CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study
BMC Cardiovascular Disorders volume 23, Article number: 185 (2023)
Genetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population.
The study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed.
The genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291–1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638–2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390–1.882, P < 0.001) may increase risk of hypertension.
CYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.
In recent years, the incidence of cardiovascular and cerebrovascular diseases has been increasing year by year [1, 2]. The prevention and control of cardiovascular and cerebrovascular diseases is one of the key tasks to further improve people’s physical fitness and reduce the social burden . Hypertension is the primary risk factor of cardiovascular and cerebrovascular diseases [4, 5]. Hypertension and its complications not only seriously affect people’s physical fitness, but also cause huge social health pressure and economic burden. It is estimated that 31.1% of adults worldwide have hypertension, and the prevalence of hypertension among adults is higher in middle-income countries than in high-income countries . The prevalence rate of hypertension among Chinese adults is about 23.2% .
There are a number of established factors that play an important role in the risk of hypertension, such as age, obesity, a family history of hypertension and diabetes, as well as a diet high in salt, alcohol consumption, smoking and other adverse lifestyles [8,9,10,11]. Hypertension is a disease with genetic predisposition, which is the result of the combined action of genetic factors and environmental factors . Cytochrome P450 (CYP450) gene superfamily plays an important role in substance metabolism in a variety of organisms . More and more studies have proposed that the pathophysiological processes of various diseases such as cancer, diabetes and atherosclerosis may be related to one or more genes in the CYP450 family . The metabolites of arachidonic acid (AA) endodermal hyperpolarized factor (EDHF) catalyzed by CYP2C gene subfamily are the most important causes of vascular endothelial relaxation , while EDHF acts as a vasodilator in all blood vessels including coronary arteries . And these metabolites are thought to be a modulator of vascular tone, regulator of renal function, as well as factors in the occurrence and development of hypertension and cardiovascular disease . In addition, reactive oxygen species (ROS) are produced in coronary endothelial cells during the reaction catalyzed by CYP2C, which can inhibit the vascular relaxation mediated by nitric oxide (NO) . Animal study has shown that CYP450 expression in endothelial cells maintains eNOS (endothelial nitric oxide synthase) activity and its loss results in an overactivation of the vasoconstrictor prostanoid system, which can lead to vascular dysfunction and hypertension . In summary, the occurrence of hypertension may be related to the activity of CYP450.
Cytochrome P450 2C19 (CYP2C19) is an important member of the CYP450 family. CYP2C19*2 (rs4244285, 681G > A) and CYP2C19*3 (rs4986893, 636G > A) are the most common polymorphisms of CYP2C19 gene. Based on CYP2C19*2 and CYP2C19*3, individuals can be classified as extensive metabolizer (EM) (CYP2C19*1/*1), intermediate metabolizer (IM) (CYP2C19*1/*2, and *1/*3), and poor metabolizer (PM) (CYP2C19*2/*2, *2/*3, and *3/*3) . Studies have found that CYP2C19 gene polymorphisms increased the risk of hypertension in Russian  and Chinese Han  populations, and a study from Kumamoto University Hospital in Japan found that CYP2C19 variants are associated with microvascular angina . However, a study in Koreans found that CYP2C19*3 genetic variant reduced the risk of hypertension .
At present, the relationship between hypertension and CYP2C19 polymorphism is still controversial. The different regions, populations, lifestyles and the interaction between some environmental factors and genetic polymorphisms will affect the occurrence of hypertension. The Hakka is a Han ethnic group with a unique genetic background formed by the Hakka ancestors from the Han nationality in central China, who migrated southward for many times and fused with the ancient Yue residents in Guangdong, Fujian, and Jiangxi . Meizhou is a city located in the northeast of Guangdong Province, is overwhelmingly populated by Hakka people. The purpose of this study was to study the relationship between CYP2C19 genotypes and hypertension among Hakka population.
