Interaction of MTHFR Gene Polymorphisms and Gut Microbiota with Folate, Vitamin B12, and Homocysteine Levels in Hypertensive Iraqi Adults

Hypertension is a leading global cardiovascular risk, and emerging evidence suggests that genetic variants particularly polymorphisms in the MTHFR (methylenetetrahydrofolate reductase) gene may influence blood pressure by modulating gut microbiota, folate, and homocysteine metabolism. In an Iraqi case-control study involving 180 adults (90 hypertensive, 90 normotensive), researchers genotyped the MTHFR C677T and A1298C variants via PCR-RFLP, measured serum homocysteine, folate, and vitamin B₁₂ by ELISA and chemiluminescence assays, and profiled gut microbiota using 16S rRNA sequencing. They found that the 677 T allele was more common in hypertensive individuals (p = 0.021), who also had significantly higher homocysteine (18.1 ± 5.2 vs 12.6 ± 4.3 µmol/L, p < 0.001), lower folate (6.8 ± 2.4 vs 9.2 ± 2.8 ng/mL, p < 0.001), and reduced B₁₂ (280 ± 85 vs 340 ± 92 pg/mL, p = 0.004). Microbiome analysis revealed gut dysbiosis in hypertensives, marked by reduced diversity (Shannon index 3.25 ± 0.42 vs 3.68 ± 0.39, p = 0.002), decreased Bifidobacterium (3.6 ± 1.4% vs 6.1 ± 1.7%, p < 0.001), and an increased Firmicutes/Bacteroidetes ratio (2.9 ± 0.8 vs 1.7 ± 0.5, p < 0.001). Critically, there was a significant gene–microbiome interaction: individuals with the TT genotype and low microbial diversity had the highest homocysteine levels (21.9 ± 5.3 µmol/L, p = 0.018 for interaction). These findings highlight a complex interplay between MTHFR polymorphisms and gut microbiota in regulating homocysteine metabolism in hypertensive Iraqi adults—and suggest that personalized nutritional or probiotic interventions might help manage hypertension.