The Effect of the MTHFR C677T Genotype Polymorphism on the Efficacy of Folic Acid Treatment for Hyperhomocysteinemia and Cardiovascular Endothelial Function

ABSTRACT Background Cardiovascular disease remains a major public health burden. This study aimed to investigate the effect of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype on folic acid treatment response and cardiovascular endothelial function in patients with hyperhomocysteinemia (HHcy). Methods We retrospectively enrolled 344 patients with HHcy genotyped for MTHFR C677T (CC, n = 141; CT, n = 169; and TT, n = 34). Plasma homocysteine (Hcy) concentrations and vascular function indicators were measured at baseline and 2, 4, and 12 months. Repeated‐measures one‐way analysis of variance, Kaplan–Meier analysis, and multivariate logistic regression were applied. Results After treatment, the Hcy concentration and pulse wave velocity decreased over time in all genotype groups, whereas the ankle‐brachial index increased. Significant main effects of time were observed for Hcy concentration ( F = 173.52, p < 0.01), pulse wave velocity ( F = 52.84, p < 0.01), and ankle‐brachial index ( F = 94.17, p < 0.01). At each time point, patients with CC showed better values than patients with CT and TT for all parameters ( p < 0.05) except for intima‐media thickness in patients with TT, which showed no significant changes ( p > 0.05). Patients with CC also had the highest Hcy concentration target achievement rate (81.6%, p < 0.01 vs. CT and TT). Patients with the CC genotype had the highest cumulative Hcy concentration target achievement rate (81.6%), which was higher than that of patients with the CT and TT genotypes ( p < 0.01). Multivariate logistic regression showed that the CT (OR = 0.320, 95% CI: 0.179–0.572) and TT (OR = 0.080, 95% CI: 0.019–0.326) genotypes were independent negative predictors of target achievement, whereas higher folate metabolism capacity was a positive predictor. Conclusion MTHFR C677T polymorphism significantly affects folic acid efficacy and endothelial improvement. Patients with the TT genotype had lower therapeutic efficacy of folic acid therapy. Genotyping may help estimate treatment responses and support individualized follow‐up.