Materials and methods
A total of 2,982 unrelated Hakka individuals were included in this retrospective study, including 1,872 hypertensive patients and 1,110 non-hypertensive controls, collected from Meizhou People’s Hospital, China between January 2016 and August 2021. This study was approved by the Ethics Committee of Meizhou People’s Hospital. Hypertension was defined as average systolic blood pressure (SBP) ≥ 140 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg or using at least one class of antihypertensive medication following the World Health Organization standards . Inclusion criteria for hypertensive patients were the following: (1) Diagnosed as hypertension clinically; (2) Medical records were complete; (3) Adults. The exclusion criteria were: (1) Incomplete data of medical records; (2) Minors. The control group consisted of healthy people who did not have hypertension. The participants are Hakka people based on questionnaires about the ethnicity. Subjects’ information was collected, such as gender, age, history of smoking, and history of alcohol consumption.
Serum lipid levels of the samples were evaluated by an Olympus AU5400 system (Olympus Corporation, Tokyo, Japan). Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) analyses were carried out using the cholesterol esterase/peroxidase (CHOD/PAP) enzymatic method. Serum homocysteine (Hcy) levels of all subjects were measured by enzymatic cycling assay on an Olympus AU5800 system (Olympus Corporation, Tokyo, Japan) according to the protocol. The results of these biochemical indicators were collected from the Hospital Information System (HIS) and Laboratory Information System (LIS) of Meizhou People’s Hospital.
Genomic DNA was extracted from whole blood using a QIAamp DNA Blood Mini Kit (Qiagen GmbH, North Rhine-Westphalia, Germany) according to the protocol. CYP2C19*2 and CYP2C19*3 variant alleles were genotyped by CYP2C19 genotyping kit. PCR was performed according to the following protocol: denaturation at 94℃ for 5 min; amplification of 35 cycles (94℃ for 25 s, 48℃ for 40 s, and 72℃ for 30 s); final elongation at 72℃ for 5 min (BaiO Technology Co, Ltd, Shanghai, China). The PCR amplification product was hybridized with the probe fixed on the chip, and the specific hybridization signal was detected by enzyme chromogenic reaction (BaiO Technology Co, Ltd, Shanghai, China).
Data analysis was performed using SPSS statistical software version 21.0 (IBM Inc., USA). Student’s t-test or the Mann-Whitney U test was used for continuous data analysis. Genotype composition ratios and allele frequencies of groups were analyzed by the χ2 test. The χ2 test was used to test the significance of the Hardy-Weinberg equilibrium (HWE) of the polymorphism of the CYP2C19 gene in the entire data of the hypertensive patients and the controls. Multivariate regression analysis with Wald forward stepwise method was performed to find the CYP2C19 genotypes that had a stronger relationship with hypertension independently, after adjusting for gender, age, history of smoking, and history of alcohol consumption. The statistical significance level of all analysis results was defined as a P < 0.05.
Characteristics of subjects
This study included 2,982 individuals, including 2,035(68.2%) men and 947(31.8%) women, and the average age was 67.5 ± 11.4 years old. There were 706(23.7%) cases younger than 60 years old and 2,276(76.3%) cases ≥ 60 years old. There were 1,872 hypertensive patients and 1,110 controls in this study. There were statistically significant differences in the gender composition ratio between the hypertension group and the control group (P = 0.010) and the percentage of subjects with a history of smoking (27.9% vs. 34.2%, P < 0.001). The serum Hcy (16.96 ± 7.39 vs. 15.80 ± 6.86 µmol/L, P < 0.001), TG (1.91 ± 1.77 vs. 1.68 ± 1.30 mmol/L, P < 0.001) levels in the hypertensive subjects were higher than that in controls. There were no significant differences in age distribution, proportion of patients with a history of alcohol consumption, and levels of TC, HDL-C, and LDL-C between the hypertension and control groups (P > 0.05) (Table 1).
