Skip to main content

Apolipoprotein E E3/E4 genotype is associated with an increased risk of premature coronary artery disease

Abstract

Objective

Dyslipidemia is one of the causes of coronary heart disease (CAD), and apolipoprotein E (APOE) gene polymorphism affects lipid levels. However, the relationship between APOE gene polymorphisms and premature CAD (PCAD, male CAD patients with ≤ 55 years old and female with ≤ 65 years old) risk had different results in different studies. The aim of this study was to assess this relationship and to further evaluate the relationship between APOE gene polymorphisms and PCAD risk in the Hakka population.

Methods

This study retrospectively analyzed 301 PCAD patients and 402 age matched controls without CAD. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) -chip technique. The distribution of APOE genotypes and alleles between the case group and the control group was compared. The relationship between APOE genotypes and PCAD risk was obtained by logistic regression analysis.

Results

The frequency of the APOE ɛ3/ɛ4 genotype (18.9% vs. 10.2%, p = 0.001) and ε4 allele (11.1% vs. 7.0%, p = 0.007) was higher in the PCAD patients than that in controls, respectively. PCAD patients with ɛ2 allele had higher TG level than those with ɛ3 allele, and controls carried ɛ2 allele had higher HDL-C level and lower LDL-C level than those carried ɛ3 allele. Regression logistic analysis showed that BMI ≥ 24.0 kg/m2 (BMI ≥ 24.0 kg/m2 vs. BMI 18.5–23.9 kg/m2, OR: 1.763, 95% CI: 1.235–2.516, p = 0.002), history of smoking (Yes vs. No, OR: 5.098, 95% CI: 2.910–8.930, p < 0.001), ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 2.203, 95% CI: 1.363–3.559, p = 0.001), ε4 allele (ε4 vs. ε3, OR: 2.125, 95% CI: 1.333–3.389, p = 0.002), and TC level (OR: 1.397, 95% CI: 1.023–1.910, p = 0.036) were associated with PCAD.

Conclusions

In summary, BMI ≥ 24.0 kg/m2, history of smoking, APOE ɛ3/ɛ4 genotype, and TC level were independent risk factors for PCAD. It means that young individuals who are overweight, have a history of smoking, and carried APOE ɛ3/ɛ4 genotype had increased risk of PCAD.

Peer Review reports

Introduction

Cardiovascular disease (CVD) is one of the major disease burdens, and cardiovascular disease has become the leading cause of death in China [1, 2]. Coronary artery disease (CAD) is a heart disease caused by the stenosis, spasm and obstruction of the artery lumen caused by atherosclerosis, which leads to myocardial ischemia, hypoxia or necrosis [3, 4]. CAD is a serious cardiovascular disease with high morbidity and mortality, and is one of the serious disease burdens [5, 6]. Although CAD is mainly in the elderly, the trend of CAD is younger at present [7, 8]. According to Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), premature coronary artery disease (PCAD) refers to the occurrence of CAD when men ≤ 55 years old and women ≤ 65 years old [9]. Compared with non-PCAD patients, PCAD patients often have no precursor symptoms, the course of the disease is rapid, and acute coronary syndrome is often the clinical manifestation [10]. Therefore, it is particularly important to understand the risk factors of PCAD and avoid the risk factors.

Lipid metabolism disorders are closely related to CAD, and apolipoprotein plays an important role in lipid metabolism. Apolipoprotein E (ApoE) is one of the important apolipoproteins involved in lipid metabolism and cholesterol metabolism, cholesterol transport and redistribution, immune regulation, cell proliferation and differentiation [11,12,13,14]. ApoE is an important component of very low density lipoprotein cholesterol (VLDL-C) and high density lipoprotein cholesterol (HDL-C), and is a ligand protein of chylomicron and VLDL receptor in hepatocytes, which can bind to chylomicron and VLDL receptor with high affinity. ApoE is also a cofactor of lipoprotein metabolic enzymes, which can mediate the intracellular phagocytosis and degradation of lipoproteins [15, 16]. The ApoE encoding gene APOE is located on chromosome 19q13.2 and contains four exons and three introns [16]. There are several single-nucleotide polymorphisms (SNPs) in APOE gene, the most important of which are rs429358 and rs7412, which form three allelic subtypes of APOE, namely ε2, ε3 and ε4 [17, 18], and six common APOE genotypes: ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4 [19, 20]. The mechanism of lipid difference caused by different APOE genotypes may be related to the differences in the ability of ApoE to bind to receptors and the rate of lipoprotein metabolism [21].

