In this study, we performed a hospital-based case–control study to investigate the potential association between the rs36071027 polymorphism and the risk of CAD and its severity. Our study demonstrated that the rs36071027 variants in the EBF1 gene in a Chinese population were significantly associated with an increased risk of CAD and its severity, which provides novel data to this field in the current era of “precision medicine” and helps improve our capacity for early CAD risk prediction.
Besides being a vital gene for the development and differentiation of B lymphocytes, EBF1 is also involved in the differentiation of adipose lineage cells [21, 22]. Studies in knockout mice have revealed a function for EBF1 in metabolism due to mouse phenotypes including lipodystrophy, hypotriglyceridemia, and hypoglycemia [11]. Compared with the wild type controls, the symptom of lipodystrophy in the EBF1 knockout mice is characterized by additional brown adipose tissue and a striking reduction in white adipose tissue in the bone marrow [11, 23]. Recently, scholars have determined that EBF1’s function in early B-cell development could be inhibited by active NOTCH signaling [24]. Moreover, the NOTCH1 signal pathway plays a critical regulatory role in the formation of unstable atherosclerotic plaques [25] and is activated in a rat model of post-acute MI [26]. These data support the role of EBF1 gene variants and the NOTCH signaling pathway in regulating metabolism of fatty acids and lipids and the formation of vulnerable atherosclerotic plaques.
In terms of previous GWAS results identifying gene variants significantly associated with cardiovascular diseases in a European population [27, 28]. The EBF1 gene has also been identified as potential critical regulatory gene for the formation of atherosclerosis and CAD [13–16]. Scholars [12] revealed that the rs36071027 variant in the EBF1 gene increases the risk of IMT, which is not only significantly associated with the severity of CAD, but is also a screening index of CAD. In the present study, the rs36071027 TT genotype frequency in CAD patients was significantly higher than in controls. Participants with the rs36071027 TT genotype or a T allele were more susceptible to CAD than those with the CC genotype or a C allele. These findings are consistent with the role of EBF1 gene variants found in previous studies.
In the present study, there is higher proportion of smoking and diabetes in the CAD group than in the control group. Smoking is well-known to be one of the main risk factors for CAD. Smoking contributes to the inflammatory process through promoting the release of inflammatory cytokines, such as C-reactive protein, interleukin-1 and tumor necrosis factor-?. Furthermore, inflammation can interact with lipoprotein metabolism and influence endothelial function [29]. In the current study, using an interaction model theory, the interaction between smoking and the genotype was used to explore gene loci and the interaction of smoking and their relationship with the risk of CAD. Interestingly, our results showed that being a carrier of the rs36071027 CT/TT genotypes or smoking both could increase the risk for CAD, although the interaction effect between the CT/TT rs36071207 genotypes and smoking on the risk of CAD was similar to either factor alone. Furthermore, only subjects with CT?+?TT genotypes and diabetes had increased risk of CAD compared to non-diabetes subjects with the CC genotype.
As another important risk factor for CAD, diabetes has a common environmental and genetic basis with CAD, which is the key concept of the theory of “common ground’ of CAD and diabetes [30]. Furthermore, Cutlip DE et al. found that comorbid diabetes is the strongest predictor of clinical vascular restenosis after a coronary intervention [31]. In the present study, a multivariate logistic regression model showed that diabetes and the rs36071027 CC?+?TT genotype have a significant association with the severity of CAD.
Limitations
This study has several limitations. First, this was an observational study, and the sample size was relatively small, which might under-power the results of our study. Second, because of the case–control design, selection bias might affect our findings. Furthermore, since all control subjects have suspicion of having significant CAD although severe coronary stenosis was ruled out by coronary angiography, the control group does not represent a general healthy population, and more concomitant risk factors could be assumed in the control group compared to the general population. Furthermore, the present study lacks direct cause-and-effect evidence indicating whether the variations of rs36071027 in the EBF1 gene are functional or not, and the pathogenic mechanism for these variants to induce CAD has not been determined. Finally, our study sample came from a Chinese population, and applying these results to other ethnic groups should be done with caution. However, our study obviously provides valuable information to future studies connecting the EBF1 gene and CAD.