Homocysteine and Multiple Health Outcomes: An Outcome-Wide Umbrella Review of Meta-analyses and Mendelian Randomization Studies.

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.