). Among 25 outcomes explored by both observational meta-analyses and MR studies, 7 had consistent results, indicating that elevated Hcy is causally associated with an increased risk of these outcomes. The 3 types of studies collectively suggested that the association of stroke with Hcy was supported by observational studies, causally by MR studies, and further validated by intervention meta-analyses showing that Hcy-lowering with folic acid significantly reduced risk of stroke. For dementia and colorectal cancer, Hcy was significantly associated in meta-analyses of observational studies and folic acid decreased disease risks in interventional meta-analyses. The current umbrella review indicates that convincing evidence for a definitive role of Hcy exposure solely exists in the context of digestive tract cancer excluding bias; however, Hcy may not be causal for this disease. All the 3 types of studies collectively support that Hcy is a key causal risk factor, and Hcy-lowering (specifically with folic acid) may serve as an effective intervention for stroke. This trial was registered at PROSPERO as CRD42024541335.
同型半胱氨酸（Hcy）水平升高与多种健康结局相关。我们旨在系统评估Hcy及降低Hcy疗法与多种健康结局之间关联证据的可信度和确定性。我们检索了考察Hcy与健康结局之间关联的观察性荟萃分析、探究与降低Hcy治疗相关健康结局的干预性荟萃分析，以及探索Hcy与健康结局因果关联的孟德尔随机化（MR）研究，以进行一项综合性综述。共纳入135项观察性荟萃分析、106项MR研究和26项干预性荟萃分析。在观察性研究中，10种疾病/结局的关联被归类为高度提示性；仅有1种结局（消化道癌症）有令人信服的证据支持（I类；比值比 = 1.27，95%置信区间 = 1.16, 1.40；P = 6.79×10；I² = 0，95%预测区间不包括无效值，>1000例；小研究效应和过度显著性偏倚检验的P>0.1）。在MR研究中，5种与Hcy相关的结局呈现出有力证据（P<0.01，检验效能>80%）。在观察性荟萃分析和MR研究均探讨的25种结局中，7种结果一致，表明Hcy升高与这些结局风险增加存在因果关联。这三种类型的研究共同表明，中风与Hcy的关联得到观察性研究支持，MR研究表明存在因果关系，干预性荟萃分析进一步验证，即使用叶酸降低Hcy可显著降低中风风险。对于痴呆症和结直肠癌，Hcy在观察性研究的荟萃分析中显著相关，在干预性荟萃分析中叶酸降低了疾病风险。当前的综合性综述表明，仅在排除偏倚的消化道癌症背景下，存在Hcy暴露明确作用的令人信服证据；然而，Hcy可能并非该疾病的病因。这三种类型的研究共同支持Hcy是一个关键的因果风险因素，降低Hcy（特别是使用叶酸）可能作为中风的有效干预措施。本试验在PROSPERO注册为CRD42024541335。
