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 one outcome (digestive tract cancer) was supported by convincing evidence (class I; OR=1.27, 95% CI=1.16-1.40; P=6.79×10-7; I2=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 for 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 three type 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. REGISTRATION PROSPERO: CRD42024541335 STATEMENT OF SIGNIFICANCE: Previous systematic reviews has not been summarized and appraised evidence of meta-analyses of observational and interventional studies, and Mendelian randomization studies on associations of homocysteine or homocysteine-lowering with a range of diseases (outcomes). Our umbrella review takes full advantage of the respective strengths of meta-analyses and MR studies by combining and comparing the findings to explore and assess the potential importance and implications of homocysteine for clinical practice and public health.