Significant Association of Methylenetetrahydrofolate dehydrogenase 1 Promoter Hypomethylation with Stroke in a Chinese Population with Primary Hypertension

Objective: Hypertension and hyperhomocysteinemia are both stroke risk factors. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) plays a vital role in one-carbon metabolism via encoding a protein with three distinct enzymatic activities (methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formate-tetrahydrofolate ligase). We aimed to elucidate the association between MTHFD1 promoter methylation and stroke in a Chinese population with primary hypertension.

Methods: Quantitative methylation-specific PCR was used to quantify MTHFD1 methylation levels in 243 hypertensive controls and 138 matched patients with stroke (also with primary hypertension). A luciferase reporter gene assay was performed to investigate the possible regulatory function of the MTHFD1 promoter.

Results: Methylation of the MTHFD1 promoter was significantly higher in hypertensive controls than in patients with stroke (median [interquartile range]: 10.16[6.61-14.00] vs. 5.41[3.15-7.53], P<0.001). The median level of homocysteine (Hcy) was 15.50 μmol/L in patients with stroke, which was higher than the (homocysteine) Hcy level of 14.40 μmol/L in the hypertensive controls (P=0.010). The diagnostic value of MTHFD1 methylation for stroke was also examined. The area under the curve was 0.789(0.743-0.836), and the sensitivity and specificity were 79.7% and 67.1%, respectively. A significant inverse correlation was observed between MTHFD1 methylation level and Hcy (r_s =-0.110, P=0.031). Subsequently, a significant gene regulatory function of the MTHFD1 promoter was discovered using a dual-luciferase reporter assay.

Conclusions: Our findings suggest a significant association between hypomethylation of the MTHFD1 promoter and stroke in Chinese hypertensive populations.