Abstract
Objective
Previous studies have shown that apolipoprotein E (ApoE) gene polymorphisms have an impact on coronary artery disease(CAD). However, many studies have small sample sizes and different conclusions. The purpose was to retrospectively study the influence of ApoE gene polymorphisms on CAD.
Methods
This study assessed the influence of different ApoE genotypes on coronary heart disease in patients who received coronary angiography and used multivariate logistic regression to assess the influence of different ApoE genotypes on CAD.
Results
Patients with different ApoE genotypes had no obvious differences in the incidence of hypertension, diabetes or obesity（P > 0.05). Patients with ε2/ε2 had higher incidence of hypertriglyceridemia than patients with other ApoE genotypes, while patients with ε3/ε3 had a lower incidence of hypertriglyceridemia than those with ε3/ε4,ε4/ε4, ε2/ε3 and ε2/ε2（P < 0.05）. Patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no significant differences in the severity or incidence of CAD （P > 0.05). ε2/ε4 and ε2/ε3 reduced the risk of high LDL-C, and reduced the severity and incidence of coronary heart（P < 0.05). ε2/ε3 reduced risk of premature coronary artery disease（PCAD）（P < 0.05). ε2/ε3 reduced risk of CAD in patients age <45,age at 60–74 and age ≥74, while ε2/ε4 reduced risk of CAD in patients age ≥74（P < 0.05).
Conclusion
Patients with ε3/ε4, ε4/ε4,ε3/ε3 and ε2/ε2 had no significant differences in the severity and occurrence of CAD. Compared to the isoform ε3 (ε3/ε3), isoform ε4 did not increased the severity and occurrence of CAD. Compared with ApoE other genotypes, ε2/ε3 and ε2/ε4 reduced the risk of high LDL-C and the severity and occurrence of CAD.
Keywords: Percutaneous coronary intervention, Coronary angiography, Apolipoprotein E polymorphisms, Coronary artery disease
1. Introduction
Cardiovascular disease is an important cause of death worldwide. Apolipoproteins take part in lipid metabolism and influence the occurrence of CAD [1]. Genetic variation in apolipoproteins may cause abnormal lipids metabolism and increase occurrence of CAD [2]. ApoE is a kind of polymorphic apolipoprotein, which is a component of many lipoproteins. ApoE plays an important role in lipoprotein metabolism [3]. Apolipoprotein E is involved in the formation of HDL and affects the clearance of lipoproteins from blood [4]. The major alleles of ApoE gene are ε3, ε4 and ε2, and the metabolism of blood lipids is different among different genotypes [5,6]. ε3 regulates the interaction between lipids and lipoprotein, and has a high affinity to high-density lipoprotein [7], ε4 has a high affinity to lipoprotein which are rich in triglyceride [8]. Genetic variation in apolipoprotein E influences lipoprotein metabolism and the occurrence of CAD [9]. Some studies have shown that ε4 allele increases the risk of cardiovascular disease, while other studies have shown that there is no statistical differences in the severity and occurrence of CAD in patients with different ApoE genotypes. According to an Italian investigation, the ε4 allele is associated with low ApoE concentrations, which is a risk factor for coronary artery diseases [10]. A recently study showed that ApoE ε3/ε4 genotype and ε4 allele were independent risk factors for T2DM complicated with CAD, but not for T2DM [11]. A comprehensive genome study involving a large number of samples with 48,457 individuals showed that individuals with ε4 allele are more susceptible to coronary heart disease than individuals with ε3 allele [12]. Other studies have also shown that ε4 allele will increase risk of cardiovascular disease [[13], [14], [15]]. However, a study reported that there was no association between ApoE gene polymorphisms and CAD in Afro-Caribbean people [16]. A recent study indicated that allele ε4 was not significantly expressed in venous tissue between control and patient groups, and ε4 was not related to the risk of cardiovascular diseases [17]. Therefore, there is controversy about the influence of ApoE gene polymorphisms on CAD, and the sample size of many studies was small. The purpose of this study is to retrospectively study the influence of ApoE gene polymorphisms on CAD.
2. Methods
2.1. Patient population
This single-center retrospective study included 7634 patients who had complete medical records and were hospitalized due to coronary angiography at Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University) between January 2017 to December 2019. Patient data, including results of ApoE genotype, coronary angiography and blood lipid, conventional cardiovascular risk factors and other clinical characteristics were obtained from the hospital electronic file. Coronary artery disease was defined as coronary angiography that confirmed at least one epicardial main vessel stenosis was more than 50 %. Multi-vessel lesions was defined as coronary angiography that confirmed that at least two epicardial main vessel stenoses were more than 50 %. Family history refers to immediate family, including parents or siblings.
2.2. Statistical analyses
Values are presented as mean ± SD or number (%) in each group. The Kruskal-Wallis test in nonparametric test was used to compare the continuous variables between different groups, and Bonferroni correction method was used to adjust the multiple comparisons. We compared categorical variables among different groups using chi-square or Fisher's exact Test. This study used multivariate hierarchical logistic regression to assess the influence of different ApoE genotypes on cardiovascular risk factors and CAD in patients who received coronary angiography after adjustment for age,gender and cardiovascular risk factors. P < 0.05 was considered to be statistically significant. All statistical analysis was carried out with SPSS 26 software.
3. Results
3.1. Clinical features of patients with different ApoE genotypes
The study used the Kruskal-Wallis test in nonparametric test to compare the continuous variables between different groups, and used Bonferroni correction method to adjust for multiple comparisons. The study compared categorical variables among different groups using chi-square or Fisher's exact Test. As shown in Table 1, among the 7634 patients who received coronary angiography, ε3/ε3 accounted for 67.28 % of all genotypes, followed by the ε4/ε4 (1.14 %) , ε2/ε3 (12.38 %), ε3/ε4 (16.99 %), ε2/ε4 (1.51 %) and ε2/ε2 (0.71 %). There were no significant differences among 4 groups in gender, drinking, hypertension, diabetes, BMI, smoking，hyperuricemia, obesity, AMI, cardiac insufficiency, chronic kidney disease, family history of hypertension, diabetes, CAD and family history of hyperlipidemia （P > 0.05）.