Studies have showed that APOE gene polymorphism was established to be related to PCAD. The APOE ɛ4 allele may be associated with an increased risk of PCAD due to elevated levels of total cholesterol (TC) and low density lipoprotein (LDL-C) [22]. The results of a meta-analysis suggested that the APOE ɛ2 allele may be a risk factor for PCAD in Asians and a protective factor in Caucasians [23]. The study by Petrovic D et al. found that APOE gene polymorphism was not an independent risk factor for PCAD in the Slovenian population [24]. It can be seen that the results on the relationship between APOE gene polymorphism and PCAD are inconsistent, which may be caused by the differences between the different regions, populations, lifestyles and the interaction between some environmental factors and genetic polymorphisms, and sample size of the subjects included in different studies. The Hakka is a Han ethnic group with a unique genetic background formed by the Hakka ancestors from the Han nationality in central China, who migrated southward for many times and fused with the ancient Yue residents in Guangdong, Fujian, and Jiangxi provinces [25]. To date, there have been no reports on the relationship between APOE polymorphisms and the risk of PCAD patients in this population. The purpose of this study was to investigate the relationship between APOE rs429358 and rs7412 polymorphisms and PCAD risk.

Materials and methods

Study participants and data collection

This study retrospectively analyzed 301 PCAD patients admitted to Meizhou People’s Hospital from November 2019 to August 2023, and 402 individuals without CAD as controls. The diagnostic criteria for CAD: Coronary angiography (CAG) showed that at least one of the main epicardial vessels (including left main branch, anterior descending branch, circumflex branch, and right coronary artery) had a diameter stenosis > 50%, and clinically diagnosed myocardial infarction [26, 27]. Basic information was collected from our hospital’s medical record system, including age, gender, body mass index (BMI), history of smoking, and history of drinking. BMI was divided into three subgroups based on the Chinese criteria [28, 29]: <18.5 kg/m2, 18.5–23.9 kg/m2, and ≥ 24.0 kg/m2. This study was approved by the Human Ethics Committees of Meizhou People’s Hospital, and performed in accordance with the Declaration of Helsinki.

Determination of serum lipids and APOE genotyping

Fasting blood was collected and serum was isolated. 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) levels in serum samples were assessed using automatic biochemical analysis system (Olympus AU5400 system, Tokyo, Japan) and corresponding kits.

Genomic DNA was extracted from venous blood collected from EDTA anticoagulant collection vessels using a blood DNA isolation kit (Qiagen GmbH, Germany). The quality and concentration of the DNA were assessed using a Nano-Drop 2000™ spectrophotometer (ThermoFisher Scientific, USA). APOE genotype was amplified by PCR - microarray method (Sinochips Bioscience Co., Ltd., China).

Statistical analysis

All statistical analysis were performed using SPSS statistical software version 26.0 (IBM Inc., USA). Continuous variables were expressed as means ± standard deviations and were compared using either Student’s t-test or the Mann-Whitney U test. Genotype composition ratios and allele frequencies between groups were analyzed with the χ2 test. Hardy-Weinberg equilibrium in the patients and controls was evaluated by χ2 test.

Individuals with the ɛ2/ɛ4 genotype (n = 9; 4 PCAD patients and 5 controls) were excluded from the analysis of the relationship between APOE alleles and clinical characteristics of patients because of the opposite effects of the ε2 and ε4 alleles in lipid metabolism [30, 31]. Univariate analysis and multivariate regression logistic analysis were applied to examine the relationship between APOE gene polymorphisms and PCAD. p < 0.05 was considered to represent statistical significance.

