Distribution of Pharmacogenetic Polymorphisms and the Intervention Effects of Folic Acid Combined with Vitamin D in Community-based Patients with H-type Hypertension

doi:10.12114/j.issn.1007-9572.2023.0457

Abstract

Abstract:

Background

H-type hypertension seriously affects people's health and quality of life. Currently, the clinical treatment of hypertension mainly selects drugs based on the experience, and the antihypertensive effect is not ideal. It is urgent to explore the pharmacogenetic polymorphisms of antihypertensive drugs and provide individualized medication guidance for hypertensive patients.

Objective

To investigate pharmacogenetic polymorphisms and the intervention effects of folic acid combined with vitamin D in patients with H-type hypertension in Jinan community, and provide reference for the implementation of integrated precision medicine for hypertension.

Methods

From June 2020 to June 2022, 200 hypertensive patients with poorly controlled blood pressure in 20 community health service centers of Huaiyin District, Jinan City, Shandong Province were randomly selected as the research objects. Before treatment, the gene polymorphisms of five commonly used individualized antihypertensive drugs, including diuretics, β-blockers, angiotensin-converting enzyme inhibitors (ACEI) , calcium channel inhibitors (CCB) , angiotensin-Ⅱ receptor antagonists (ARB) , were detected. Patients were randomly divided into the gene-directed treatment group (genome group) and gene-directed synergistic folic acid and vitamin D treatment group (gene-directed group) , with 100 cases in each group. The genome group adjusted the drug according to the characteristics of the detected hypertension gene loci; the gene-directed group received folic acid and vitamin D in addition to the genomic therapy regimen. Sitting systolic and diastolic blood pressures in the morning without antihypertensive drugs were collected from patients at the initial intervention (M₀) , 3 months of intervention (M₃) , and 6 months of intervention (M₆) . Case status, adverse reactions and stroke were recorded, gene sequencing was performed, and serum homocysteine (Hcy) concentration was detected. Pearson correlation analysis or Spearman's rank correlation analysis were used to explore the correlation between sex, age, systolic blood pressure, diastolic blood pressure and Hcy.

Results

Gender (r_s=-0.463) , systolic blood pressure (r=0.181) and diastolic blood pressure (r=0.188) were correlated with Hcy level (P<0.05) . Among the 5 antihypertensive drug genes, CYP3A5 (A6986G) , CYP2C9 (c.1075A>C) , CYP2D6 (c.100C>T) were associated with polymorphism loci of drug metabolism enzyme genes, respectively. ADRB1, ACEI (I/D) , AGTR1 and NPPA were associated with the polymorphic loci of drug target sensitivity genes. Genome A6986G:CYP3A5*1/*1 (AA) , ACEI (I/D) :D/D, C.100 C>T:CYP2D6*1/*1 (CC) patients at M₃ and M₆ had lower diastolic blood pressure than M₀, A6986G:CYP3A5a1/a3 (AG) , ADRB1 C.1165 G>C:GG, c.1075A>C:CYP2C9*1/*3 (AC) , c.1075A>c:CYP2C9*3/*3 (CC) patients at M₆ had lower systolic and diastolic blood pressure than M₀, A6986G:CYP3A5*3/*3 (GG) , ADRB1 C.1165 G>C:CC, ACEI (I/D) :I/I, c.1075A>C:CYP2C9*1/*1 (AA) , AGTR1 C.1166A>c:AA, NPPA T2238C:TT, c.100 C>T:CYP2D6*10/*10 (TT) patients at M₃ and M₆ had lower systolic and diastolic blood pressure than M₀, ADRB1 C.1165 G>C:GC, ACEI (I/D) :I/D, c.100 C>T:CYP2D6*1/*10 (CT) patients at M₆ had lower systolic blood pressure than M₀, and lower diastolic blood pressure than M₀, the difference was statistically significant (P<0.05) . The results of intergroup comparison of Hcy levels showed that the Hcy level at M₃ and M₆ in the genome group was lower than the genome group, and the difference was statistically significant (P<0.05) . The results of intra-group comparison showed that Hcy level in the genome group at M₆ was lower than M₀, Hcy level in the gene-directed group at M₃ and M₆ was lower than M₀, and Hcy level at M₆ was lower than M₃, the differences was statistically significant (P<0.05) . The results of inter-group comparison of systolic and diastolic blood pressure showed that systolic and diastolic blood pressure of M₃ and M₆ gene-directed group were lower than the genome group, and the difference was statistically significant (P<0.05) . The results of intra-group comparison showed that systolic and diastolic blood pressure at M₆ in the genome group and gene-directed group were lower than M₀, and the systolic blood pressure at M₆ was lower than M₃, and the difference was statistically significant (P<0.05) .