Table 1.
Baseline Clinical Characteristics of patients with different apolipoprotein E genotypes.
| Variable | ε4/ε4 (n = 87) | ε3/ε4 (n = 1297) | ε2/ε4 (n = 115) | ε2/ε3 (n = 945) | ε2/ε2 (n = 54) | ε3/ε3 (n = 5136) | p Value |
|---|---|---|---|---|---|---|---|
| Age, years | 58.54 ± 10.92 | 62.70 ± 10.53 | 62.07 ± 11.96 | 64.02 ± 10.56 | 63.09 ± 10.84 | 62.94 ± 10.72 | 0.000a |
| Male Sex, n(%) | 55（63.21 %） | 785（60.52 %） | 70（60.87 %） | 551（58.31 %） | 41（75.93 %） | 3085（60.06 %） | 0.253 |
| Drinking, n(%) | 28（32.18 %） | 397（30.61 %） | 27（23.48 %） | 259（27.41 %） | 16（29.63 %） | 1453（28.29 %） | 0.354 |
| Smoking, n(%) | 38（43.67 %） | 538（41.48 %） | 43（37.39 %） | 343（36.30 %） | 34（62.92 %） | 2041（39.74 %） | 0.002a |
| Hypertension, n (%) | 46（52.87 %） | 737（56.82 %） | 67（58.26 %） | 558（59.05 %） | 31（57.41 %） | 2848（55.45 %） | 0.402 |
| Diabetes, n (%) | 16（18.39 %） | 240（18.50 %） | 23（20 %） | 207（21.90 %） | 16（29.63 %） | 1008（19.63 %） | 0.190 |
| Triglyceride, mmol/l | 2.24 ± 1.84 | 1.90 ± 1.75 | 1.91 ± 1.36 | 1.87 ± 1.50 | 2.79 ± 2.09 | 1.70 ± 1.26 | 0.000a |
| LDL-C，mmol/l | 2.92 ± 0.88 | 2.84 ± 0.85 | 2.66 ± 0.82 | 2.43 ± 0.75 | 2.38 ± 1.07 | 2.73 ± 0.81 | 0.000a |
| HDL-C，mmol/l | 1.08 ± 0.28 | 1.10 ± 0.28 | 1.11 ± 0.29 | 1.15 ± 0.30 | 1.15 ± 0.34 | 1.12 ± 0.31 | 0.000a |
| Total cholesterol，mmol/l | 4.54 ± 1.20 | 4.40 ± 1.14 | 4.18 ± 1.09 | 3.96 ± 1.07 | 4.24 ± 1.58 | 4.26 ± 1.07 | 0.000a |
| BMI | 24.47 ± 3.06 | 24.34 ± 3.25 | 24.48 ± 3.48 | 24.32 ± 3.29 | 24.80 ± 3.98 | 24.38 ± 3.30 | 0.929 |
| High triglyceride, n (%) | 44（50.57 %） | 482（37.16 %） | 47（40.87 %） | 364（38.52 %） | 36（66.67 %） | 1733（33.74 %） | 0.000a |
| High LDL-C，n (%) | 34（39.08 %） | 435（33.54 %） | 25（21.74 %） | 155（16.40 %） | 16（29.63 %） | 1463（28.49 %） | 0.000a |
| High total cholesterol，n(%) | 13（14.94 %） | 138（10.64 %） | 9（7.83 %） | 53（5.61 %） | 8（14.81 %） | 456（8.88 %） | 0.000* |
| Hyperuricemia，n (%) | 6（6.90 %） | 131（10.10 %） | 9（7.83 %） | 93（9.84 %） | 5（9.26 %） | 533（10.38 %） | 0.890 |
| Overweight,n(%) | 36（41.38 %） | 471（36.31 %） | 41（35.65 %） | 327（34.60 %） | 16（29.63 %） | 1758（34.23 %） | 0.498 |
| Obese,n(%) | 4（4.60 %） | 60（4.63 %） | 6（5.22 %） | 42（4.44 %） | 5（9.26 %） | 279（5.43 %） | 0.469 |
| Coronary heart disease, n(%) | 53（60.92 %） | 767（59.14 %） | 54（46.96 %） | 484（51.22 %） | 35（64.81 %） | 3028（58.96 %） | 0.000a |
| Multivessel lesion,n(%) | 29（33.33 %） | 445（34.31 %） | 26（22.61 %） | 246（26.03 %） | 18（33.33 %） | 1679（32.69 %） | 0.000a |
| PCI，n(%) | 40（45.98 %） | 541（41.71 %） | 34（29.57 %） | 352（37.25 %） | 28（51.85 %） | 2152（41.90 %） | 0.004a |
| AMI，n(%) | 16（18.39 %） | 166（12.80 %） | 10（8.70 %） | 79（8.36 %） | 7（12.96 %） | 641（12.48 %） | 0.002a |
| Cardiac insufficiency, n(%) | 2（2.30 %） | 75（5.78 %） | 4（3.48 %） | 63（6.67 %） | 1（1.85 %） | 312（6.07 %） | 0.388 |
| CKD, n(%) | 2（2.30 %） | 46（3.55 %） | 4（3.48 %） | 30（3.17 %） | 1（1.85 %） | 162（3.15 %） | 0.975 |
| Family history of hypertension, n(%) | 8（9.20 %） | 104（8.02 %） | 7（6.09 %） | 81（8.57 %） | 3（5.56 %） | 413（8.04 %） | 0.934 |
| Family history of diabetes, n(%) | 1（1.15 %） | 42（3.24 %） | 1（0.87 %） | 25（2.64 %） | 3（5.56 %） | 135（2.63 %） | 0.378 |
| Family history of CAD, n(%) | 6（6.90 %） | 58（4.47 %） | 2（1.74 %） | 38（4.02 %） | 3（5.56 %） | 254（4.95 %） | 0.371 |
| Family history of hyperlipidemia, n(%) | 0 | 5（0.39 %） | 0 | 3（0.32 %） | 0 | 12（0.23 %） | 0.762 |
Values are mean ± SD or number (%).
