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CYP2C19 Loss-of-Function is an Associated Risk Factor for Premature Coronary Artery Disease: A Case–Control Study
Authors Chen W, Liu Y, Deng X, Li B, Wang H, Wei G, Chen K, Wang S
Received 15 August 2024
Accepted for publication 26 October 2024
Published 3 November 2024 Volume 2024:17 Pages 5049—5058
DOI https://doi.org/10.2147/IJGM.S486187
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Redoy Ranjan
Wenhao Chen,1 Yuanliang Liu,2 Xunwei Deng,3 Bin Li,1 Hao Wang,1 Guoliang Wei,1 Kehui Chen,1 Shen Wang1
1Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou, People’s Republic of China; 2Department of Computer Tomography, Meizhou People’s Hospital, Meizhou, People’s Republic of China; 3Research Experimental Center, Meizhou People’s Hospital, Meizhou, People’s Republic of China
Correspondence: Wenhao Chen, Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou, People’s Republic of China, Email [email protected]
Objective: Cytochrome P450 2C19 (CYP2C19) is a major enzyme involved in the biotransformation and metabolism of various substances. Loss-of-function of the CYP2C19 gene represents downregulation of CYP2C19 enzyme indication limited or no enzymatic function, which may be, in turn, associated with some disease susceptibility. The relationship between CYP2C19 polymorphisms and susceptibility to premature coronary artery disease (PCAD) is not fully understood. This study aimed to assess this relationship.
Methods: This study included 635 PCAD patients, and 548 age-matched non-CAD individuals as controls, from November 2019 to August 2023. The CYP2C19 rs4244285 (681G > A, *2) and rs4986893 (636G > A, *3) were genotyped, and the distribution of CYP2C19 polymorphisms between patients and controls and the relationship between CYP2C19 polymorphisms and PCAD risk were analyzed.
Results: A total of 442 (37.4%), 543 (45.9%), and 198 (16.7%) individuals had CYP2C19 extensive metabolizer (EM) (*1/*1), intermediate metabolizer (IM) (*1/*2 and *1/*3), and poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) phenotypes, respectively. CYP2C19 *2/*2 genotype frequency was higher, *1/*1 genotype was lower in PCAD patients than controls. Individuals with CYP2C19 PM phenotype had higher triglyceride (TG) levels than those with CYP2C19 EM or IM phenotypes. Logistic regression analysis showed that body mass index (BMI) ≥ 24.0 kg/m2 (≥ 24.0 kg/m2 vs 18.5– 23.9 kg/m2, odds ratio (OR): 1.326, 95% confidence interval (CI): 1.041– 1.688, p = 0.022), smoking (OR: 1.974, 95% CI: 1.283– 3.306, p = 0.002), hypertension (OR: 1.327, 95% CI: 1.044– 1.687, p = 0.021), diabetes mellitus (OR: 1.390, 95% CI: 1.054– 1.834, p = 0.020), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.701, 95% CI: 1.200– 2.411, p = 0.003), and CYP2C19 IM+PM phenotypes (IM+PM vs EM phenotype, OR: 1.369, 95% CI: 1.077– 1.740, p = 0.010) were associated with PCAD.
Conclusion: CYP2C19 PM or IM+PM phenotypes, overweight, smoking, hypertension, and diabetes mellitus were associated with PCAD.
Keywords: premature coronary artery disease, cytochrome P450, CYP2C19, loss-of-function
Introduction
Cardiovascular diseases (CVDs) are a group of diseases of the human cardiovascular system that mainly affects the heart, arteries, veins, capillaries, and other parts of the abnormal.1,2 Survey data show that the prevalence and mortality rates of CVDs in China are on the rise, with the mortality rate being the highest among urban and rural residents.3,4 Coronary artery disease (CAD) caused by myocardial ischemia or necrosis due to stenosis, blockage and spasm of the coronary artery atherosclerosis.5,6 CAD is a major public health problem that seriously threatens the health of residents.7,8 A high incidence of CAD is generally observed in the elderly, but with the acceleration of the pace of life, accompanied by bad living habits, the incidence of CAD in young and middle-aged people has gradually increased.9,10 The onset of CAD in men aged ≤55 years and in women aged ≤65 years is defined as premature coronary artery disease (PCAD).11,12 Compared with mature coronary artery disease (MCAD), most patients with PCAD patients are acute, without precursor symptoms, and most have acute myocardial infarction (AMI) or even sudden death.13 It is necessary to analyze the risk factors for PCAD to provide a basis for the targeted prevention of PCAD risk groups.
