Coronary atherosclerosis (CAS) is a chronic progressive disease mainly characterized by lipid deposition, inflammatory cell infiltration, fibrous tissue hyperplasia, and atherosclerotic plaque formation in the coronary artery vessel wall (1, 2). As the disease progresses, the coronary artery plaques continuously enlarge and protrude into the vascular lumen, resulting in lumen stenosis and hindering myocardial blood supply (3). When plaques rupture or thrombosis forms, it can trigger acute coronary syndrome (ACS), including severe cardiovascular events such as unstable angina pectoris and myocardial infarction (4). The pathological process not only involves lipid metabolism disorders, but is also closely related to multiple mechanisms such as inflammatory responses, oxidative stress, and vascular endothelial dysfunction (5–7). CAS has become one of the cardiovascular diseases with the highest incidence and mortality rates worldwide (8, 9). Cardiovascular diseases cause approximately 17.9 million deaths each year, among which coronary artery disease (CAD) accounts for the major proportion according to statistical data (10). CAS not only causes patients to suffer from long-term symptoms such as angina pectoris and breathing difficulties, seriously affecting their quality of life (11), but may also trigger complications such as heart failure and arrhythmia (12).

Patients with diabetes mellitus, due to being in a state of high blood glucose for a long time, will trigger a series of metabolic disorders, thereby accelerating the process of CAS (13). High blood glucose can cause damage to vascular endothelial cells, making the originally smooth inner lining of blood vessels rough and creating conditions for lipid deposition (14). Meanwhile, it activates signaling pathways such as protein kinase C (PKC), promotes the release of inflammatory factors, and intensifies the inflammatory response of the vascular wall (15). In addition, high blood glucose can also affect platelet function and increase the risk of thrombosis (16). The risk of cardiovascular disease for diabetic patients is 2–4 times that of non-diabetic patients, among which CAD is one of the leading causes of death for patients with diabetes mellitus (17). Moreover, once patients with diabetes mellitus develop CAS, their condition is often more severe, the prognosis is worse, and the incidence of adverse cardiovascular events such as acute myocardial infarction and heart failure increases significantly (18, 19).

Cytochrome P450 2C19 (CYP2C19), as an important drug-metabolizing enzyme in the human body, its genetic polymorphism can lead to significant differences in enzyme activity and be classified into different metabolic types. The rs4244285 (681G > A, *2) and rs4986893 (636G > A, *3) are the two common single-nucleotide polymorphisms (SNPs) in CYP2C19 (20, 21). Based on the variants of these two SNPs, there are 6 genotypes for CYP2C19: *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3 (22), and 3 phenotypes: extensive metabolizer (EM) (*1/*1), intermediate metabolizer (IM) (*1/*2 and *1/*3), and poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) (23, 24). CYP2C19 is involved in the metabolic processes of some cardiovascular drugs, such as antiplatelet drugs like clopidogrel (25). CYP2C19 can also affect the pathological process of CAS by participating in endogenous substance metabolism in the body, such as the metabolic regulation of lipids, inflammatory factors, and oxidative stress-related molecules (26). CYP2C19 may be involved in the arachidonic acid metabolic pathway and affect the generation of inflammatory mediators, while the inflammatory response plays a key role in the formation, progression and rupture of atherosclerotic plaques (27, 28). Furthermore, the reactive oxygen species (ROS) generated during the metabolic reactions of coronary endothelial cells involving CYP450 will inhibit the vasodilation mediated by nitric oxide (NO) (29). The relationship between CYP2C19 gene polymorphisms and the risk of CAS in patients with T2DM remains unclear. This study intends to conduct research on it.

The clinical management of diabetes mellitus complicated with CAS remains challenging (37). Moreover, the more severe the degree of diabetes mellitus, the higher the probability of cardiovascular events in patients, and the corresponding risk also increases (38). Identifying patients at high risk of CAS in diabetes mellitus patients is the key to prevention. In this study, CYP2C19 IM + PM phenotype, advanced age, overweight, history of smoking, history of alcoholism, hypertension, and dyslipidemia were associated with CAS risk in T2DM.

Polymorphisms in the CYP2C19 gene may display substantial racial variations (39–42). In the present study, the proportions of CYP2C19 EM, IM, and PM phenotypes were 39.5, 46.9, and 13.6%, respectively, which are consistent with the findings of several prior studies (43–45). Park et al.’s (46) study on a group of patients undergoing percutaneous coronary intervention (PCI) from East Asia revealed that the proportions of CYP2C19 EM, IM, and PM were 39.8, 45.8, and 14.3%, respectively. A study on the genetic polymorphisms of CYP2C19 in the Chinese Hakka population revealed that the proportions of CYP2C19 EM, IM, and PM were 41.73, 45.21, and 13.06%, respectively (47). Another study conducted among the Hakka population in China revealed that CYP2C19 EM, IM, and PM were 40.8, 46.9, and 12.4%, respectively (22). The distributions of CYP2C19 genotypes reported in most studies of the Asian population is largely similar (43). In addition, CYP2C19 IM and PM statuses were significantly associated with CAS in patients with T2DM in this study. To our knowledge, relatively few investigations have explored the association between CYP2C19 gene polymorphisms and the risk of CAS. For instance, Chen et al. (48) demonstrated that gene polymorphisms leading to CYP2C19 dysfunction constitute a risk factor for premature coronary artery disease (PCAD). Additionally, Hokimoto et al. (49) revealed that CYP2C19 PM status might be a risk factor for CAD in female populations. Han et al. (50) further found that CYP2C19 PM status is an independent risk factor for premature myocardial infarction (PMI).