Indicates p < 0.05. LDL-C: Low-density lipoprotein cholesterol; HDL-C:High-density lipoprotein cholesterol; PCI: Percutaneous coronary intervention; AMI: Acute myocardial infarction; CKD: Chronic kidney disease, CAD:Coronary artery disease.
3.2. The influence of different ApoE genotypes on obesity, diabetes and hypertension
This study used a multivariate logistic regression model to assess the occurrence of different ApoE genotypes on hypertension, diabetes and obesity. As shown in Table 2, patients with different apolipoprotein E genotypes had no significant differences in the occurrence of obesity, diabetes or hypertension.
Table 2.
A multivariate Logistic regression model on the association of hypertension, diabetes and obese with ApoE gene polymorphisms after adjustment for sex,age and the clinical characteristic factors.
| Variables | Adjusted Odd Ratio (OR) (95 % CI), p Value |
||
|---|---|---|---|
| Hypertension | Diabetes | Obese | |
| ε3/ε4 vs ε4/ε4 | 1.047(0.665–1.649), P = 0.841 | 0.961(0.542–1.704), P = 0.892 | 1.279(0.447–3.662), P = 0.646 |
| ε3/ε3 vs ε4/ε4 | 0.968(0.621–1.507), P = 0.885 | 1.072(0.613–1.876), P = 0.807 | 1.623(0.581–4.529), P = 0.355 |
| ε2/ε4 vs ε4/ε4 | 1.103(0.613–1.986), P = 0.744 | 1.031(0.498–2.137), P = 0.934 | 1.479(0.397–5.508), P = 0.559 |
| ε2/ε3 vs ε4/ε4 | 1.051(0.663–1.666), P = 0.832 | 1.178(0.661–2.099), P = 0.579 | 1.400(0.482–4.072), P = 0.536 |
| ε2/ε2 vs ε4/ε4 | 0.898(0.440–1.837), P = 0.769 | 1.654(0.729–3.753), P = 0.229 | 2.899(0.721–11.657), P = 0.134 |
| ε3/ε4 vs ε3/ε3 | 1.082(0.952–1.231), P = 0.228 | 0.896(0.763–1.052), P = 0.181 | 0.788(0.590–1.054), P = 0.108 |
| ε2/ε4 vs ε3/ε3 | 1.140(0.767–1.693), P = 0.517 | 0.962(0.596–1.551), P = 0.873 | 0.912(0.393–2.113), P = 0.829 |
| ε2/ε3 vs ε3/ε3 | 1.086(0.936–1.260), P = 0.276 | 1.099(0.922–1.309), P = 0.293 | 0.863(0.615–1.210), P = 0.393 |
| ε2/ε2 vs ε3/ε3 | 0.928(0.526–1.638), P = 0.797 | 1.543(0.840–2.833), P = 0.162 | 1.787(0.686–4.654), P = 0.235 |
| ε3/ε4 vs ε2/ε2 | 1.166(0.655–2.075), P = 0.602 | 0.581(0.312–1.081), P = 0.087 | 0.441(0.165–1.182), P = 0.104 |
| ε2/ε4 vs ε2/ε2 | 1.228(0.618–2.439), P = 0.558 | 0.623(0.290–1.341), P = 0.227 | 0.510(0.145–1.801), P = 0.296 |
| ε2/ε3 vs ε2/ε2 | 1.170(0.655–2.091), P = 0.596 | 0.712(0.382–1.329), P = 0.286 | 0.483(0.178–1.313), P = 0.154 |
| ε2/ε4 vs ε3/ε4 | 1.053(0.700–1.583), P = 0.804 | 1.073(0.655–1.759), P = 0.780 | 1.156(0.483–2.766), P = 0.744 |
| ε2/ε3 vs ε3/ε4 | 1.004(0.839–1.201), P = 0.970 | 1.226(0.988–1.521), P = 0.065 | 1.095(0.725–1.652), P = 0.667 |
| ε2/ε3 vs ε2/ε4 | 0.953(0.630–1.442), P = 0.820 | 1.142(0.694–1.880), P = 0.601 | 0.947(0.389–2.302), P = 0.904 |
* indicates p < 0.05.
3.3. The influence of different ApoE genotypes on dyslipidemia
This study used multivariate logistic regression model to assess the influence of different ApoE genotypes on dyslipidemia. As shows in Table 3, patients with ε3/ε4, ε4/ε4, ε2/ε4 and ε2/ε3 had no significant differences in the occurrence of hypertriglyceridemia（P > 0.05）. Patients with ε2/ε2 had higher occurrence of hypertriglyceridemia than patients with other ApoE genotypes（P < 0.05）. Patients with ε3/ε4, ε4/ε4, ε2/ε3, and ε2/ε2 had higher occurrence of hypertriglyceridemia than patients with ε3/ε3（P < 0.05）.
Table 3.