Results

Characteristics of subjects

In this study, there were 355(50.5%) males and 348(49.5%) females, and the difference in sex distribution between PCAD patients and controls was not statistically significant (p = 0.819). There were 62 (15.4%) cases with BMI < 18.5 kg/m2 and 117 (29.1%) cases with BMI ≥ 24.0 kg/m2 in controls, while 14 (4.7%) cases BMI < 18.5 kg/m2 and 155 (51.5%) cases with BMI ≥ 24.0 kg/m2 in PCAD patients. The difference in BMI distribution among the two groups was statistically significant (p < 0.001). The differences of TC (5.07 ± 1.23 vs. 4.46 ± 1.13 mmol/L, p < 0.001), TG (2.19 ± 1.88 mmol/L vs. 1.52 ± 1.40 mmol/L, p < 0.001), LDL-C (2.72 ± 0.82 mmol/L vs. 2.41 ± 0.75 mmol/L, p = 0.023), Apo-A1 (1.15 ± 0.26 g/L vs. 1.09 ± 0.33 g/L, p = 0.009) and Apo-B (0.88 ± 0.25 g/L vs. 0.76 ± 0.22 g/L, p < 0.001) levels among patients and controls were statistically significant. The proportions of PCAD patients with history of smoking (26.9% vs. 7.2%, p < 0.001), and history of alcoholism (8.6% vs. 2.2%, p < 0.001) were significantly higher than those of controls (Table 1).

Table 1 Clinical characteristics of the subjects of this study

Distribution of the APOE genotypes and alleles between the patients and controls

The results of Hardy-Weinberg equilibrium test showed that the APOE genotypes in the PCAD patients (χ2 = 0.801, p = 0.938), and controls (χ2 = 6.333, p = 0.176) confirmed to the Hardy-Weinberg equilibrium, respectively. The frequency of the APOE ɛ3/ɛ3 genotype was lower (68.1% vs. 75.4%, p = 0.034), while the frequency of the APOE ɛ3/ɛ4 genotype was higher in the PCAD patients (18.9% vs. 10.2%, p = 0.001) than that in controls. The frequency of the ε4 allele was higher (11.1% vs. 7.0%, p = 0.007) in the PCAD patients than that in controls (Table 2).

Table 2 Distribution frequencies of APOE genotypes and alleles in patients and controls

Comparison of clinical features and lipid levels among PCAD patients and controls with different APOE ε2, ε3, ε4 alleles

Clinical characteristics and serum lipid-lipoprotein levels were compared among PCAD patients and controls carried different APOE alleles, respectively. The PCAD patients with ɛ4 allele had higher level in ApoB (0.90 ± 0.20 g/L vs. 0.77 ± 0.31 g/L) than those with ɛ2 allele; PCAD patients with ɛ2 allele had higher TG level (2.94 ± 3.14 mmol/L vs. 2.04 ± 1.69 mmol/L), while had lower LDL-C level (2.46 ± 0.90 mmol/L vs. 2.77 ± 0.83 mmol/L) and Apo-B level (0.77 ± 0.31 g/L vs. 0.90 ± 0.24 g/L) than those with ɛ3 allele (all p < 0.05). There were no statistically significant differences in the distributions of gender, BMI, history of alcoholism, and the level of TC and LDL-C among PCAD patients carried APOE ɛ2, ɛ3 and ɛ4 alleles, respectively. The controls carried ɛ4 allele had higher LDL-C (2.57 ± 0.77 mmol/L vs. 2.03 ± 0.58 mmol/L) and Apo-B (0.82 ± 0.22 g/L vs. 0.63 ± 0.17 g/L) level than those with ɛ2 allele; controls carried ɛ2 allele had higher HDL-C level (1.42 ± 0.46 mmol/L vs. 1.22 ± 0.44 mmol/L) and lower LDL-C level (2.03 ± 0.58 mmol/L vs. 2.46 ± 0.75 mmol/L) than those carried ɛ3 allele (all p < 0.05) (Table 3).

Table 3 Clinical characteristics and serum lipid levels of PCAD patients and controls, stratified by APOE ɛ2, ɛ3, ɛ4 alleles