Conclusion

There are differential expression of hypertension drug-related gene polymorphisms in community-based H-hypertensive patients, and the effect of individualized medication is remarkable. And combination therapy of folic acid and vitamin D can significantly reduce the level of H-hypertension.

Key words: Hypertension, Hyperhomocysteinemia, H type hypertension, Genetic polymorphism, Folic acid, Vitamin D

摘要：

背景

H型高血压严重影响着人们的健康及生活质量，目前临床上治疗高血压主要根据患者症状和临床经验选择药物，降压效果不理想，急需探寻降压药物基因分布的多态性，为高血压患者进行个体化用药指导。

目的

探讨济南市社区H型高血压药物作用靶点基因多态性分布及叶酸联合维生素D的干预作用，为该地区开展高血压医防融合精准医疗提供参考依据。

方法

2020年6月—2022年6月随机抽取山东省济南市槐荫区20家街道办事处社区卫生服务中心200例血压控制不佳的高血压患者为研究对象，治疗前首先进行5类常用抗高血压药物[利尿剂、β受体阻滞剂、血管紧张素转化酶抑制剂（ACEI）、钙离子通道抑制剂（CCB）、血管紧张素Ⅱ受体拮抗剂（ARB）]相关高血压个体化用药基因位点的基因多态性检测。将患者随机分为基因导向治疗组（基因组）与基因导向协同叶酸、维生素D治疗组（基因导向组），每组100例。基因组根据检测的高血压基因作用位点的特点调整用药；基因导向组在基因组治疗方案的基础上同时服用叶酸、维生素D。干预初始（M₀）、干预3个月（M₃）、干预6个月（M₆）时采集患者晨间未服用降压药物情况下坐位收缩压和舒张压。记录患者患病情况、不良反应发生情况、脑卒中发生情况，进行基因测序，检测血清同型半胱氨酸（Hcy）浓度。采用Pearson相关性分析或Spearman秩相关分析探究性别、年龄、收缩压、舒张压与Hcy的相关性。

结果

研究对象性别（r_s=-0.463）、收缩压（r=0.181）、舒张压（r=0.188）与Hcy水平有相关性（P<0.05）。5类抗高血压药物基因作用靶点中，与药物代谢酶基因多态性位点相关的分别是CYP3A5（A6986G）、CYP2C9（c.1075A>C）、CYP2D6（c.100C>T），与药物作用靶点敏感性基因多态性位点相关的是ADRB1、ACEI（I/D）、AGTR1、NPPA。基因组A6986G:CYP3A5*1/*1（AA）、ACEI（I/D）:D/D、c.100 C>T:CYP2D6*1/*1（CC）患者M₃、M₆舒张压低于M₀，A6986G:CYP3A5a1/a3（AG）、ADRB1 c.1165 G>C:GG、c.1075 A>C:CYP2C9*1/*3（AC）、c.1075 A>C:CYP2C9*3/*3（CC）患者M₆舒张压低于M₀，A6986G:CYP3A5*3/*3（GG）、ADRB1 c.1165 G>C:CC、ACEI（I/D）:I/I、c.1075 A>C:CYP2C9*1/*1（AA）、AGTR1 c.1166 A>C:AA、NPPA T2238C:TT、c.100 C>T:CYP2D6*10/*10（TT）患者M₃、M₆收缩压、舒张压低于M₀，ADRB1 c.1165 G>C:GC、ACEI（I/D）:I/D、c.100 C>T:CYP2D6*1/*10（CT）患者M₆收缩压低于M₀，M₃、M₆舒张压低于M₀，差异有统计学意义（P<0.05）。Hcy水平组间比较结果显示，M₃、M₆基因导向组Hcy水平低于基因组，差异有统计学意义（P<0.05）。组内比较结果显示，基因组M₆ Hcy水平低于M₀，基因导向组M₃、M₆ Hcy水平低于M₀，M₆ Hcy水平低于M₃，差异有统计学意义（P<0.05）。收缩压、舒张压组间比较结果显示，M₃、M₆基因导向组收缩压、舒张压低于基因组，差异有统计学意义（P<0.05）。组内比较结果显示，基因组、基因导向组M₆收缩压、舒张压低于M₀，M₆收缩压低于M₃，差异有统计学意义（P<0.05）。