A multivariate Logistic regression model on the association of serum lipid with ApoE gene polymorphisms after adjustment for sex,age and the clinical characteristic factors.
| Variables | Adjusted Odd Ratio (OR) (95 % CI), p Value |
||
|---|---|---|---|
| High triglyceride | High total cholesterol | High LDL-C | |
| ε3/ε4 vs ε4/ε4 | 0.638(0.404–1.005), P = 0.052 | 0.716(0.384–1.333), P = 0.292 | 0.840(0.535–1.318), P = 0.448 |
| ε3/ε3 vs ε4/ε4 | 0.542(0.348–0.845), P = 0.007* | 0.586(0.321–1.072), P = 0.083 | 0.661(0.426–1.025), P = 0.064 |
| ε2/ε4 vs ε4/ε4 | 0.723(0.402–1.298), P = 0.277 | 0.511(0.206–1.266), P = 0.147 | 0.453(0.243–0.845), P = 0.013a |
| ε2/ε3 vs ε4/ε4 | 0.693(0.437–1.098), P = 0.118 | 0.359(0.186–0.693), P = 0.002a | 0.329(0.206–0.525), P = 0.000a |
| ε2/ε2 vs ε4/ε4 | 2.237(1.070–4.675), P = 0.032* | 1.190(0.453–3.123), P = 0.724 | 0.747(0.359–1.555), P = 0.435 |
| ε3/ε4 vs ε3/ε3 | 1.175(1.031–1.341), P = 0.016* | 1.221(0.997–1.494), P = 0.053 | 1.271(1.115–1.450), P = 0.000a |
| ε2/ε4 vs ε3/ε3 | 1.332(0.901–1.970), P = 0.151 | 0.872(0.437–1.740), P = 0.697 | 0.686(0.437–1.077), P = 0.101 |
| ε2/ε3 vs ε3/ε3 | 1.277(1.100–1.482), P = 0.001* | 0.612(0.456–0.822), P = 0.001a | 0.498(0.414–0.598), P = 0.000a |
| ε2/ε2 vs ε3/ε3 | 4.124(2.276–7.472), P = 0.000* | 2.029(0.944–3.361), P = 0.070 | 1.130(0.624–2.046), P = 0.686 |
| ε3/ε4 vs ε2/ε2 | 0.285(0.156–0.521), P = 0.000* | 0.602(0.276–1.312), P = 0.201 | 1.125(0.616–2.053), P = 0.701 |
| ε2/ε4 vs ε2/ε2 | 0.323(0.159–0.655), P = 0.002* | 0.430(0.155–1.193), P = 0.105 | 0.607(0.289–1.272), P = 0.186 |
| ε2/ε3 vs ε2/ε2 | 0.310(0.169–0.568), P = 0.000* | 0.302(0.134–0.677), P = 0.004a | 0.440(0.238–0.815), P = 0.009a |
| ε2/ε4 vs ε3/ε4 | 1.133(0.757–1.698), P = 0.544 | 0.714(0.352–1.448), P = 0.351 | 0.539(0.340–0.856), P = 0.009a |
| ε2/ε3 vs ε3/ε4 | 1.086(0.908–1.300), P = 0.367 | 0.502(0.361–0.698), P = 0.000a | 0.391(0.318–0.482), P = 0.000a |
| ε2/ε3 vs ε2/ε4 | 0.958(0.636–1.444), P = 0.839 | 0.702(0.336–1.470), P = 0.348 | 0.726(0.449–1.172), P = 0.190 |
Indicates p < 0.05. LDL-C: Low-density lipoprotein cholesterol.
Patients with ε3/ε4, ε4/ε4, ε2/ε4 and ε2/ε2 had no obvious differences in the occurrence of high total cholesterol （P > 0.05）. Patients with ε2/ε4 and ε2/ε3 had no obvious differences in the occurrence of high total cholesterol （P > 0.05）. Patients with ε2/ε3 had lower occurrence of high total cholesterol than patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2（P < 0.05）.
Patients with ε2/ε2, ε4/ε4 and ε3/ε3 had no obvious differences in the occurrence of high LDL-C（P > 0.05）. Patients with ε2/ε4 and ε2/ε3 had no obvious differences in the occurrence of high LDL-C （P > 0.05）. Patients with ε3/ε3 had lower occurrence of high LDL-C than patients with ε3/ε4（P < 0.05）. Patients with ε2/ε4 had lower occurrence of high LDL-C than patients with ε3/ε4 and ε4/ε4（P < 0.05）. Patients with ε2/ε3 had lower occurrence of high LDL-C than patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2（P < 0.05）.
3.4. The influence of different ApoE genotypes on CAD
This study used a multivariate logistic regression to assess the influence of different ApoE genotypes on CAD. As shown in Table 4, patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no obvious differences in the occurrence of CAD. Patients with ε2/ε3 had lower occurrence of CAD than patients with ε3/ε3 and ε3/ε4（P < 0.05）. Patients with ε2/ε4 had lower occurrence of CAD than patients with ε3/ε4, ε4/ε4 and ε3/ε3（P < 0.05）.
Table 4.
A multivariate Logistic regression model on the association of coronary artery disease with ApoE gene polymorphisms after adjustment for sex,age and cardiovascular risk factors.
| Variables | Adjusted Odd Ratio (OR) (95 % CI) | pValue |
|---|---|---|
| ε3/ε4 vs ε4/ε4 | 0.825(0.512–1.327) | 0.427 |
| ε3/ε3 vs ε4/ε4 | 0.866(0.544–1.379) | 0.545 |
| ε2/ε4 vs ε4/ε4 | 0.504(0.275–0.925) | 0.027a |
| ε2/ε3 vs ε4/ε4 | 0.627(0.387–1.016) | 0.058 |
| ε2/ε2 vs ε4/ε4 | 0.938 (0.434–2.023) | 0.870 |
| ε3/ε4 vs ε3/ε3 | 0.952(0.833–1.088) | 0.470 |
| ε2/ε4 vs ε3/ε3 | 0.582(0.391–0.868) | 0.008a |
| ε2/ε3 vs ε3/ε3 | 0.724(0.621–0.844) | 0.000a |
| ε2/ε2 vs ε3/ε3 | 1.083(0.582–2.012) | 0.802 |
| ε3/ε4 vs ε2/ε2 | 0.879 (0.469–1.650) | 0.689 |
| ε2/ε4 vs ε2/ε2 | 0.583(0.259–1.117) | 0.096 |
| ε2/ε3 vs ε2/ε2 | 0.669(0.357–1.253) | 0.209 |
| ε2/ε4 vs ε3/ε4 | 0.612(0.405–0.923) | 0.019a |
| ε2/ε3 vs ε3/ε4 | 0.760(0.631–0.915) | 0.004a |
| ε2/ε3 vs ε2/ε4 | 1.243 (0.818–1.888) | 0.308 |
Indicates p < 0.05.