Association of APOE gene polymorphisms with PCAD patients

The results of univariate analysis showed that BMI ≥ 24.0 kg/m2 (BMI ≥ 24.0 kg/m2 vs. BMI 18.5–23.9 kg/m2, odds ratio (OR): 2.238, 95% confidence interval (CI): 1.621–3.090, p < 0.001), history of smoking (Yes vs. No, OR: 4.736, 95% CI: 3.002–7.469, p < 0.001), history of alcoholism (Yes vs. No, OR: 4.128, 95% CI: 1.905–8.948, p < 0.001), ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 2.055, 95% CI: 1.325–3.187, p = 0.001), ε4 allele (ε4 vs. ε3, OR: 1.928, 95% CI: 1.263–2.943, p = 0.002), TC level (OR: 1.562, 95% CI: 1.362–1.791, p < 0.001), TG level (OR: 1.418, 95% CI: 1.236–1.628, p < 0.001), and LDL-C level (OR: 1.648, 95% CI: 1.352–2.008, p < 0.001) were significantly associated with PCAD. Multivariate regression logistic analysis showed that BMI ≥ 24.0 kg/m2 (BMI ≥ 24.0 kg/m2 vs. BMI 18.5–23.9 kg/m2, OR: 1.763, 95% CI: 1.235–2.516, p = 0.002), history of smoking (Yes vs. No, OR: 5.098, 95% CI: 2.910–8.930, p < 0.001), ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 2.203, 95% CI: 1.363–3.559, p = 0.001), ε4 allele (ε4 vs. ε3, OR: 2.125, 95% CI: 1.333–3.389, p = 0.002), and TC level (OR: 1.397, 95% CI: 1.023–1.910, p = 0.036) were independent risk factors for PCAD (Table 4).

Table 4 Logistic regression analysis of risk factors for PCAD

Discussion

The population covered by the onset age of PCAD is the main group of society, which not only has a huge impact on the physical and mental health of patients, but also has a significant impact on the family and social economy of patients. Therefore, we should not only pay attention to the high burden of CVDs to our country, but also pay attention to the loss of production and life ability of young and middle-aged people after CAD, early screening, early identification, early intervention has important significance. In this study, BMI ≥ 24.0 kg/m2, history of smoking, APOE ɛ3/ɛ4 genotype, and TC level were independent risk factors for PCAD.

ApoE is a major lipid-binding protein that serves as a carrier for chylomicron, HDL-C, LDL-C, and VLDL-C [32]. However, the results on the relationship between APOE gene polymorphisms and serum lipid level are not consistent. Rajesh Chaudhary et al. evaluated the effect of ApoE on lipids has shown that carriers of the ε2 allele have lower TC level and higher TG level, while carriers of the ε4 allele have higher TC and LDL levels [33]. Wang et al. reported that ε4 carriers had significantly lower ApoE levels and higher LDL-C, and ApoB levels [34]. APOE ε3/ε4 genotype carriers had a significantly higher rate of TC in a Senegalese population [35]. Another study showed that the APOE ε4 allele is associated with higher serum lipid levels, whereas the ε2 allele is associated with the lower levels [36]. A Pablos-Méndez et al. reported that the presence of ε2 has been associated with lower LDL-C level but with no influence on the HDL-C level [37]. In this study, the PCAD patients with ɛ4 allele had higher level in ApoB than those with ɛ2 allele; PCAD patients with ɛ2 allele had higher TG level, and lower LDL-C level and Apo-B level than those with ɛ3 allele. In recent years, scholars at home and abroad have realized the importance of PCAD and analyzed the pathogenic factors of PCAD successively, such as APOE polymorphisms. Abd El-Aziz TA et al. found that APOE ε4 allele may be associated with an increased risk of PCAD [22]. Balcerzyk et al. found that the synergistic effect of the ɛ4 allele with some traditional risk factors (such as smoking, high cholesterol levels) is associated with an increased risk of PCAD [38]. However, in a Slovenian population, APOE polymorphisms has not been shown to be an independent risk factor for PCAD [24]. These inconsistent results may be due to differences in the study population and sample size included in different studies. In addition, APOE ɛ4/ɛ4 genotype was not associated with the risk of PCAD in this study. It may be related to the low number of individuals carried APOE ε4/ε4 genotype.

Moreover, traditional cardiovascular risk factors like smoking, diabetes mellitus, and hypertension are associated with premature atherosclerotic artery disease [39, 40]. Fallahzadeh A et al. considered that smoking is more prevalent in PCAD patients [41]. Wei et al. investigated that smoking showed a positive association with multivessel disease PCAD [42]. Smoking was an independent risk factor for early onset of multiple coronary heart disease in a Chinese population [43]. Smoking was significantly positively correlated with PCAD in an Iran population [44]. Indian researchers have found that smoking, low HDL-C level, and obesity are major risk factors for CAD in young rural Indians [45]. The risk of cardiovascular disease from smoking is largely undisputed.

