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. 2025 Oct;16(5):1536-1549.
doi: 10.1007/s12975-024-01324-y. Epub 2025 Jan 8.

Association Between Folate Metabolism Risk, Collateral Circulation, and Hemorrhagic Risk in Moyamoya Disease

Junsheng Li #  1   2 , Qiheng He #  1   2 , Chenglong Liu  1   2 , Chaofan Zeng  1   2 , Zhiyao Zheng  1   2 , Bojian Zhang  1   2 , Siqi Mou  1   2 , Wei Liu  1   2 , Wei Sun  1   2 , Peicong Ge  3   4 , Dong Zhang  5 , Jizong Zhao  6   7
Affiliations

Association Between Folate Metabolism Risk, Collateral Circulation, and Hemorrhagic Risk in Moyamoya Disease

Junsheng Li et al. Transl Stroke Res. 2025 Oct.

Abstract

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms are known risk factors for vascular diseases due to the impact on folate metabolism dysfunction and homocysteine (Hcy) accumulation. This study aimed to investigate the association between folate metabolism risk and hemorrhagic risk in moyamoya disease (MMD). In this prospective study, we enrolled 350 MMD patients with complete genotype data for MTHFR and MTRR. Patients were divided into non-hemorrhagic and hemorrhagic MMD groups. Folate metabolism risk was classified into three levels according to genotype configurations. We analyzed the association between folate metabolism risk and hemorrhagic risk in MMD. Furthermore, the association between folate metabolism risk, collateral circulation, and periventricular anastomosis (PA) was assessed. In vitro experiments were conducted on HBMECs to explore the potential mechanism. TT genotype and T allele in MTHFR C677T were significantly associated with a lower risk of hemorrhage, whereas AC genotype and C allele in MTHFR A1298C were significantly linked to a higher risk of hemorrhage. Patients with high folate metabolism risk exhibited a significantly decreased risk of hemorrhage compared to those with low folate metabolism risk. Further analyses demonstrated that high folate metabolism risk was significantly correlated with poor collateral circulation and PA dilation and elevated levels of Hcy. In vitro experiments showed that increased Hcy levels significantly inhibited the proliferation, migration, and tube formation of HBMECs. This study identified a significant negative correlation between folate metabolism risk and hemorrhagic risk in MMD. URL: http://www.chictr.org.cn . Unique identifier: ChiCTR2200061889.

Keywords: Collateral circulation; Folate metabolism; Hemorrhage; Homocysteine; Moyamoya disease.

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Conflict of interest statement

Declarations. Ethical Approval: The Beijing Tiantan Hospital Ethics Committee has reviewed and approved this research (KY2022-051–02). Informed Consent: All patients have signed the informed consent to participate in this study. Conflict of Interest: The authors declare no competing interests.

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