3.5. The influence of different ApoE genotypes on the severity of CAD
This study used a multivariate logistic regression to assess the influence of different ApoE genotypes on the severity of CAD. As shown in Table 5, patients with ε3/ε4, ε4/ε4, ε3/ε3,ε2/ε3 and ε2/ε2 had no obvious differences in the occurrence of PCI （P > 0.05）. Patients with ε2/ε4 had lower occurrence of PCI than patients with other ApoE genotypes（P < 0.05）. Patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no obvious differences in the occurrence of multi-vessel lesion（P > 0.05）. Patients with ε2/ε4 and ε2/ε3 had lower occurrence of multi-vessel lesion than patients with ε3/ε4 and ε3/ε3（P < 0.05）. Patients with ε3/ε4, ε4/ε4, ε3/ε3, ε2/ε4 and ε2/ε2 had no obvious differences in the occurrence of acute myocardial infarction (AMI) （P > 0.05）. Patients with ε2/ε3 had lower occurrence of AMI than patients with ε3/ε3 and ε3/ε4（P < 0.05）.
Table 5.
A multivariate Logistic regression model on the association of the severity of coronary artery disease（ PCI, multivessel lesion and AMI) with ApoE gene polymorphisms after adjustment for sex,age and cardiovascular risk factors.
| Variables | Adjusted Odd Ratio (OR) (95 % CI), p Value |
||
|---|---|---|---|
| PCI | multivessel lesion | AMI | |
| ε3/ε4 vs ε4/ε4 | 0.762(0.478–1.214), P = 0.252 | 0.951(0.581–1.558), P = 0.843 | 0.626(0.346–1.133), P = 0.122 |
| ε3/ε3 vs ε4/ε4 | 0.817(0.518–1.287), P = 0.383 | 0.921(0.568–1.492), P = 0.737 | 0.651(0.366–1.157), P = 0.144 |
| ε2/ε4 vs ε4/ε4 | 0.463(0.249–0.859), P = 0.015a | 0.539(0.277–1.050), P = 0.069 | 0.479(0.200–1.147), P = 0.098 |
| ε2/ε3 vs ε4/ε4 | 0.724(0.451–1.163), P = 0.182 | 0.691(0.417–1.144), P = 0.151 | 0.496(0.267–0.920), P = 0.026a |
| ε2/ε2 vs ε4/ε4 | 1.206(0.577–2.521), P = 0.618 | 0.870(0.399–1.897), P = 0.726 | 0.911(0.334–2.483), P = 0.856 |
| ε3/ε4 vs ε3/ε3 | 0.933(0.817–1.064), P = 0.298 | 1.033(0.900–1.186), P = 0.643 | 0.962(0.796–1.162), P = 0.688 |
| ε2/ε4 vs ε3/ε3 | 0.566(0.369–0.869), P = 0.009a | 0.585(0.366–0.936), P = 0.025a | 0.736(0.377–1.436), P = 0.368 |
| ε2/ε3 vs ε3/ε3 | 0.887(0.759–1.036), P = 0.131 | 0.750(0.633–0.890), P = 0.001a | 0.762(0.591–0.982), P = 0.036a |
| ε2/ε2 vs ε3/ε3 | 1.477(0.821–2.657), P = 0.193 | 0.945(0.508–1.756), P = 0.857 | 1.400(0.609–3.215), P = 0.428 |
| ε3/ε4 vs ε2/ε2 | 0.631(0.348–1.147), P = 0.131 | 1.094(0.582–2.054), P = 0.781 | 0.687(0.295–1.601), P = 0.385 |
| ε2/ε4 vs ε2/ε2 | 0.384(0.187–0.788), P = 0.009a | 0.620(0.287–1.341), P = 0.224 | 0.525(0.182–1.515), P = 0.234 |
| ε2/ε3 vs ε2/ε2 | 0.601(0.331–1.091), P = 0.094 | 0.794(0.422–1.494), P = 0.475 | 0.544(0.232–1.279), P = 0.163 |
| ε2/ε4 vs ε3/ε4 | 0.607(0.391–0.943), P = 0.026a | 0.567(0.350–0.917), P = 0.021a | 0.765(0.386–1.516), P = 0.442 |
| ε2/ε3 vs ε3/ε4 | 0.951(0.789–1.147), P = 0.599 | 0.726(0.594–0.888), P = 0.002a | 0.792(0.590–1.063), P = 0.120 |
| ε2/ε3 vs ε2/ε4 | 1.566(1.002–2.448), P = 0.049a | 1.281(0.785–2.093), P = 0.322 | 1.036(0.512–2.096), P = 0.922 |
Indicates p < 0.05. PCI:Percutaneous coronary intervention; AMI: Acute myocardial infarction.
3.6. The influence of different ApoE genotypes on premature coronary heart disease
This study used a multivariate hierarchical logistic regression to assess the occurrence of different ApoE genotypes on PCAD. As shown in Table 6, patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε4 had no obvious differences in the occurrence of PCAD（P > 0.05）. Patients with ε2/ε3 had lower occurrence of PCAD than patients with ε3/ε3 and ε2/ε2（P < 0.05）. Patients with ε3/ε4, ε4/ε4 and ε2/ε4 had lower occurrence of PCAD than patients with ε2/ε2（P < 0.05）.
Table 6.
