Study on the Relationship between Homocysteine Levels, Polymorphisms of Homocysteine Metabolizing Enzyme Genes, Blood Pressure, and Oxidative Stress Levels in Hypertensive Patients at Different Altitudes

doi:10.12114/j.issn.1007-9572.2024.0496

Abstract

Abstract:

Background

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.

Objective

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.

Methods

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.

Results

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) .

Conclusion

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.

Key words: Hypertension, Hyperhomocysteinemia, Homocysteine, Altitude, MTHFR gene polymorphisms, MTRR gene polymorphisms, Oxidative stress

摘要：

背景

随着高海拔地区高同型半胱氨酸血症（HHcy）及高血压发病率的增加，同型半胱氨酸（Hcy）及其代谢酶基因多态性与血压、氧化应激水平之间的关系尚不明确，探讨其相关性或许可为高海拔地区H型高血压提供新的诊疗思路。

目的

分析海拔对Hcy代谢酶基因多态性的影响，比较不同基因型之间血压、Hcy及氧化应激水平的差异，探讨Hcy水平与血压、氧化应激之间的相关性。

方法

纳入2023年7月—2024年7月在青海大学附属医院诊治的玉树地区（海拔3 800~4 200 m）高血压患者60例（高海拔高血压组）、健康受试者30例（高海拔健康组）；纳入西宁地区（海拔2 260 m）高血压患者60例（低海拔高血压组）、健康受试者30例（低海拔健康组）为研究对象。收集研究对象的基线资料和实验室检查结果，检测Hcy代谢酶基因多态性。采用Pearson相关性分析探讨Hcy、血压、血清氧化型谷胱甘肽（GSSG）、一氧化氮（NO）、超氧化物歧化酶（SOD）水平的相关性。

结果

各组受试者年龄、性别、BMI、吸烟史、饮酒史、服药史、高血压家族史、民族比较，差异无统计学意义（P>0.05）。高海拔高血压组Hcy、收缩压（SBP）、舒张压（DBP）、GSSG高于高海拔健康组、低海拔高血压组，NO、SOD低于高海拔健康组、低海拔高血压组（P<0.05）；高海拔健康组SBP、DBP、GSSG高于低海拔健康组，SOD低于低海拔健康组（P<0.05）；低海拔高血压组Hcy、SBP、DBP、GSSG高于低海拔健康组，SOD低于低海拔健康组（P<0.05）。不同海拔地区高血压组受试者亚甲基四氢叶酸还原酶（MTHFR）C677T基因型频率比较，差异有统计学意义（P<0.05），MTHFR A1298C、蛋氨酸合酶还原酶（MTRR）A66G基因型频率比较，差异无统计学意义（P>0.05）；不同海拔地区健康组受试者MTHFR C677T、MTHFR A1298C、MTRR A66G基因型频率比较，差异无统计学意义（P>0.05）。120例高血压患者MTHFR C677T位点中CC基因型56例（46.67%），CT基因型43例（35.83%），TT基因型21例（17.5%），MTHFR A1298C位点中AA基因型62例（51.67%）、AC基因型51例（42.50%）、CC基因型7例（5.83%），MTRR A66G位点中AA基因型62例（51.67%）、AG基因型48例（40.00%）、GG基因型10例（8.33%）。MTHFR C677T位点中TT基因型Hcy、SBP、NO、SOD水平高于CT基因型和CC基因型，GSSG低于CT基因型和CC基因型，CT基因型Hcy、SBP、NO、SOD水平高于CC基因型，GSSG低于CC基因型（P<0.05）；MTHFR A1298C位点中CC基因型Hcy水平、HHcy比例高于AC基因型和AA基因型，AC基因型Hcy水平、HHcy比例高于AA基因型（P<0.05）；MTRR A66G位点中GG基因型Hcy、NO、HHcy比例高于CC基因型和CT基因型，CT基因型Hcy、NO、HHcy比例高于CC基因型（P<0.05）。HHcy患者DBP、GSSG高于非HHcy血症患者，NO、SOD低于非HHcy患者。相关性分析结果表明，高血压受试者Hcy与DBP、GSSG水平呈正相关，与NO、SOD水平呈负相关，NO与DBP水平呈负相关（P<0.05）。

结论

高海拔地区高血压患者血压相较于低海拔地区高血压患者更高，氧化应激水平更高，但MTHFR C677T基因分型趋向于正常型，导致Hcy升高的突变型比例较低，与传统观点存在一定的偏差，关于Hcy代谢酶基因多态性与Hcy、血压水平的关系尚不明确，未来仍需更多探索。

关键词: 高血压, 高同型半胱氨酸血症, 同型半胱氨酸, 高海拔, MTHFR基因多态性, MTRR基因多态性, 氧化应激

ZHANG Ning,FAN Shiming,REN Ming, et al. Study on the Relationship between Homocysteine Levels, Polymorphisms of Homocysteine Metabolizing Enzyme Genes, Blood Pressure, and Oxidative Stress Levels in Hypertensive Patients at Different Altitudes[J]. Chinese General Practice, 2025, 28(15): 1862-1870. DOI: 10.12114/j.issn.1007-9572.2024.0496.
张柠,樊世明,任明等. 不同海拔地区高血压患者同型半胱氨酸水平及代谢酶基因多态性与血压及氧化应激水平的关系研究[J]. 中国全科医学, 2025, 28(15): 1862-1870. DOI: 10.12114/j.issn.1007-9572.2024.0496.