In addition, Wei et al. investigated that hypertension, diabetes mellitus, and obesity showed a positive association with multivessel disease PCAD [42]. Type 2 diabetes mellitus was an independent risk factor for early onset of multiple CAD in a Chinese population [43]. Through systematic review and meta-analysis, Iranian scholars found that diabetes mellitus, family history of CAD, dyslipidemia, smoking, and hypertension were significantly positively correlated with PCAD in Iranian youth [44]. TIAN R et al. showed that the level of oxidative stress in PCAD patients was significantly higher than that of healthy adults, and their BMI, serum TC, TG, and hypersensitive C-reactive protein (CRP) also showed high levels [46]. Compared with MCAD patients, cardiovascular related risk factors (smoking, type 2 furfururia, abnormal lipid metabolism, hypertension, family history of CAD) were more common in PCAD patients, whereas cardiovascular protective factors (HDL-C levels) were significantly lower [46]. Reynolds HR et al. found complex sex differences between angina pectoris, atherosclerosis, and ischemia [47]. Sex differences in PCAD risk may be related to sex differences in coagulation function, inflammation, and the renin-angiotensin system [48]. In addition, PACD is heterogeneous among different populations, which may be related to their different traditional lifestyles [49]. It can be seen that CAD is influenced by both environmental and genetic factors.

Several studies have also been reported on the relationship between lipid levels and PCAD risk. Sanjeev K Sharma et al. found that high cholesterol was associated with premature CAD [50]. Adeel Khoja et al. suggested that dyslipidaemia was a risk factor for PCAD [51]. Familial hypercholesterolaemia was an independent predictor of PCAD [52,53,54]. T A Abdel-Aziz et al. found that TC, TG, LDL-C, and HDL-C were independent risk factors for the development of PCAD [55]. And elevated plasma oxidized-low-density lipoprotein (ox-LDL) level was independently associated with the very-early CAD (VECAD) [56]. In this study, TC level was an independent risk factor for PCAD.

The risk factors for PCAD are complex and intertwined with each other. At present, traditional risk factors are mainly intervened in clinical practice, and some emerging risk factors are not included in early prevention. It is believed that with further research on the risk factors of PCAD, early warning of risk factors and early intervention can be carried out to reduce the occurrence of adverse cardiovascular events and reduce the burden on families and society. In this study, BMI ≥ 24.0 kg/m2, history of smoking, and APOE ɛ3/ɛ4 genotype, and TC level were independent risk factors for PCAD. It suggests that overweight and smoking individuals with APOE ɛ3/ɛ4 genotype need to be monitored for PCAD risk. There are some shortcomings in this study. First, this study is a retrospective study, with the possibility of information bias and selection bias, and limited sample size and types of collection indicators, which may reduce the reproducibility of results. Second, this study is a single-center study, and although the data analysis shows that the model has good robustness, it still needs to be verified with external data. Third, this study did not analyze the relationship between APOE gene polymorphism and clinical treatment effect of PCAD.

Conclusion

In summary, APOE rs429358 and rs7412 polymorphisms were associated with PCAD susceptibility. Genetic factors and traditional risk factors play a role in the development of PCAD. Generally, BMI ≥ 24.0 kg/m2, history of smoking, APOE ɛ3/ɛ4 genotype, and TC level were independent risk factors for PCAD. It means that young individuals who are overweight, have a history of smoking, and carried APOE ɛ3/ɛ4 genotype need to be aware of the risk of developing PCAD.

Data availability

The datasets used and analyzed during the current study available from the corresponding author on request.

References

  1. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, et al. Global Burden of Cardiovascular diseases and Risk factors, 1990–2019: Update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982–3021.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Report on Cardiovascular Health and Diseases in China 2021. An updated Summary. Biomed Environ Sci. 2022;35(7):573–603.

    Google Scholar 

  3. Shaya GE, Leucker TM, Jones SR, Martin SS, Toth PP. Coronary heart disease risk: low-density lipoprotein and beyond. Trends Cardiovasc Med. 2022;32(4):181–94.