Atherosclerosis is the main pathological basis of CAD and other arterial vascular diseases. It is characterized by the accumulation of lipids, the formation of diseased plaques, thickening of intima, and narrowing of arterial spaces, which lead to ischemia or necrosis of tissues and organs supplied by arteries.14,15 Diabetes mellitus, hypertension, hyperlipidemia, obesity, smoking, alcoholism, and other unhealthy lifestyles, in addition to social psychological stress are the risk factors of CAD.16,17 Cytochrome P450 (CYP450) enzymes are involved in the biotransformation and metabolism of some important substances in the body.18,19 The metabolite in arachidonic acid (AA) catalyzed by cytochrome enzymes has the function of relaxation of blood vessels,20 and acting as a vasodilating agent.21 The imbalance of these metabolites is believed to be involved in the occurrence and development of CVDs.22 On the other hand, reactive oxygen species (ROS) produced by coronary endothelial cells during the cytochrome enzyme-catalyzed reaction can inhibit vasodilation.23 Some studies have suggested that CYP450 enzymes are involved in cancer, diabetes mellitus, and cardiovascular and cerebrovascular diseases.24–26 Cytochrome P450 2C19 (CYP2C19) is a major member of the CYP450 family.27 Two major loss-of-function single-nucleotide polymorphisms (SNPs) rs4244285 (681G > A, known as CYP2C19*2) and rs4986893 (636G > A, known as CYP2C19*3) are the most common SNPs in CYP2C19. CYP2C19 can be divided into six genotypes: *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3.28 According to the genotypes of CYP2C19, the enzyme activity types of CYP2C19 can be divided into three phenotypes: 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)).29,30
At present, CYP2C19 gene variants mainly focuses on their impact on antiplatelet efficacy in CAD patients,31,32 and the relationship between CYP2C19 polymorphisms and CAD risk has not been well studied. Some studies found that CYP2C19 polymorphisms were associated with CAD in Japanese women,33 and a Chinese population.34 The probability of PCAD and its influencing factors may be different in different regions and populations with different genetic backgrounds. The distribution of CYP2C19 polymorphisms among PCAD patients in different populations may be different.35 Hakka people are a branch of the Han people in China, and Meizhou is one of the Hakka people’s settlements.36 To date, the relationship in this population is unclear, and this study aimed to investigate it.
Materials and Methods
Study Participants and Data Collection
A total of 635 patients with PCAD who were admitted to Meizhou People’s Hospital from November 2019 to August 2023 were retrospectively analyzed. The control group consisted of age- and sex-matched healthy individuals who underwent physical examination and CYP2C19 gene polymorphisms detection during the same period. A total of 548 age-matched patients without CAD were used as the controls.
The diagnostic criteria for CAD: coronary angiography (CAG) shows that at least one of the main epicardial vessels had a diameter stenosis >50%.37,38 The inclusion criteria for PCAD were as follows: (1) patients were diagnosed with CAD; (2) men aged ≤55 years and women aged ≤65 years; and (3) complete clinical data. The inclusion criteria for the controls were as follows: (1) non-CAD individuals who had been tested for CYP2C19 rs4244285 and rs4986893 polymorphisms; (2) men aged ≤55 years and women aged ≤65 years; and (3) complete demographic information. The exclusion criteria were as follows: (1) congenital heart disease, cardiomyopathy, or congestive heart failure; (2) severe organ dysfunction; (3) malignant tumor; and (4) serious infectious diseases.