Figures/Tables 9

References 28

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组别	例数	年龄（岁）	性别（男/女）	BMI （kg/m²）	吸烟史[例（%）]	饮酒史[例（%）]	服药史[例（%）]	高血压家族史[例（%）]	民族[例（%）]
组别	例数	年龄（岁）	性别（男/女）	BMI （kg/m²）	吸烟史[例（%）]	饮酒史[例（%）]	服药史[例（%）]	高血压家族史[例（%）]	藏族	汉族
高海拔高血压组	60	60.1±14.3	24/36	25.7±3.9	15（25.0）	17（28.3）	19（31.7）	12（20.0）	25（41.7）	35（58.3）
高海拔健康组	30	59.7±15.5	13/17	22.5±2.7	8（26.7）	3（10.0）	0	2（6.7）	13（43.3）	17（56.7）
低海拔高血压组	60	55.7±11.1	16/44	25.1±2.5	25（41.7）	11（18.3）	12（20.0）	9（15.0）	33（55.0）	27（45.0）
低海拔健康组	30	51.7±11.9	12/18	24.7±4.3	6（20.0）	4（13.3）	0	1（3.3）	12（40.0）	18（60.0）
F（χ²）值		3.339	3.588^a	5.061	6.190^a	5.498^a	2.131^a	6.202^a	2.929^a
P值		0.243	0.310	0.134	0.103	0.139	0.144	0.102	0.403

组别	例数	年龄（岁）	性别（男/女）	BMI （kg/m²）	吸烟史[例（%）]	饮酒史[例（%）]	服药史[例（%）]	高血压家族史[例（%）]	民族[例（%）]
组别	例数	年龄（岁）	性别（男/女）	BMI （kg/m²）	吸烟史[例（%）]	饮酒史[例（%）]	服药史[例（%）]	高血压家族史[例（%）]	藏族	汉族
高海拔高血压组	60	60.1±14.3	24/36	25.7±3.9	15（25.0）	17（28.3）	19（31.7）	12（20.0）	25（41.7）	35（58.3）
高海拔健康组	30	59.7±15.5	13/17	22.5±2.7	8（26.7）	3（10.0）	0	2（6.7）	13（43.3）	17（56.7）
低海拔高血压组	60	55.7±11.1	16/44	25.1±2.5	25（41.7）	11（18.3）	12（20.0）	9（15.0）	33（55.0）	27（45.0）
低海拔健康组	30	51.7±11.9	12/18	24.7±4.3	6（20.0）	4（13.3）	0	1（3.3）	12（40.0）	18（60.0）
F（χ²）值		3.339	3.588^a	5.061	6.190^a	5.498^a	2.131^a	6.202^a	2.929^a
P值		0.243	0.310	0.134	0.103	0.139	0.144	0.102	0.403

组别	例数	Hcy（μmol/L）	SBP（mmHg）	DBP（mmHg）	GSSG（U/L）	NO（g/mol）	SOD（ng/mL）
高海拔高血压组	60	15.72±2.32^ab	171±14^ab	109±10^ab	9.73±3.97^ab	17.31±2.22^ab	1.18±0.52^ab
高海拔健康组	30	12.44±2.61	125±2^c	87±1^c	1.37±0.67^c	22.74±2.96	2.13±0.49^c
低海拔高血压组	60	12.17±3.17^a	158±8^a	105±2^a	7.88±3.90^a	24.64±2.96	1.87±0.59^a
低海拔健康组	30	11.71±3.19	122±9	84±2	0.79±0.37	22.17±4.27	2.43±0.69
F值		8.710	7.866	11.508	57.718	62.731	39.394
P值		<0.001	0.006	<0.001	<0.001	<0.001	<0.001

组别	例数	Hcy（μmol/L）	SBP（mmHg）	DBP（mmHg）	GSSG（U/L）	NO（g/mol）	SOD（ng/mL）
高海拔高血压组	60	15.72±2.32^ab	171±14^ab	109±10^ab	9.73±3.97^ab	17.31±2.22^ab	1.18±0.52^ab
高海拔健康组	30	12.44±2.61	125±2^c	87±1^c	1.37±0.67^c	22.74±2.96	2.13±0.49^c
低海拔高血压组	60	12.17±3.17^a	158±8^a	105±2^a	7.88±3.90^a	24.64±2.96	1.87±0.59^a
低海拔健康组	30	11.71±3.19	122±9	84±2	0.79±0.37	22.17±4.27	2.43±0.69
F值		8.710	7.866	11.508	57.718	62.731	39.394
P值		<0.001	0.006	<0.001	<0.001	<0.001	<0.001

组别	例数	MTHFR C677T			MTHFR A1298C			MTRR A66G
组别	例数	CC	CT	TT	AA	AC	CC	AA	AG	GG
高海拔高血压组	60	41（68.4）	17（28.3）	2（3.3）	30（50.0）	26（43.3）	4（6.7）	26（43.3）	27（45.0）	7（11.7）
低海拔高血压组	60	15（25.0）	26（43.3）	19（31.7）	32（53.3）	25（41.7）	3（5.0）	36（60.0）	21（35.0）	3（5.0）
χ²值		27.717			0.227			3.963
P值		<0.001			0.893			0.138