结论

社区H型高血压患者中存在高血压药物相关基因多态性的表达差异，个体化用药效果显著；叶酸联合维生素D协同治疗更能显著降低H型高血压水平。

关键词: 高血压, 高同型半胱氨酸血症, H型高血压, 基因多态性, 叶酸, 维生素D

PANG Aimei,GAO Wei,ZHANG Heng, et al. Distribution of Pharmacogenetic Polymorphisms and the Intervention Effects of Folic Acid Combined with Vitamin D in Community-based Patients with H-type Hypertension[J]. Chinese General Practice, 2024, 27(06): 704-710. DOI: 10.12114/j.issn.1007-9572.2023.0457.
庞爱梅,高伟,张恒等. 社区H型高血压患者药物基因作用靶点多态性分布及叶酸联合维生素D干预效果研究[J]. 中国全科医学, 2024, 27(06): 704-710. DOI: 10.12114/j.issn.1007-9572.2023.0457.

Figures/Tables 6

References 24

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性别	例数	年龄（岁）	收缩压（mmHg）	舒张压（mmHg）
男	101	57.0±6.0	148±15	89±10
女	99	56.0±6.0	148±15	90±10
t值		0.815	0.110	-0.093
P值		0.417	0.912	0.926

性别	例数	年龄（岁）	收缩压（mmHg）	舒张压（mmHg）
男	101	57.0±6.0	148±15	89±10
女	99	56.0±6.0	148±15	90±10
t值		0.815	0.110	-0.093
P值		0.417	0.912	0.926

指标	r（r_s）值	P值
年龄（45~55岁/56~65岁）	0.032^a	0.677
性别	-0.463^a	<0.001
收缩压	0.181	0.013
舒张压	0.188	0.001

指标	r（r_s）值	P值
年龄（45~55岁/56~65岁）	0.032^a	0.677
性别	-0.463^a	<0.001
收缩压	0.181	0.013
舒张压	0.188	0.001

药物种类	基因	基因多态性	药物酶代谢活性	药物作用靶点敏感性	例（%）
CCB	CYP3A5	A6986G:CYP3A51/1（AA）	代谢功能正常		14（7.00）
		A6986G:CYP3A51/3（AG）	代谢功能略低		67（33.50）
		A6986G:CYP3A53/3（GG）	代谢功能较低		119（59.50）
ARB	CYP2C9	c.1075 A>C:CYP2C91/1（AA）	氯沙坦活性能力正常，其他ARB药物代谢功能正常		176（88.00）
		c.1075 A>C:CYP2C91/3（AC）	氯沙坦活性能力略低，其他ARB药物代谢功能略低		23（11.50）
		c.1075 A>C:CYP2C93/3（CC）	氯沙坦活性能力较低，其他ARB药物代谢功能较低		1（0.50）
β受体阻断剂	CYP2D6	c.100 C>T:CYP2D61/1（CC）	代谢功能正常		52（26.26）
		c.100 C>T:CYP2D61/10（CT）	代谢功能略低		76（38.38）
		c.100 C>T:CYP2D610/10（TT）	代谢功能较低		70（35.35）
		c.100 C>T:CYP2D65/5^a	代谢功能较低		2（1.00）
	ADRB1	ADRB1 c.1165 G>C:CC		敏感性较高	101（50.50）
		ADRB1 c.1165 G>C:GC		敏感性略高	83（41.50）
		ADRB1 c.1165 G>C:GG		敏感性正常	16（8.00）
ACEI	ACEI（I/D）	ACEI（I/D）:D/D		敏感性较高	18（9.00）
		ACEI（I/D）:I/D		敏感性略高	87（43.50）
		ACEI（I/D）:I/I		敏感性正常	95（47.50）
氯沙坦	AGTR1	AGTR1 c.1166 A>C:AA		敏感性正常	182（91.00）
		AGTR1 c.1166 A>C:AC		敏感性略高	18（9.00）
利尿剂	NPPA	NPPA T2238C:CT		敏感性略高	3（1.50）
		NPPA T2238C:TT		敏感性正常	197（98.50）