Impact of Folate Metabolism Risk on Hemorrhagic Risk and Collateral Circulation in Moyamoya Disease

Introduction: Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms are known risk factors for vascular diseases due to the impact on folate metabolism risk and homocysteine (Hcy) accumulation. This study aimed to investigate the association between folate metabolism risk and hemorrhagic risk of moyamoya disease (MMD).

Methods: A total of 350 MMD patients with complete genotype data for MTHFR and MTRR were consecutively enrolled from September 2020 to December 2021. Based on the genotypes of MTHFR and MTRR, patients were classified into three folate metabolism risk levels. We analyzed the association between gene polymorphisms, folate metabolism risk levels, and the hemorrhagic risk in MMD. Furthermore, we analyzed the association between folate metabolism risk levels, Hcy levels, and collateral circulation. In vitro experiments on HBMECs were performed, including CCK-8, EdU, Wound healing, Transwell, and tube formation.

Results: The frequencies of TT genotype and T allele in MTHFR C677T were significantly higher in the non-hemorrhagic MMD group and associated with a lower risk of hemorrhage, whereas AC genotype and C allele in MTHFR A1298C were more prevalent in the hemorrhagic MMD group and linked to a higher risk of hemorrhage. Compared to low folate metabolism risk, MMD patients with high folate metabolism risk exhibited a significantly decreased risk of hemorrhage. Further analysis revealed that high folate metabolism risk was significantly associated with elevated levels of Hcy and poor collateral circulation. With the increase of Hcy levels, the proliferation, migration, and tube formation of HBMECs were significantly inhibited in vitro.

Conclusion : Our study has revealed that the folate metabolism risk levels were significantly negatively associated with the hemorrhagic risk of MMD. Moreover, high folate metabolism risk led to elevated Hcy levels and poor collateral circulation. It suggested that MMD patients with specific MTHFR polymorphisms and folate metabolism risk might benefit from positive clinical management to reduce the risk of hemorrhage.