The l-Arginine pathway may act as a mediator in the association between impaired one-carbon metabolism and hypertension

Elevated fasting plasma total homocysteine (tHcy) and the methylenetetrahydrofolate reductase C677T polymorphism (rs1801133) have been associated with hypertension. Whether the l-Arginine pathway is involved, is unclear. We aimed to investigate whether the association between tHcy, the rs1801133 polymorphism and hypertension involves the l-Arginine pathway. THcy, plasma folate and cobalamin, erythrocyte glutathionine reductase activation coefficient, rs1801133 genotype, plasma l-Arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were determined in a cross-sectional study of 788 adults (aged 18 to 75), randomly selected from 2 town population registers. Participants participated in a medical checkup and provided a fasting blood sample. Associations between tHcy, rs1801133 genotype and l-Arginine pathway metabolites were assessed by multiple linear regression analysis and whether the tHcy and rs1801133 genotype are associated with hypertension via the l-Arginine pathway was investigated using mediation analysis. tHcy was positively associated with ADMA (B = 0.003; SE = 0.001; P < 0.001) and SDMA (B = 0.007; SE = 0.002; P < 0.001) and negatively associated with the l-Arginine/ADMA (B = -1.140; SE = 0.451; P < 0.05) and ADMA/SDMA (B = -0.006; SE = 0.003; P < 0.05) ratios. The MTHFR 677 CT vs CC genotype was negatively associated with ADMA (B = -0.013; SE = 0.007; P < 0.05) and with SDMA (B = -0.029; SE = 0.013; P < 0.05) in participants under 50 years. Each standard deviation increase (37.6) in the l-Arginine/ADMA ratio was associated with reduced hypertension risk (OR [95%CI], 0.6 [0.5, 0.8]). Mediation analysis showed that tHcy and ADMA were mediators in the association between the rs1801133 TT vs CC genotypes and hypertension. Our results support the l-Arginine pathway as a mediator in the association of impaired One-Carbon metabolism and hypertension.