Data including age, sex, body mass index (BMI), smoking, drinking, hypertension, diabetes mellitus, serum lipids (total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (Apo-A1), and apolipoprotein B (ApoB)) was collected. According to the Chinese standards, BMI was divided into three grades: <18.5 kg/m2, 18.5–23.9 kg/m2, and ≥24.0 kg/m.239,40 CYP2C19*2 and CYP2C19*3 variant alleles were genotyped using a CYP2C19 genotyping kit (BaiO Technology Co, Ltd, Shanghai, China).28,34
Statistical Analysis
Statistical analyses were performed using SPSS 26.0 (IBM Inc., USA). Continuous variables were compared using Student’s t-test, the Mann–Whitney U-test or analysis of variance (ANOVA). Genotype composition ratios and allele frequencies between groups were analyzed by the χ2 test. Logistic regression analyses were performed to examine the relationship between CYP2C19 metabolic phenotypes and PCAD. Gender, BMI, history of smoking, history of alcoholism, hypertension, and diabetes mellitus were selected as covariates in the multivariate logistic regression analysis for PCAD, based on estimating the odds ratios (OR) and their 95% confidence intervals (CIs). p<0.05 was considered to represent statistical significance.
Results
Baselines of Subjects
There were 447 (37.8%) patients were males and 736 (62.2%) were females. There were 250 males (39.4%) and 385 females (60.6%) in the PCAD group, 197 males (35.9%) and 351 females (64.1%) in the control group; however the sex distribution difference between the PCAD patients and controls was not statistically significant (p = 0.230). In the controls, there were 14 (2.6%), 249 (45.4%), and 285 (52.0%) patients with BMI <18.5 kg/m2, 18.5–23.9 kg/m2, and ≥24.0 kg/m2, respectively. There were 23 (3.6%) PCAD patients with BMI <18.5 kg/m2 and 360 (56.7%) PCAD patients with BMI ≥24.0 kg/m2, with not statistically significant in the two groups (p = 0.100). The proportion of PCAD patients with a history of smoking (16.9% vs 9.5%, p < 0.001) was significantly higher than controls. The PCAD patients had higher TC (5.21±1.35 vs 4.86±1.15 mmol/L, p < 0.001), TG (2.12±1.72 mmol/L vs 1.83±1.49 mmol/L, p = 0.002), LDL-C (2.97±0.91 mmol/L vs 2.81±0.89 mmol/L, p = 0.002), and Apo-B (0.94±0.26 g/L vs 0.88±0.25 g/L, p < 0.001) levels than controls. The differences of history of alcohol consumption, hypertension, and diabetes mellitus were not statistically significant between the patients and controls (Table 1).
 |
Table 1 Clinical Characteristics of the Subjects of This Study |
Distribution Frequencies of the CYP2C19 Genotypes and Alleles in PCAD Patients and Controls
There were 442 (37.4%), 462 (39.1%), 81 (6.8%), 149 (12.6%), 45 (3.8%), and 4 (0.3%) individuals with CYP2C19 *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3 genotype, respectively. There were 442 (37.4%), 543 (45.9%), and 198 (16.7%) individuals with CYP2C19 EM, IM, and PM phenotypes, respectively. CYP2C19 genotypes in the PCAD patients (χ2 = 4.139, p = 0.388), and controls (χ2 = 1.300, p = 0.861) conformed to the Hardy-Weinberg equilibrium, respectively. The frequency of the CYP2C19 *2/*2 genotype was higher (15.0% vs 9.9%, p = 0.008), whereas that of the CYP2C19 *1/*1 genotype was lower in the PCAD patients than controls. The PCAD patients had a higher frequency of the *2 allele (36.3% vs 31.4%, p = 0.013) and a lower frequency of the *1 allele (57.2% vs 63.9%, p = 0.001) than controls (Table 2).
 |
Table 2 Distribution Frequencies of CYP2C19 Genotypes and Alleles in PCAD Patients and Controls |
Clinical Characteristics of Subjects Stratified by CYP2C19 Phenotypes
The proportion of male individuals in CYP2C19 PM group was higher than CYP2C19 EM and IM groups (44.4% vs 34.2% and 38.3%, p = 0.043). The proportion of smoking in CYP2C19 PM group was higher than CYP2C19 EM and IM groups (18.2% vs 10.4% and 14.2%, p = 0.022). The individuals with CYP2C19 PM phenotype had higher TG level than those with CYP2C19 EM and IM phenotypes (2.27±2.04 mmol/L vs 1.85±1.24 mmol/L and 2.00±1.72 mmol/L, p < 0.05) (Table 3).