Frequencies of CYP2C19 rs4244285 and rs4986893 genotypes in patients and controls
The χ2 test was used to test the significance of the Hardy-Weinberg equilibrium of the polymorphism of the CYP2C19 gene in the hypertensive patients and the controls. The genotype distributions of CYP2C19 rs4244285 in controls (χ2 = 1.654, P = 0.198) and hypertensive patients (χ2 = 1.462, P = 0.227) were consistent with Hardy-Weinberg equilibrium, respectively. The genotype distributions of CYP2C19 rs4986893 in controls (χ2 = 0.144, P = 0.705) and hypertensive patients (χ2 = 0.0002, P = 0.990) were consistent with Hardy-Weinberg equilibrium, respectively. The frequencies of CYP2C19 rs4244285 and rs4986893 genotypes and alleles were compared between hypertensive patients and controls. The proportion of CYP2C19 rs4244285 G/A genotype (46.0% vs. 39.6%, P < 0.001), A/A genotype (10.8% vs. 5.9%, P < 0.001), and A allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. There was no significant difference in the distribution of genotypes (P = 0.633) and alleles (P = 0.424) of CYP2C19 rs4986893 between patients and controls (P > 0.05) (Table 2).
The CYP2C19 wild-type homozygote *1/*1 was the most predominant among the subjects (40.8%), followed by the CYP2C19*2 heterozygote *1/*2 (40.5%). The percentages of CYP2C19*1, CYP2C19*2, and CYP2C19*3 alleles were 64.2%, 30.8%, and 5.0%, respectively. Of the 2,982 individuals included in this study, 1,766 (59.2%) were carriers of CYP2C19∗2 or ∗3 LOF allele. On the CY92C19 metabolic phenotypes, 1,216 (40.8%) individuals were extensive metabolizers (EMs), 1,399 (46.9%) individuals were intermediate metabolizers (IMs), and 367 (12.3%) individuals were poor metabolizers (PMs). The proportion of IMs (49.3% vs. 42.9%), PMs (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group (Table 3).
Clinical characteristics of subjects stratified by CYP2C19*2 and *3 loss-of-function alleles
There were significant differences in age distribution (P < 0.001) and HDL-C (P = 0.007) level among different metabolic genotypes of CYP2C19. Specifically, the HDL-C level of CYP2C19 IM group (1.29 ± 0.39 vs. 1.24 ± 0.35 mmol/L) and PM (1.28 ± 0.37 vs. 1.24 ± 0.35 mmol/L) group was higher than that of EM group. There were no significant differences in age distribution, gender composition ratio, proportion of patients with a history of smoking and alcohol consumption, and levels of Hcy, TG, TC, and LDL-C among different metabolic genotypes of CYP2C19 (P > 0.05) (Table 4).
Association of CYP2C19 different genotypes and different metabolic genotypes with hypertension
To gain insight into the independent influence of CYP2C19 different genotypes and different metabolic genotypes on hypertension, logistic regression analysis was performed. The results of univariate logistic regression indicated that CYP2C19 *1/*2 (*1/*2 vs. *1/*1: odds ratio (OR) 1.537, 95% confidence interval (CI): 1.304–1.811, P < 0.001), *1/*3 (*1/*3 vs. *1/*1: OR 1.442, 95% CI: 1.049–1.983, P = 0.024), *2/*2 (*2/*2 vs. *1/*1: OR 2.441, 95% CI: 1.806–3.301, P < 0.001) genotypes may increase risk of hypertension. And the CYP2C19 IM genotypes (IM vs. EM: OR 1.523, 95% CI: 1.300-1.785, P < 0.001), PM genotypes (PM vs. EM: OR 2.127, 95% CI: 1.645–2.749, P < 0.001) may increase risk of hypertension.
The results of multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2 (*1/*2 vs. *1/*1: OR 1.529, 95% CI: 1.296–1.803, P < 0.001), *1/*3 (*1/*3 vs. *1/*1: OR 1.423, 95% CI: 1.034–1.960, P = 0.030), *2/*2 (*2/*2 vs. *1/*1: OR 2.433, 95% CI: 1.797–3.293, P < 0.001) genotypes may increase risk of hypertension. And the CYP2C19 IM genotypes (IM vs. EM: OR 1.514, 95% CI: 1.291–1.774, P < 0.001), PM genotypes (PM vs. EM: OR 2.119, 95% CI: 1.637–2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390–1.881, P < 0.001) may increase risk of hypertension (Table 5).