A multivariate Logistic regression model on the association of premature coronary artery disease with ApoE gene polymorphisms after adjustment for age and cardiovascular risk factors.
| Variables | Adjusted Odd Ratio (OR) (95 % CI) | pValue |
|---|---|---|
| ε3/ε4 vs ε4/ε4 | 0.734(0.373–1.444) | 0.370 |
| ε3/ε3 vs ε4/ε4 | 0.746(0.386–1.439) | 0.382 |
| ε2/ε4 vs ε4/ε4 | 0.526(0.214–1.290) | 0.160 |
| ε2/ε3 vs ε4/ε4 | 0.539(0.269–1.084) | 0.083 |
| ε2/ε2 vs ε4/ε4 | 2.228(0.651–7.626) | 0.202 |
| ε3/ε4 vs ε3/ε3 | 0.984(0.793–1.221) | 0.883 |
| ε2/ε4 vs ε3/ε3 | 0.705(0.376–1.321) | 0.275 |
| ε2/ε3 vs ε3/ε3 | 0.724(0.553–0.946) | 0.018a |
| ε2/ε2 vs ε3/ε3 | 2.989(1.047–8.531) | 0.041a |
| ε3/ε4 vs ε2/ε2 | 0.329 (0.114–0.954) | 0.041a |
| ε2/ε4 vs ε2/ε2 | 0.236(0.070–0.793) | 0.020a |
| ε2/ε3 vs ε2/ε2 | 0.242(0.083–0.704) | 0.009a |
| ε2/ε4 vs ε3/ε4 | 0.717(0.375–1.371) | 0.314 |
| ε2/ε3 vs ε3/ε4 | 0.735(0.535–1.011) | 0.058 |
| ε2/ε3 vs ε2/ε4 | 1.419 (0.913–2.206) | 0.120 |
Indicates p < 0.05.
3.7. The influence of age on the correlation between different ApoE genotypes and CAD
This study used a multivariate hierarchical logistic regression to assess the influence of age on the correlation between different ApoE genotypes and CAD. This study divided the 7634 patients into four age groups (age <45, age at 45–59,age at 60–74, age ≥75). As shown in Table 7, patients with ε3/ε4, ε4/ε4, ε2/ε2, ε2/ε4 and ε3/ε3 had no obvious differences in the occurrence of CAD in age under 45 and age at 60–74 group （P > 0.05）. Patients with ε2/ε3 had lower occurrence of CAD than patients with ε4/ε4 and ε3/ε4 in age under 45 group（P < 0.05）. Patients with different ApoE genotypes had no obvious differences in the occurrence of CAD in age at 45–59 group （P > 0.05）. Patients with ε2/ε3 had lower occurrence of CAD than patients with ε3/ε4 and ε3/ε3 in age at 60–74 group（P < 0.05）.
Table 7.
To exclude the potentially confounding effects of age on the association of coronary artery disease with ApoE gene polymorphisms, multivariate logistic regression analysis stratified according to age was performed.
| Variables | Adjusted Odd Ratio (OR) (95 % CI), p Value |
|||
|---|---|---|---|---|
| ＜45 years old | ≥45 and ≤ 59 years old | ≥60 and ≤ 74 years old | ≥75 years old | |
| ε3/ε4 vs ε4/ε4 | 0.334(0.057–1.952), P = 0.223 | 0.617(0.306–1.245), P = 0.177 | 1.404(0.670–2.940), P = 0.369 | 1.043(0.100–10.899), P = 0.972 |
| ε3/ε3 vs ε4/ε4 | 0.233(0.042–1.284), P = 0.094 | 0.684(0.347–1.346), P = 0.272 | 1.413(0.684–2.917), P = 0.351 | 1.212(0.118–12.461), P = 0.872 |
| ε2/ε4 vs ε4/ε4 | 0.357(0.042–3.059), P = 0.347 | 0.404(0.152–1.073), P = 0.069 | 0.790(0.312–2.000), P = 0.619 | 0.342(0.027–4.298), P = 0.406 |
| ε2/ε3 vs ε4/ε4 | 0.096(0.014–0.658), P = 0.017* | 0.517(0.252–1.062), P = 0.072 | 1.063(0.504–2.242), P = 0.872 | 0.757(0.072–7.935), P = 0.816 |
| ε2/ε2 vs ε4/ε4 | 0.146(0.005–4.059), P = 0.256 | 1.092(0.318–3.748), P = 0.888 | 0.908(0.288–2.866), P = 0.869 | 3.021(0.130–70.197), P = 0.491 |
| ε3/ε4 vs ε3/ε3 | 1.433(0.753–2.729), P = 0.274 | 0.902(0.708–1.149), P = 0.404 | 0.994(0.825–1.197), P = 0.947 | 0.861(0.591–1.253), P = 0.434 |
| ε2/ε4 vs ε3/ε3 | 1.534(0.398–5.917), P = 0.534 | 0.590(0.287–1.214), P = 0.152 | 0.559(0.309–1.014), P = 0.055 | 0.282(0.102–0.784), P = 0.015a |
| ε2/ε3 vs ε3/ε3 | 0.414(0.158–1.083), P = 0.072 | 0.756(0.567–1.007), P = 0.056 | 0.753(0.607–0.933), P = 0.009a | 0.624(0.427–0.914), P = 0.015a |
| ε2/ε2 vs ε3/ε3 | 0.625(0.035–11.315), P = 0.751 | 1.597(0.564–4.523), P = 0.378 | 0.643(0.260–1.588), P = 0.338 | 2.493(0.296–20.977), P = 0.401 |
| ε3/ε4 vs ε2/ε2 | 2.292(0.122–43.080), P = 0.579 | 0.565(0.196–1.628), P = 0.290 | 1.546(0.618–3.871), P = 0.352 | 0.345(0.040–2.967), P = 0.333 |
| ε2/ε4 vs ε2/ε2 | 2.453(0.105–57.512), P = 0.577 | 0.369(0.105–1.295), P = 0.120 | 0.870(0.298–2.545), P = 0.800 | 0.113(0.011–1.185), P = 0.069 |
| ε2/ε3 vs ε2/ε2 | 0.661(0.033–13.164), P = 0.786 | 0.473(0.164–1.366), P = 0.166 | 1.171(0.469–2.924), P = 0.735 | 0.250(0.029–2.132), P = 0.205 |
| ε2/ε4 vs ε3/ε4 | 1.070(0.254–4.507), P = 0.926 | 0.654(0.310–1.380), P = 0.265 | 0.563(0.305–1.037), P = 0.065 | 0.328(0.113–0.948), P = 0.040a |
| ε2/ε3 vs ε3/ε4 | 0.289(0.097–0.856), P = 0.025a | 0.838(0.593–1.183), P = 0.314 | 0.757(0.584–0.982), P = 0.036a | 0.725(0.447–1.176), P = 0.193 |
| ε2/ε3 vs ε2/ε4 | 0.270(0.054–1.347), P = 0.110 | 1.281(0.599–2.740), P = 0.524 | 1.346(0.725–2.499), P = 0.347 | 2.214(0.768–6.379), P = 0.141 |
Indicates p < 0.05.
Patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no obvious differences in the occurrence of CAD in age over 74 group （P > 0.05）. Patients with ε2/ε3 had lower occurrence of CAD than patients with ε3/ε3, while Patients with ε2/ε4 had lower occurrence of CAD than patients with ε3/ε3 and ε3/ε4 in age over 74 group（P < 0.05）.
4. Discussion
ApoE is a circulating glycoprotein, which palys an important role in lipid metabolism and promotes the removal of triglyceride-rich lipoprotein residues from the circulation to liver [18]. ε4, ε3 and ε2 are the major alleles of ApoE, the prevalence of ε4 and ε2 is relatively low, while ε3 is the most common subtype [19]. In this study, among the 7634 patients undergoing coronary angiography, ε3/ε3 accounted for 67.29 % of all genotypes, followed by the ε4/ε4 (1.14 %) , ε2/ε3 (12.38 %), ε3/ε4 (16.99 %), ε2/ε4 (1.51 %) and ε2/ε2 (0.71 %).
ApoE gene polymorphism is associated with many diseases, ApoE gene is a major genetic risk determinant of late-onset Alzheimer disease, with the APOE ε4 allele conferring an increased risk and the ApoE ε2 allele conferring a decreased risk, relative to the common ApoE ε3 allele [20]. In addition to Alzheimer disease, ApoE gene polymorphisms also play a role in other neurological diseases, such as Lewy body dementia [21], Parkinson disease [22], and frontotemporal dementia [23]. The activation of Sirtuin 1 confers protective effects on atherosclerosis involving vascular endothelial and smooth muscle cell senescence [24]. Compared to ApoE ε3 and ApoE ε2, sirtuin 1 showed a higher affinity to ApoE ε4 [25]. Sirtuin 1 levels were significantly reduced in the frontal cortex of ApoE4 mice, and Sirtuin 1 reduction hinder its protective role against the formation of plaques and tangles and diminish its anti-inflammatory actions. Therefore, Sirtuin 1 reduction play a role in ApoE4-associated memory impairments [26].
Coronary artery disease causes great physical and mental harm to patients worldwide. Both the environment and genes can influence the occurrence of CAD [27]. ApoE participates in the regulation of triglyceride and cholesterol metabolism, and influences the occurrence of CAD [28]. This study investigated the influence of different ApoE genotypes on CAD in patients who received coronary angiography. The results indicated that ε2/ε2 is associated with an increased risk of hypertriglyceridemia, while ε3/ε3 is associated with a decreased risk of hypertriglyceridemia. ε2/ε3 and ε2/ε4 are associated with a decreased risk of high total cholesterol and high LDL-C. Patients with different apolipoprotein E genotypes had no significant differences in the occurrence of hypertension, diabetes and obesity.
The influence of ApoE gene polymorphism on CAD is controversial, and the sample size of many studies is small. Some studies indicated that ε4 allele has increased the occurrence of CAD [29,30],but other studies have showed that ε4 allele does not increase the occurrence of CAD [31,32]. Therefore, this study investigated the influence of different ApoE genotypes on CAD in patients who received coronary angiography. As shown in Table 4, patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no obvious differences in the occurrence of CAD. Patients with ε2/ε3 had lower occurrence of CAD than patients with ε3/ε3 and ε3/ε4, while patients with ε2/ε4 had lower occurrence of CAD than patients with ε3/ε4, ε4/ε4 and ε3/ε3. The results suggest that ε2/ε4 and ε2/ε3 decrease the occurrence of CAD. Compare with ε3/ε3，ε4 allele did not obviously increase the occurrence of CAD.
This study also evaluated the influence of different ApoE genotypes on the severity of CAD. As shown in Table 5, patients with ε3/ε4, ε4/ε4, ε3/ε3,ε2/ε3 and ε2/ε2 had no obvious differences in the occurrence of PCI. Patients with ε4/ε4, ε3/ε4, ε3/ε3 and ε2/ε2 had no obvious differences in the occurrence of multi-vessel lesion. Patients with ε3/ε4, ε4/ε4, ε3/ε3, ε2/ε4 and ε2/ε2 had no obvious differences in the occurrence of AMI. Patients with ε2/ε4 and ε2/ε3 had lower occurrence of multi-vessel lesion than patients with ε3/ε3 and ε3/ε4. Patients with ε2/ε4 had lower occurrence of PCI than patients with other ApoE genotypes, while patients with ε2/ε3 had lower occurrence of AMI than patients with ε3/ε3 and ε3/ε4. The results suggest that patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no obvious differences in the severity of CAD. ε2/ε4 and ε2/ε3 have decreased the severity of CAD.
