Hyperhomocysteinemia and Ischemic Stroke: A Potential Dose-Response Association—A Systematic Review and Meta-analysis

Background and Purpose Previous studies suggest an association between increased homocysteine (Hcy) and risk of ischemic stroke. Yet, it remains unknown whether a dose-response association exists between Hcy levels and risk of ischemic stroke. Methods Systematic literature searches were performed in PubMed, Embase, Scopus, and Web of Science. Inclusion criteria were studies investigating ischemic stroke risk in an adult population with measured Hcy levels. We computed odds ratios (ORs) for a 5 µmol/L increase in Hcy levels using a random effects meta-analysis. Results In total, 108 studies met the inclusion criteria of which 22 were rated as high-quality studies, and 20 studies included a dose-response analysis. Hcy levels were analyzed either as a continuous or categorical variable. The majority of the studies found an increased risk of ischemic stroke when comparing the highest-to-lowest Hcy strata. A graded association was observed over the Hcy strata, indicating a dose-response association, with the most apparent effect when Hcy levels exceeded approximately 15 µmol/L. No studies explored a potential nonlinear association between Hcy levels and ischemic stroke. Six studies were included in a meta-analysis, showing an OR of 1.43 (95% confidence interval [CI]: 1.28–1.61) per 5 µmol/L increase in Hcy levels. Conclusion This review and meta-analysis indicate a dose-response association between Hcy levels and ischemic stroke. An evident increase in effect measures was observed when Hcy levels exceeded 15 µmol/L, indicating a nonlinear association between ischemic stroke and Hcy levels. This nonlinear association warrants further study. This study is registered with clinical trial ( https://www.crd.york.ac.uk/prospero/ ; unique identifier: CRD42019130371).