MTHFR C677T TT genotype associated with poor blood pressure control in H-type hypertension without folic acid: a retrospective cohort study.

BACKGROUND

H-type hypertension, defined as primary hypertension combined with elevated plasma homocysteine (Hcy) ≥10 μmol/L, represents the predominant hypertensive phenotype in China. Although current guidelines recommend folic acid (FA) supplementation alongside antihypertensive therapy, a substantial treatment gap persists in routine clinical practice. The MTHFR C677T polymorphism is the principal genetic determinant of Hcy metabolism, yet its independent impact on blood pressure (BP) control in FA-untreated patients remains unknown.

METHODS

We conducted a single-centre, retrospective cohort study of 660 H-type hypertensive patients who received guideline-compliant antihypertensive therapy but no FA supplementation, enrolled from a tertiary hospital in Xinjiang, China (January 2019-December 2022). The primary outcome was BP control at follow-up (systolic BP < 140 mmHg and diastolic BP < 90 mmHg). Given the known dosage effect of MTHFR C677T on enzyme activity (CC > CT > TT), we evaluated three standard genetic models: a dominant model (CC vs. CT + TT), a recessive model (CC + CT vs. TT), and an additive model (CC vs. CT vs. TT). The recessive model was used as the primary contrast in PSM analysis to evaluate the high-risk TT homozygous group while maximising matched sample size.

RESULTS

The overall BP control rate was 61.5% (406/660). MTHFR genotype distribution was: CC 28.6%, CT 47.0%, TT 24.4%. In multivariable logistic regression using the recessive model, the TT genotype was associated with higher odds of uncontrolled BP compared with CC + CT carriers (OR = 1.89, 95% CI: 1.21-2.97; P = 0.005). LASSO-selected multivariable regression confirmed this association (OR = 1.83, 95% CI: 1.19-2.82; P = 0.006). After 1:2 PSM (CC + CT, n = 218; TT, n = 138), the TT genotype remained associated with higher odds of uncontrolled BP (OR = 1.75, 95% CI: 1.09-2.84; P = 0.022). Across all models, Grade 3 hypertension (OR range: 1.92-2.10 across the models), high psychological stress, high-salt dietary pattern, and physical inactivity were consistently identified as additional independent risk factors.

CONCLUSION

In H-type hypertensive patients not receiving FA supplementation, the MTHFR 677 TT genotype was associated with poor BP control across multiple analytical models (adjusted OR range: 1.75-1.89 under recessive contrast; 2.06-2.48 under additive contrast). These findings suggest that the TT genotype may serve as a potential marker for identifying patients at higher risk of treatment resistance; whether genotype-guided FA supplementation improves BP control requires confirmation in prospective interventional studies.