Integrated analysis of the association between methionine cycle and risk of moyamoya disease

OBJECTIVE: The role of methionine (Met) cycle in the pathogenesis and progression of cardiovascular and cerebrovascular diseases has been established, but its association with moyamoya disease (MMD) has rarely been studied. This study aimed to analyze the levels of Met cycle‐related metabolites and constructed a risk model to explore its association with the risk of MMD. METHODS: In this prospective study, a total of 302 adult MMD patients and 88 age‐matched healthy individuals were consecutively recruited. The serum levels of Met cycle‐related metabolites were quantified by liquid chromatography‐mass spectrometry (LC–MS). Participants were randomly divided into training set and testing set at a ratio of 1:1. The training set was used to construct the risk score model by LASSO regression. The association between Met cycle‐related risk score and the risk of MMD was analyzed using logistic regression and assessed by ROC curves. The testing set was used for validation. RESULTS: The levels of methionine sulfoxide and homocysteine were significantly increased, while the levels of betaine and choline were significantly decreased in MMD and its subtypes compared to healthy controls (p < 0.05 for all). The training set was used to construct the risk model and the risk score of each participant has been calculated. After adjusting for potential confounders, the risk score was independently associated with the risk of MMD and its subtypes (p < 0.05 for all). We then divided the participants into low‐risk and high‐risk groups, the high‐risk score was significantly associated with the risk of MMD and its subtypes (p < 0.05 for all). The risk scores were further assessed as tertiles, the highest tertile was significantly associated with a higher risk of MMD and its subtypes compared to the lowest (p < 0.05 for all). The results were validated in the testing set. CONCLUSION: This study has constructed and validated a risk model based on Met cycle‐related metabolites, which was independently associated with the risk of MMD and its subtypes. The findings provided a new perspective on the risk evaluation and prevention of MMD.