Hypertension is a cardiovascular disease characterized by the continuous increase of systemic arterial blood pressure . It is an important risk factor for coronary atherosclerosis, myocardial infarction, stroke and other serious cardiovascular and cerebrovascular diseases . Hypertension is a disease caused by the combined action of genetic factors and environmental factors . Studies have found that CYP2C19-catalyzed arachidonic acid (AA) endoderm hyperpolarization factor (EDHF) metabolites have been shown to induce vascular endothelial relaxation and vasodilation [15, 16]. In addition, CYP2C19 biotransform 5-hydroxytryptamine (5-HT) to produce hydroxylamine, which is converted to nitric oxide in the presence of catalase, and this process can relax the pre-contracted aortic ring in vitro . In this study, we investigated whether common polymorphisms of CYP2C19 gene are associated with hypertension susceptibility in Hakka population. We found that CYP2C19 *1/*2, *1/*3, *2/*2 genotypes, and the CYP2C19 IM, PM phenotypes may increase risk of hypertension. The possible mechanism that CYP2C19 gene variant increases the risk of hypertension is that CYP2C19 gene variant reduces the activity of CYP2C19, and the lower activity of CYP2C19 significantly weakens the effect of vascular endothelial relaxation and vascular relaxation.
To our knowledge, there have been few studies on the relationship between CYP2C19 polymorphism and hypertension susceptibility. Study has shown that the interaction of CYP2C19*3 and smoking was independent risk factor for hypertension in a Uighur population from China . Combination of genotypes CYP2C8 rs7909236 TT and CYP2C19 rs4244285 GG was associated with increased hypertension risk in a Russian population . On the contrary, a study from a Korean population found that the CYP2C19*3 defective allele may contribute to reduced risk for the development of hypertension . In addition to the common polymorphisms (rs4244285, rs4986893) of CYP2C19 gene, other polymorphisms may also be associated with the susceptibility to hypertension. A study from the Han Chinese population showed that the CYP2C19 rs10509676 polymorphism is associated with hypertension . CYP2C19 rs12721054 may be a genetic factor contributing to hypertension susceptibility in Filipinos .
Moreover, CYP2C19 gene polymorphism is also associated with some other cardiovascular and cerebrovascular diseases. CYP2C19 loss-of-function was associated with increased risk of first-time ischemic stroke for intracranial atherosclerotic disease patients treated with clopidogrel after transient ischemic attack . CYP2C19 PM may be a candidate risk factor for coronary microvascular disorder in the female population . Major adverse cardio- and cerebro-vascular event (MACCE) is more likely to occur in post-percutaneous coronary intervention (PCI) patients with CYP2C19 PM . CYP2C19*2 or *3 allele carriers with peripheral endothelial dysfunction were significantly correlated with cardiovascular events . Intermediate and poor CYP2C19 metabolizers had a higher risk of ischemic stroke recurrence . The CYP2C19 G681A AA genotype and A allele may be related to the occurrence and recurrence of cerebral ischemic stroke .
In this study, the CYP2C19 wild-type homozygote *1/*1 accounted for 40.8%, followed by the CYP2C19*2 heterozygote *1/*2 (40.5%). The percentages of CYP2C19*1, *2, and *3 alleles was 64.2%, 30.8%, and 5.0%, respectively. It is basically consistent with the results of frequency analysis of CYP2C19 gene polymorphism in Chinese Han population . There have been some corresponding studies in other populations. In a Taiwanese population, the prevalence of the CYP2C19*2 and *3 allele was 53.1% and 10.2%, respectively . The percentage of CYP2C19*1, *2, and *3 allele was 76%, 20.5%, and 2.5% in the Vietnamese population, respectively . The percentage of CYP2C19*2, and *3 allele was 25.60% and 2.50% in a Thai population , 30.14% and 15.69% in Bhutanese population . The prevalence of the CYP2C19*2 allele was 16.3% in the population from the Republic of Srpska in Bosnia and Herzegovina , and 13.1% in a Greek population . In Moroccan population, the percentage of CYP2C19 *2, and *3 allele was 11.38%, and 0%, respectively , whereas 6%, and 0% in a Ghanaian population , 12.6% and 0.3% in the Egyptian population . The percentage of CYP2C19*2, and *3 allele was 12.5%, and 0.6% respectively, in Iranian population , 13% and 3% in Lebanese population . In the populations from Americas, the percentage of CYP2C19*2, and *3 allele was 7.8% and 0.1% respectively in a Bolivian population , 8.3% and 0% in a Nicaraguan Mestizo population . To sum up, the frequency of CYP2C19*2 and *3 in populations from Southeast Asia was higher than that in populations from Europe, Middle East, Africa and America. The frequency of CYP2C19*2 and *3 in populations from Europe, Middle East and Africa was similar, while those in populations from America was the lowest. In other words, the proportion of people with CYP2C19 loss-of-function is higher in Southeast Asia than in other regions, which also proves that there are differences in genetic background between different regions and different populations.