 |
Table 3 Clinical Characteristics of Subjects Stratified by CYP2C19 Phenotypes |
Logistic Regression Analysis of Risk Factors for PCAD
The results of univariate analysis showed that smoking (odds ratio (OR): 1.933, 95% confidence interval (CI): 1.358–2.752, p < 0.001), diabetes mellitus (OR: 1.311, 95% CI: 1.001–1.716, p = 0.049), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.732, 95% CI: 1.229–2.439, p = 0.002) and CYP2C19 IM+PM phenotypes (IM+PM phenotypes vs EM phenotype, OR: 1.381, 95% CI: 1.091–1.750, p = 0.007) were significantly associated with PCAD. In multivariate logistic regression analysis, BMI ≥24.0 kg/m2 (≥24.0 kg/m2 vs 18.5–23.9 kg/m2, OR: 1.326, 95% CI: 1.041–1.688, p = 0.022), smoking (OR: 1.974, 95% CI: 1.283–3.306, p = 0.002), hypertension (OR: 1.327, 95% CI: 1.044–1.687, p = 0.021), diabetes mellitus (OR: 1.390, 95% CI: 1.054–1.834, p = 0.020), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.701, 95% CI: 1.200–2.411, p = 0.003), and CYP2C19 IM+PM phenotypes (IM+PM phenotypes vs EM phenotype, OR: 1.369, 95% CI: 1.077–1.740, p = 0.010) were associated risk factors for PCAD (Table 4).
 |
Table 4 Logistic Regression Analysis of Risk Factors for PCAD |
Discussion
At present, there are abundant research results on CAD and its risk factors, but it has not been well studied in PCAD. Many studies have ignored the different clinical characteristics and risk factors of patients with different ages, and there is still much space worth exploring. The group covered by PCAD is the main working group of the society, and PCAD is not just the physical damage, but also affect their family life and social production of patients. Therefore, attention should be paid to the identification and screening of people at risk for PCAD, as well as to the determination of risk factors. In terms of mechanism, the metabolite of arachidonic acid (AA) catalysed by CYP450 plays an antihypertensive, anti-inflammatory, and anticoagulant role by activating potassium ion and calcium ion channels, inhibiting platelet aggregation, inhibiting white blood cell adhesion to blood vessel wall, and reducing the expression of vascular cell adhesion molecules.20,21 Nitric oxide produced by 5-hydroxytryptamine (5-HT) catalyzed by CYP450 and catalase can relax blood vessels.41 CYP2C19 is an important member of the CYP450 family, CYP2C19 loss-of-function with only weak enzyme activity, and its metabolites are not enough to maintain the balance of the above processes, so poor metabolizers are more prone to atherosclerosis. CYP2C19 gene polymorphisms have racial differences.35,42 In this study, the relationship of CYP2C19 polymorphisms and susceptibility to PCAD were investigated. BMI ≥24.0 kg/m2, smoking, hypertension, diabetes mellitus, CYP2C19 loss-of-function were associated with PCAD.
