With the increasing incidence of hyperhomocysteinemia (HHcy) and hypertension in high-altitude regions, the relationships among homocysteine (Hcy), polymorphisms of Hcy metabolizing enzyme genes, blood pressure, and oxidative stress levels remain unclear. Exploring these correlations may provide new diagnostic and therapeutic insights for H-type hypertension in high-altitude areas.

To analyze the impact of altitude on polymorphisms of Hcy metabolizing enzyme genes, compare differences in blood pressure, Hcy levels, and oxidative stress levels among different genotypes, and explore the correlations between Hcy levels and blood pressure as well as oxidative stress.

From July 2023 to July 2024, 60 hypertensive patients (high-altitude hypertension group) and 30 healthy subjects (high-altitude healthy group) from the Yushu region (altitude: 3 800-4 200 m) were recruited from the Affiliated Hospital of Qinghai University. Additionally, 60 hypertensive patients (low-altitude hypertension group) and 30 healthy subjects (low-altitude healthy group) from the Xining region (altitude: 2 260 m) were included in the study. Baseline information and laboratory test results were collected from the subjects, and polymorphisms of Hcy metabolizing enzyme genes were detected. Pearson correlation tests were used to investigate the correlations among Hcy, blood pressure, serum oxidized glutathione (GSSG), nitric oxide (NO), and superoxide dismutase (SOD) levels.

There were no significant differences in age, gender, BMI, smoking history, drinking history, medication history, family history of hypertension, or ethnicity among the groups (P>0.05). The high-altitude hypertension group had higher Hcy, systolic blood pressure (SBP), diastolic blood pressure (DBP), and GSSG levels, and lower NO and SOD levels compared to the high-altitude healthy group and the low-altitude hypertension group (P<0.05). The high-altitude healthy group had higher SBP, DBP, and GSSG levels, and lower SOD levels compared to the low-altitude healthy group (P<0.05). The low-altitude hypertension group had higher Hcy, SBP, DBP, and GSSG levels, and lower SOD levels compared to the low-altitude healthy group (P<0.05). There was a significant difference in the genotype frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism between the hypertension groups at different altitudes (P<0.05), but no significant differences in the genotype frequencies of the MTHFR A1298C and methionine synthase reductase (MTRR) A66G polymorphisms (P>0.05). There were no significant differences in the genotype frequencies of the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms between the healthy groups at different altitudes (P>0.05). Among the 120 hypertensive patients, 56 (46.67%) had the CC genotype, 43 (35.83%) had the CT genotype, and 21 (17.5%) had the TT genotype at the MTHFR C677T locus; 62 (51.67%) had the AA genotype, 51 (42.50%) had the AC genotype, and 7 (5.83%) had the CC genotype at the MTHFR A1298C locus; 62 (51.67%) had the AA genotype, 48 (40.00%) had the AG genotype, and 10 (8.33%) had the GG genotype at the MTRR A66G locus. At the MTHFR C677T locus, the TT genotype was associated with higher Hcy, SBP, NO, and SOD levels and lower GSSG levels compared to the CT and CC genotypes, and the CT genotype was associated with higher Hcy, SBP, NO, and SOD levels and lower GSSG levels compared to the CC genotype (P<0.05). At the MTHFR A1298C locus, the CC genotype was associated with higher Hcy levels and a higher proportion of HHcy compared to the AC and AA genotypes, and the AC genotype was associated with higher Hcy levels and a higher proportion of HHcy compared to the AA genotype (P<0.05). At the MTRR A66G locus, the GG genotype was associated with higher Hcy, NO levels, and a higher proportion of HHcy compared to the CC and AG genotypes, and the AG genotype was associated with higher Hcy, NO levels, and a higher proportion of HHcy compared to the CC genotype (P<0.05). Patients with HHcy had higher DBP and GSSG levels and lower NO and SOD levels compared to non-HHcy patients. Correlation analysis showed that Hcy was positively correlated with DBP and GSSG and negatively correlated with NO and SOD in hypertensive subjects, and NO was negatively correlated with DBP (P<0.05) .

Hypertensive patients in high-altitude regions have higher blood pressure and oxidative stress levels compared to those in low-altitude regions. However, the genotype distribution of the MTHFR C677T polymorphism tends towards the normal type, with a lower proportion of mutant genotypes that lead to increased Hcy levels, which deviates from traditional views. The relationship between polymorphisms of Hcy metabolizing enzyme genes and Hcy and blood pressure levels remains unclear, and further exploration is needed in the future.