Premature coronary artery disease (PCAD) is defined as CAD occurring in women <65 years and men <55 years of age and become an area of growing concern [33]. A previous meta-analysis indicated that ε2 allele increased the occurrence of PCAD in Asians while decreased the occurrence of PCAD in Caucasians [34]. Another study indicated that ε4 allele increased the occurrence of PCAD in Egyptian [35]. In this study, patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε4 had no obvious differences in the occurrence of PCAD. Patients with ε2/ε3 had lower occurrence of PCAD than patients with ε3/ε3 and ε2/ε2, while patients with ε4/ε4,ε3/ε4 and ε2/ε4 had lower occurrence of PCAD than patients with ε2/ε2. The results suggest that ε2/ε3 have decreased the risk of PCAD, while ε2/ε2 have increased the risk of PCAD.
This study further used multivariate logistic regression to assess the influence of age on the relationship between different ApoE genotypes and CAD. As shown in Table 7, ε2/ε3 has decreased risk of CAD in patients age under 45,age at 60–74 and age over 74, while ε2/ε4 has decreased risk of CAD in patients age over 74. The results further indicated that patients with ε3/ε4, ε4/ε4, ε3/ε3 and ε2/ε2 had no significant differences in the occurrence of CAD, ε2/ε4 and ε2/ε3 have decreased risk of CAD.
Comparisons with other studies and what the current work adds to the existing knowledge.
The results of this study have some differences from many previous studies. Many previous studies indicated that compared to isoform ε3 (ε3/ε3), isoform ε4 (ε4/ε4, ε3/ε4 and ε2/ε4) has increased risk of cardiovascular disease, while isoform ε2 (ε2/ε4, ε2/ε3 and ε2/ε2) has decreased risk of cardiovascular disease. However,in this study, patients with ε4/ε4, ε3/ε4, ε3/ε3 had no obvious differences in the severity and occurrence of CAD, while patients with ε2/ε4 had lower severity and occurrence of CAD than patients with ε3/ε3. Therefore, compared to the isoform ε3, the isoform ε4 (ε4/ε4, ε3/ε4 and ε2/ε4) did not increased the severity and occurrence of CAD. Patients with ε2/ε2 and ε3/ε3 had no obvious differences in the severity and occurrence of CAD,while patients with ε2/ε4 and ε2/ε3 had lower severity and occurrence of CAD than patients with ε3/ε3. Therefore, compared to the isoform ε3, the isoform ε2 has decreased risk of the severity and occurrence of CAD.
For future clinical application, this study provided evidences that patients with ε4/ε4 and ε3/ε4 had higher occurrence of high LDL-C than patients with ε2/ε4 and ε2/ε3, and thus patients with ε4/ε4 and ε3/ε4 had higher severity and occurrence of CAD than patients with ε2/ε3 and ε2/ε4. In order to reduce risk of CAD, patients with ε4/ε4 and ε3/ε4 should pay more attention to their serum lipid than patients with ε2/ε4 and ε2/ε3.
4.1. Study strengths and limitations
This study assess the influence of different ApoE genotypes on coronary artery disease in patients undergoing coronary angiography. Firstly, the sample size of many previous studies is small, their statistical results may be influenced by the sample size. In order to reduce the impact of sample size, this study included 7634 patients who were hospitalized due to coronary angiography. Secondly, many previous studies undetected the influence of different ApoE genotypes on CAD. This study assess the influence of different ApoE genotypes on the severity and occurrence of CAD, the occurrence of PCAD, and traditional cardiovascular risk factors.
This study has some limitations. Firstly, this was a retrospective study, It's hard to rule out the factors of activities and diet, which may cause certain bias. Secondly, this study is a single-center study, different ethnic population may have different results. Thirdly, this study did not include the prognosis of CAD after treatment in patients with different ApoE genotypes, and the effect of statin treatment on different ApoE genotypes.
5. Conclusions
Patients with ε3/ε4, ε4/ε4,ε3/ε3 and ε2/ε2 had no significant differences in the severity and occurrence of CAD. Compared to the isoform ε3 (ε3/ε3), isoform ε4 did not increased the severity and occurrence of CAD. Compared with ApoE other genotypes, ε2/ε3 and ε2/ε4 reduced the risk of high LDL-C and the severity and occurrence of CAD.
Availability of data and material
The datasets used during the current study are available from the corresponding author on reasonable request.
Funding
This study was supported by the National Natural Science Foundation of China, fund No. 81930008.
Ethics approval
This study was conducted in accordance with the Declaration of Helsinki, approved by the Ethical Committee of Daping Hospital. The requirement for informed consent was waived because it is a retrospective observational study and patient records and information were anonymized prior to analysis, and the Ethical Committee of Daping Hospital also provided the informed consent waive.
Consent for publication
Not applicable.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
CRediT authorship contribution statement
Azhi ShaMa: Writing – original draft, Supervision, Investigation, Data curation, Conceptualization. Yingying Huang: Supervision, Investigation, Data curation. Chunlan Ma: Supervision, Investigation, Data curation. Chunmei Xu: Supervision, Investigation, Data curation. Jingyue Hu: Writing – original draft, Supervision, Resources, Investigation, Data curation. Zhuxin Li: Supervision, Investigation, Data curation. Chunyu Zeng: Writing – review & editing, Supervision, Methodology, Investigation, Conceptualization.
Declaration of competing interest
There are no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
None.
Abbreviations
- PCAD
Premature coronary artery disease
- AMI
Acute myocardial infarction
- ApoE
Apolipoprotein E
- CAD
Coronary artery disease
- LDL-C
Low density lipoprotein cholesterol
- HDL-C
High density lipoprotein cholesterol
- PCI
Percutaneous coronary intervention
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used during the current study are available from the corresponding author on reasonable request.