There were several reports on the relationship between CYP2C19 polymorphisms and some CVDs susceptibility. CYP2C19*3 was associated with CAD in the Chinese Uyghur population.43 The CYP2C19 PM was a risk factor of CAD in Japanese women.33 CYP2C19 EM was common in CAD patients among a Chinese population.34 Akasaka T et al found that female sex, smoking, and hypertension were associated with coronary microvascular disorder (CMVD), and CYP2C19 PM was predictive factor for CMVD in the female population.44 CAD patients with the CYP2C19 PM phenotype are more likely to experience major adverse cardiovascular and cerebrovascular events (MACCE) after interventional therapy.45 In addition, Cai et al found that CYP2C19 polymorphisms were associated with hypertension susceptibility in the Hakka population.28 Xie et al found that CYP2C19 *2/*2 is a risk factor for multi-site atherosclerosis.46 CYP2C19*2 allele was associated with stent thrombosis after stent implantation in CAD patients.47 Patients with peripheral endothelial dysfunction who carried the CYP2C19*2 or *3 alleles were prone to cardiovascular events.48
CAD may be influenced by environmental factors, living habits, and genetic factors, such as smoking, diabetes, and hypertension are associated with CAD.49,50 Smoking was more common in PCAD patients,51 smoking was associated with multivessel disease PCAD.52 And smoking was a risk for premature multiple CAD in a Chinese population,53 an Iran population.54 Smoking was a major risk for CAD in a rural Indian population.55 Hypertension, diabetes mellitus, and obesity were positively associated with multivessel disease PCAD.52 Diabetes mellitus was an independent risk factor for PCAD.53 Iranian scholars found that diabetes mellitus, smoking, and hypertension were associated with PCAD in Iranian youth.54 A study found that PCAD patients had high levels of BMI, serum TC, TG, and C-reactive protein (CRP) than healthy adults.56 Compared with MCAD patients, the percentages of smoking, abnormal lipid metabolism, and hypertension were higher in PCAD patients.56 PCAD risk was associated with gender differences,57 as well as differences in populations with different traditional lifestyles and genetic backgrounds.58
Moreover, there was a significant difference in the TG levels among different CYP2C19 metabolizers in this study. Specifically, TG level in individuals with CYP2C19 PM phenotype higher than those with CYP2C19 EM phenotype and IM phenotype. Bai et al found that the levels of TC and LDL-C in individuals with CYP2C19 PM phenotype are significantly higher than those in individuals with CYP2C19 EM and IM; however, no differences showed in HDL-C.59 Cai et al found that HDL-C levels vary with CYP2C19 metabolic phenotypes.28 The relationship between CYP2C19 and lipid levels needs more clinical studies and foundation to reveal.
Clinically, when clopidogrel is used for antiplatelet therapy, there are individual differences in treatment effectiveness among patients. Moreover, poor clopidogrel responsiveness is closely associated with the occurrence of major adverse cardiovascular events (MACE) after stenting, a phenomenon called clopidogrel resistance (CR).60,61 The most important internal cause of CR is the difference in metabolic enzyme activity caused by CYP2C19 gene polymorphism.62,63 Many studies have confirmed the association between CYP2C19 loss-of-function and adverse cardiovascular events.64–70 It can be seen that CYP2C19 gene screening can not only be used as a genetic predictor of PCAD but also can effectively help patients select appropriate antiplatelet drugs and dosages.
In this study, CYP2C19 IM + PM phenotypes, overweight, smoking, hypertension, and diabetes mellitus were associated with PCAD. This means that individuals who are overweight, have a history of smoking, hypertension, and diabetes mellitus; and carried the CYP2C19 IM or PM phenotype need to be aware of the risk of developing PCAD. However, this study has some limitations. First, as a retrospective study, the selection of subjects and collection of clinical information in this study may be biased. Second, this study was based on data from a single medical institution, and although data analysis showed that the results were statistically significant, the results of this study require additional data and external case validation. Third, this study did not not analyze the association of CYP2C19 gene polymorphisms with interventional procedures, treatment, and clinical prognosis of PCAD patients.
Conclusion
In summary, CYP2C19 IM+PM phenotypes (CYP2C19 loss-of-function), overweight, smoking, hypertension, and diabetes mellitus are associated risk factors for PCAD. In other words, individuals who are overweight, have a history of smoking, hypertension, diabetes mellitus, and carried the CYP2C19 loss-of-function phenotype are advised to be aware of the risk of PCAD.
Data Sharing Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics Approval
All participants were informed on the study procedures and goals and the informed consent from all the participants. The study was performed under the guidance of the Declaration of Helsinki and approved by the Ethics Committee of Medicine, Meizhou People’s Hospital.
Acknowledgments
The authors thank their colleagues, who were not listed in the authorship, for their helpful comments on this study.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
This study was supported by the Science and Technology Program for Social Development of Meizhou (Grant No.: 2023B44).
Disclosure
The authors declare that they have no competing interests.
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