Cardiovascular disease (CVD) is a major cause of death worldwide and is primarily responsible for the loss of health throughout the world [1, 2]. Coronary artery disease (CAD), the most common CVD, remains the major cause of morbidity and mortality in the largest developing country, China [3, 4]. CAD is a complicated, multifactorial disease that involves both genetic and environmental factors [5]. In the past decade, genome-wide association studies (GWAS) have provided abundant evidence to help determine the quantity of susceptibility gene loci associated with CAD and its severity [6‐10].

Adaptor-related protein complex 2 (AP2) is a protein complex that is involved in the formation of clathrin-coated pits and functions as an adaptor by linking lipid and protein membrane components with the clathrin lattice [11]. It has four non-identical polypeptide chains [12]. The AP2 subunit α2- (AP2A2) has been identified as playing a pivotal role in regulating clathrin-mediated endocytosis [13]. More recently, AP2 has evolved as a key regulatory node to coordinate clathrin-coated pits formation and ensure high spatial and temporal regulation of clathrin-mediated endocytosis [14].

Benzodiazepine receptor-associated protein 1 (BZRAP1), also known as PRAX-1 and rab-interacting molecule-binding protein 1 (RIM-BP1), is an 1857-amino acid protein encoded by the BZRAP1 gene. Previous studies have shown that BZRAP1 is prevalent in the mesolimbic system, especially abundant in the CA1 subfield of the hippocampus [15]. Scholars have observed the upregulation of BZRAP1 after chronic antidepressant treatment [16]. In addition, BZRAP1 mutations are demonstrated to be associated with autism-spectrum disorder and schizophrenia [17, 18].

Recently, an epidemiological study reported that two genetic variants of single nucleotide polymorphisms (SNPs), rs7396366, whose closest gene is AP2A2, and rs2526378, whose closest gene is BZRAP1, are associated with higher plasma lipids and Alzheimer’s disease [19].

Because both Alzheimer’s and CAD are metabolic-related and age-related diseases, we analyzed the potential relationship of rs7396366 and rs2526378 to CAD. However, as far as we know, no data to date have demonstrated the in-depth links between them. To advance our knowledge of the functions of AP2A2 and BZRAP1 in CAD and to seek new methods predicting CAD earlier, we studied the association between the two SNPs and the risk of CAD and its severity based on a Chinese population.

In this hospital-based case-control study, we confirmed an association between rs7396366 polymorphism, closest to the AP2A2 gene, and a higher risk of CAD and its severity based on a Chinese population. These findings are useful for early risk assessment and severity prediction of CAD.

Recently, a role for AP2A2 in hematopoietic stem cell activity was identified in adult mouse and embryonic 14.5-day old fetal liver cells [23]. More importantly, Buroker et al. found that compared with the DMSO-treated cells, an increase in AP2A2 activity is apparent in cardiomyocytes treated for 24 h with Wy14643 (a PPAR activator) [24]. All these data point to the possibility that AP2A2 plays a remarkable role in energy metabolism and lipid transport and is potentially associated with nerve and cardiac disease.

Based on the rapid progress of GWAS, several genetic variants of SNPs are considered to be associated with human diseases [25‐27]. The AP2A2 gene has also been seen as an underlying risk gene for the pathogenesis of CAD [24]. A recent study [19] has demonstrated genetic overlap between CAD, C-reactive protein, and plasma lipids and have reported that the rs7396366 variant closest to the AP2A2 gene and the rs2526378 variant closest to the BZRAP1 gene were two suggested CAD susceptibility loci. Moreover, several studies reported the potential association between AP2A2 gene variants and asthma, wheeze in childhood and adolescence [28], and chronic bronchitis [29], and BZRAP1 variants and Alzheimer’s disease [30]. However, further studies concerning the association between the two SNPs and CAD have not been conducted. According to our results, rs7396366 TT genotype in CAD patients was significantly higher than in the controls. Subjects with rs7396366 TT genotype or T allele were more vulnerable to CAD than those with the GG genotype or G allele. Unfortunately, rs2526378 showed no such results, which may partly owe to the circumscription of sample size and thus needs further study.

In our study, age, sex, hypertension, and T2DM, which are all well-known risk factors for CAD, were also significantly different between CAD patients and non-CAD controls. A large prospective cohort study revealed that the incidence of new cardiovascular disease continued to increase after age 80 [31]. Similarly, a recent study showed that individuals > 65 years of age experience higher risk-adjusted hazards for major adverse cardiac events for non-obstructive, one-, and two-vessel disease, with similar event rates for three-vessel or left main artery disease compared with those < 65 years of age [32]. Interestingly, a study of Danish nonagenarians and centenarians demonstrated that although the individual risk for disability rose with age, disability in the population was not increased during the ninth decade of life [33]. One explanation for this is that everybody dies eventually; various causes of death competing in old people lead to further paradoxes [34]. Sex differences in the incidence, morbidity, and mortality from CAD are well documented [35, 36]. Substantial evidence shows that men, compared with women, experience a higher incidence and prevalence of CAD. The reason may partially be explained by their sex-based propensity to engage in higher-risk behaviors like smoking or excessive alcohol consumption [37]. According to an interaction model theory conducted in the present study, a male carrier of rs7396366 GT/TT genotypes has a higher risk for CAD.

Hypertension plays an important role in the development of CAD. When blood pressure increases, mechanical pressure, impaired endothelial function, and vascular active substances interact with each other to prompt coronary artery intimal injury, vascular wall hypertrophy, lipid deposition, atherosclerotic plaque formation, and the final CAD stage. T2DM is a major risk factor for CAD [38], and the cardiovascular system is particularly susceptible to the biological perturbations caused by this disease. Many patients die from T2DM-related cardiovascular complications [39]. In the current study, both T2DM and fasting plasma glucose were significantly associated with the severity of CAD.

In this hospital-based case-control study, we found that TT genotype of rs7396366 polymorphism of the AP2A2 gene may enhance the risk of CAD and reflect the severity of CAD. The rs7396366 TT genotype might be considered a potential risk marker to predict CAD and its severity. Nevertheless, due to the complexity of CAD, the role of AP2A2 gene in the formation of CAD remains to be further investigated.