    Article  CAS  PubMed  Google Scholar 

  4. Stone PH, Libby P, Boden WE. Fundamental pathobiology of coronary atherosclerosis and clinical implications for chronic ischemic heart Disease Management-the Plaque hypothesis: a narrative review. JAMA Cardiol. 2023;8(2):192–201.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bauersachs R, Zeymer U, Brière JB, Marre C, Bowrin K, Huelsebeck M. Burden of Coronary Artery Disease and Peripheral Artery Disease: A Literature Review. Cardiovasc Ther. 2019:8295054.

  6. Duggan JP, Peters AS, Trachiotis GD, Antevil JL. Epidemiology of coronary artery disease. Surg Clin North Am. 2022;102(3):499–516.

    Article  PubMed  Google Scholar 

  7. Wang X, Gao M, Zhou S, Wang J, Liu F, Tian F, Jin J, Ma Q, Xue X, Liu J, et al. Trend in young coronary artery disease in China from 2010 to 2014: a retrospective study of young patients ≤ 45. BMC Cardiovasc Disord. 2017;17(1):18.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Salomaa V. Worrisome trends in the incidence of coronary artery disease events among young individuals. Eur J Prev Cardiol. 2020;27(11):1175–7.

    Article  PubMed  Google Scholar 

  9. National Cholesterol Education Program (NCEP). Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143–421.

    Article  Google Scholar 

  10. Zeitouni M, Clare RM, Chiswell K, Abdulrahim J, Shah N, Pagidipati NP, Shah SH, Roe MT, Patel MR, Jones WS. Risk factor burden and long-term prognosis of patients with premature coronary artery disease. J Am Heart Assoc. 2020;9(24):e017712.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Singh PP, Singh M, Mastana SS. APOE distribution in world populations with new data from India and the UK. Ann Hum Biol. 2006;33(3):279–308.

    Article  CAS  PubMed  Google Scholar 

  12. Tersigni C, Furqan Bari M, Cai S, Zhang W, Kandzija N, Buchan A, Miranda F, Di Simone N, Redman CW, Bastie C, et al. Syncytiotrophoblast-derived extracellular vesicles carry apolipoprotein-E and affect lipid synthesis of liver cells in vitro. J Cell Mol Med. 2022;26(1):123–32.

    Article  CAS  PubMed  Google Scholar 

  13. Hong S, Washington PM, Kim A, Yang CP, Yu TS, Kernie SG. Apolipoprotein E regulates Injury-Induced activation of hippocampal neural stem and progenitor cells. J Neurotrauma. 2016;33(4):362–74.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhu K, Zhang H. KDM4C promotes mouse hippocampal neural stem cell proliferation through modulating ApoE expression. FASEB J. 2024;38(5):e23511.

    Article  CAS  PubMed  Google Scholar 

  15. Rahmany S, Jialal I. Biochemistry, Chylomicron. StatPearls. Edn. Treasure Island (FL) ineligible companies. Disclosure: Ishwarlal Jialal declares no relevant financial relationships with ineligible companies.: StatPearls Publishing Copyright © 2024. StatPearls Publishing LLC.; 2024.

  16. Marais AD. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology. 2019;51(2):165–76.

    Article  CAS  PubMed  Google Scholar 

  17. Khalil YA, Rabès JP, Boileau C, Varret M. APOE gene variants in primary dyslipidemia. Atherosclerosis. 2021;328:11–22.

    Article  CAS  PubMed  Google Scholar 

  18. Lan X, Wang Z, Zeng Z, Yao H, Xu W, Zhang Y. Association of different combinations of ALDH2 rs671, APOE rs429358, rs7412 polymorphisms with hypertension in Middle-aged and Elderly people: a case-control study. Int J Gen Med. 2023;16:915–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Seripa D, D’Onofrio G, Panza F, Cascavilla L, Masullo C, Pilotto A. The genetics of the human APOE polymorphism. Rejuvenation Res. 2011;14(5):491–500.

    Article  CAS  PubMed  Google Scholar 

  20. Chen W, Li B, Wang H, Wei G, Chen K, Wang W, Wang S, Liu Y. Apolipoprotein E E3/E4 genotype is associated with an increased risk of type 2 diabetes mellitus complicated with coronary artery disease. BMC Cardiovasc Disord. 2024;24(1):160.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life. 2014;66(9):616–23.