Dyslipidemia plays a key role in the process of CAS in patients with T2DM. In patients with T2DM, the hyperglycemic state can promote the glycation modification of LDL-C particles, and the glycated LDL is more likely to be oxidized to form oxidized LDL (ox-LDL) (51). ox-LDL is highly cytotoxic and can induce vascular endothelial cells to express adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), promoting the adhesion of monocytes to the vascular endothelium and their migration to the vascular intima (52). Monocytes entering the intima take up ox-LDL and transform into foam cells. A large number of foam cells accumulate to form a lipid core, accelerating the formation of atherosclerotic plaques (53). Elevated triglyceride (TG) level also has significant effects in T2DM complicated with CAS. Lipoprotein residues rich in TG accumulate in the body. These residues are easily taken up by macrophages and promote the formation of foam cells (54). Meanwhile, there is lipid exchange between TG and HDL-C as well as LDL-C. An increase in TG will cause the cholesterol esters in HDL-C to transfer to lipoproteins rich in TG, resulting in smaller HDL-C particles and reduced quantity, weakening its mediated reverse cholesterol transport function, and preventing cholesterol from being effectively transported from the vascular wall to the liver for excretion from the body (55). In addition, insulin resistance is widespread among patients with T2DM. Insulin resistance prompts the liver to synthesize more very low-density lipoprotein (VLDL), causing dyslipidemia, especially elevated triglycerides and decreased high-density lipoprotein cholesterol (HDL-C) (56). Both of these dyslipidemia are important risk factors for CAS.

In addition, hypertension and T2DM often coexist (57). The hemodynamic changes caused by hypertension exert mechanical stress on the vascular wall, disrupt the integrity of the vascular endothelium, increase the permeability of vascular endothelial cells, promote lipid infiltration and the aggregation of inflammatory cells, and together with diabetes mellitus, significantly increase the risk of CAS (58). Overweight cannot be ignored in the development of CAS in patients with T2DM. Adipose tissue, as an important endocrine organ, is characterized by excessive proliferation and hypertrophy of adipocytes in patients with central obesity, which secretes a large amount of free fatty acids, inflammatory factors (such as tumor necrosis factor -α, interleukin-6), and adipokines (such as decreased adiponectin levels and elevated resistin levels) (59). Free fatty acids can interfere with insulin signal transduction and aggravate insulin resistance. Inflammatory factors can activate the inflammatory response of vascular endothelial cells and promote the adhesion and migration of monocytes (60). These factors interweave with each other, creating conditions for the occurrence of CAS.

To our knowledge, this study is one of the few that have reported the relationship between CYP2C19 gene polymorphism and the risk of CAS in patients with T2DM. Although this study has identified some risk factors for coronary atherosclerosis in patients with T2DM, there are still some deficiencies. Firstly, in this retrospective study, only common risk factors were included, and some rare and potential factors were not investigated. Secondly, without data on whether patients with T2DM complicated with hypertension received antihypertensive treatment, it is impossible to study the relationship between post-treatment blood pressure and the risk of CAS. Thirdly, this study lacks information regarding the medication history of the enrolled patients. Detailed data on the medications used by the subjects both before and after disease onset were not collected. Consequently, we cannot rule out the confounding effect of pharmacotherapy on the association analysis between CYP2C19 genotypes and CAS risk, nor can we clarify whether pharmacotherapy modifies the impact of genotypes on the incidence risk of CAS. Finally, our study is observational in design and cannot establish a direct causal link between CYP2C19 metabolizer status and CAS risk in T2DM patients; additionally, our findings are specific to the T2DM cohort, and caution against extrapolating this role of CYP2C19 to non-T2DM populations. Future prospective cohort studies or randomized controlled trials are warranted to validate the modulatory role of CYP2C19 genotype in this context.

CAS, as a preventable disease, the identification of high-risk patients is the key to the prevention and control of the disease. In future research, several aspects deserve attention. First, there may be different pathogenic factors in the occurrence process of CAS. What are the interaction patterns and mechanisms of these pathogenic factors? Second, there are many risk factors for cardiovascular diseases, including CAS. Is it genetic or external factor that plays a dominant role? Which risk factors can be effectively controlled to reduce the incidence of cardiovascular diseases?

This study investigated the association between CYP2C19 gene polymorphism and CAS in patients with T2DM. The results indicated that the intermediate metabolizer and poor metabolizer phenotypes of CYP2C19 may be correlated with CAS in T2DM patients. This finding provides a novel perspective for exploring the pathogenesis of CAS in T2DM patients, as well as potential targets and a reference basis for precise prevention and treatment. However, this study has limitations including a small sample size and the lack of clarification regarding specific molecular mechanisms. Future research should conduct multicenter, large-sample prospective studies and basic experiments for further verification and investigation. The ultimate goal is to translate the CYP2C19 metabolic phenotype into a biomarker for CAS risk assessment in T2DM patients, thereby facilitating the development of individualized prevention and treatment strategies.