BACKGROUND: MTHFD1, involved in folate metabolism, has been associated with various health outcomes, including cardiovascular diseases. This study aimed to investigate the association between four single nucleotide polymorphisms (SNPs) in MTHFD1 and the risk of hypertension. METHODS: We conducted a case-control study involving 838 hypertensive patients and 438 controls. Genotyping for four MTHFD1 SNPs was performed using the Agena MassARRAY platform. The association between these SNPs and hypertension risk was evaluated using logistic regression, adjusting for age and sex. Stratified analysis was conducted and visualized using Sangerbox software. The Multifactor Dimensionality Reduction (MDR) method was applied to assess SNP-SNP interactions. RESULTS: Our results analysis revealed a significant correlation between the rs1950902 SNP and an increased risk of hypertension in overall, males and individuals aged 69 years or younger
rs8016556 was associated with a decreased risk of hypertension, particularly in females
and rs11849530 was also linked to a reduced risk of hypertension, especially in older individuals. SNP-SNP interaction analysis revealed significant interactions between the four SNPs, suggesting a joint effect on hypertension risk. CONCLUSIONS: Our findings suggest that certain MTHFD1 polymorphisms (rs1950902, rs8016556, and rs11849530) are associated with the risk of hypertension, and these associations may be influenced by gender and age.