Homocysteine and Multiple Health Outcomes: An Outcome-Wide Umbrella Review of Meta-analyses and Mendelian Randomization Studies
Futao Zhou, Yue He, Xinhua Xie, Ning Guo, Wanjiao Chen, Yushi Zhao
Abstract
= 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.