The U-shaped Relationship Between Serum Methylene Tetrahydrofolate Reductase and Large-artery Atherosclerotic Stroke

Background: Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with ischemic stroke. However, the association between serum MTHFR level and ischemic stroke has not yet been studied. We aimed to examine the association between them in patients with large-artery atherosclerotic stroke and community-based healthy controls. Methods: This study includes three hundred ninety-five patients with large-artery atherosclerotic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and 395 age- and sex-matched healthy controls from Chinese communities. Serum MTHFR concentrations were examined and some conventional risk factors of stroke were collected. The association between serum MTHFR and large-artery atherosclerotic stroke was evaluated. Results: A U-shaped association of serum MTHFR level with large-artery atherosclerotic stroke was observed (p for nonlinearity =0.008). After multivariate adjustment, the odds ratios (95% confidence intervals) of large-artery atherosclerotic stroke associated with the first, second, fourth, and fifth quintiles of MTHFR were 5.62 (1.10-28.87), 2.13 (0.51-8.99), 1.08 (0.21-5.56), and 2.31 (0.57-9.34), respectively, compared with the third quintiles of MTHFR. Adding MTHFR quintiles to a model containing conventional risk factors improved the predictive power for large-artery atherosclerotic stroke (continuous net reclassification improvement=63.78%, p<0.001; categorical net reclassification improvement=2.54%, p=0.012). Conclusion: There is a significant U-shaped relationship between serum MTHFR levels and largeartery atherosclerotic stroke. Our findings raise the possibility that serum MTHFR may have a potential role in the pathogenesis of large-artery atherosclerotic stroke.