In this study, there was significant difference HDL-C level among different CYP2C19 metabolizers. Specifically, the HDL-C level of CYP2C19 IM group and PM group was higher than that of EM group. There are few studies on the relationship between CYP2C19 genotypes and serum lipid level. A study has found that, compared with EM group, PM group had higher levels of TC, LDL-C and ApoB, but no differences showed in HDL-C . CYP450 enzyme, lipoxygenase (LOX) and cyclooxygenase (COX) are the main metabolic enzymes of lipid, and the products of polyunsaturated fatty acids (PUFA) catalyzed by these three enzymes are signaling molecules of endogenous lipid metabolism . PUFA products of CYP450 mainly include a variety of epoxide fatty acids (EpFAs) and arachidonic acid products, both of which are important lipid signaling molecules involved in lipid regulation . More research is needed to confirm the relationship between CYP2C19 genotypes and serum lipid level in the future.
Our study found that CYP2C19 IM and PM genotypes were risk factors for hypertension in a cohort with a certain number of Hakka people. To our knowledge, this study is the first report of this population. It is of great significance for the screening of high risk individuals with hypertension and prevention of hypertension in this population. However, there are some limitations in this study. First, the association between these polymorphisms and the grade of hypertension was not investigated in this study because some medical records of some patients were incomplete. Second, it is a study conducted among patients and examiners in a medical institution, there was inevitably selection bias as the population is not completely representative. Third, this study did not investigate the relationship between the full-length variation of CYP2C19 gene, gene expression and the risk of hypertension. Finally, some parameters related to hypertension (such as body mass index (BMI), and diabetes history) were not included in the analysis in this study, which may bias the analysis results of this study. Therefore, future studies need to include larger sample size, include more parameters related to hypertension as much as possible, the classification of hypertension, and the analysis of full-length variation of CYP2C19 gene.
In summary, the association between CYP2C19 genotypes and hypertension was identified in a cohort study in Meizhou, China. After adjusting gender, age, smoking, and alcohol consumption, we found CYP2C19 *1/*2, *1/*3, *2/*2 genotypes, and the CYP2C19 IM, PM genotypes may increase risk of hypertension. When considering CYP2C19 variants, clinicians can improve the efficiency of clinical prediction of hypertension risk. Of course, further research is needed to verify our results and investigate the mechanism of the reported association.
The datasets used and analyzed during the current study available from the corresponding author on request.
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The author would like to thank other colleagues whom were not listed in the authorship of Center for Cardiovascular Diseases, Meizhou People’s Hospital, for their helpful comments on the manuscript.
This study was supported by the Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translation Research of Hakka Population (Grant No.: 2018B030322003), and Science and Technology Program of Meizhou (Grant No.: 2019B0202001).
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All participants were informed on the study procedures and goals and the study obtained written informed consent from all the participants. We confirm that all methods were performed in accordance with relevant guidelines and regulations. This study was approved by the Human Ethics Committees of Meizhou People’s Hospital (Clearance No.: 2016-A-55).
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Cai, N., Li, C., Gu, X. et al. CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study. BMC Cardiovasc Disord 23, 185 (2023). https://doi.org/10.1186/s12872-023-03207-w