    Article  CAS  PubMed  Google Scholar 

  22. Abd El-Aziz TA, Mohamed RH. LDLR, ApoB and ApoE genes polymorphisms and classical risk factors in premature coronary artery disease. Gene. 2016;590(2):263–9.

    Article  CAS  PubMed  Google Scholar 

  23. Zhao QR, Lei YY, Li J, Jiang N, Shi JP. Association between apolipoprotein E polymorphisms and premature coronary artery disease: a meta-analysis. Clin Chem Lab Med. 2017;55(2):284–98.

    Article  CAS  PubMed  Google Scholar 

  24. Petrovic D, Zorc M, Peterlin B. Effect of apolipoprotein E polymorphism and apolipoprotein A-1 gene promoter polymorphism on lipid parameters and premature coronary artery disease. Folia Biol (Praha). 2000;46(5):181–5.

    CAS  PubMed  Google Scholar 

  25. Wang WZ, Wang CY, Cheng YT, Xu AL, Zhu CL, Wu SF, Kong QP, Zhang YP. Tracing the origins of Hakka and Chaoshanese by mitochondrial DNA analysis. Am J Phys Anthropol. 2010;141(1):124–30.

    Article  PubMed  Google Scholar 

  26. Lee SE, Sung JM, Rizvi A, Lin FY, Kumar A, Hadamitzky M, Kim YJ, Conte E, Andreini D, Pontone G, et al. Quantification of coronary atherosclerosis in the Assessment of Coronary Artery Disease. Circ Cardiovasc Imaging. 2018;11(7):e007562.

    Article  PubMed  Google Scholar 

  27. Liu J, Huang S, Wang X, Li B, Ma J, Sun H, Xi X, Sun Y, Zhang L, Liu J, et al. Effect of the coronary arterial diameter derived from coronary computed tomography angiography on fractional Flow Reserve. J Comput Assist Tomogr. 2022;46(3):397–405.

    Article  PubMed  Google Scholar 

  28. He W, Li Q, Yang M, Jiao J, Ma X, Zhou Y, Song A, Heymsfield SB, Zhang S, Zhu S. Lower BMI cutoffs to define overweight and obesity in China. Obes (Silver Spring). 2015;23(3):684–91.

    Article  Google Scholar 

  29. Tang J, Zhu X, Chen Y, Huang D, Tiemeier H, Chen R, Bao W, Zhao Q. Association of maternal pre-pregnancy low or increased body mass index with adverse pregnancy outcomes. Sci Rep. 2021;11(1):3831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu Q, Wu H. APOE gene ɛ4 allele (388 C-526 C) effects on serum lipids and risk of coronary artery disease in southern Chinese Hakka population. J Clin Lab Anal. 2021;35(9):e23925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rao H, Wu H. APOE Genetic Polymorphism rs7412 T/T Genotype May Be a Risk Factor for Essential Hypertension among Hakka People in Southern China. Int J Hypertens. 2022:8145896.

  32. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Volume 240. New York, NY: Science; 1988. pp. 622–30. 4852.

    Google Scholar 

  33. Chaudhary R, Likidlilid A, Peerapatdit T, Tresukosol D, Srisuma S, Ratanamaneechat S, Sriratanasathavorn C. Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease. Cardiovasc Diabetol. 2012;11:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang Y, Yang S, Zhang S, Lu X, Ma W. Apolipoprotein E Gene Polymorphism effects on lipid metabolism and risk of cerebral infarction in Northwest Han Chinese Population. Pharmgenomics Pers Med. 2023;16:303–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Touré M, Diouf NN, Thiam S, Diop JP, Coly MS, Mbengue A, Sar FB, Ba A, Diallo FA, Samb A. Frequencies and distribution of APOE Gene Polymorphisms and its Association with lipid parameters in the Senegalese Population. Cureus. 2022;14(4):e24063.

    PubMed  PubMed Central  Google Scholar 

  36. Mahley RW, Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507–37.

    Article  CAS  PubMed  Google Scholar 

  37. Pablos-Méndez A, Mayeux R, Ngai C, Shea S, Berglund L. Association of apo E polymorphism with plasma lipid levels in a multiethnic elderly population. Arterioscler Thromb Vasc Biol. 1997;17(12):3534–41.

    Article  PubMed  Google Scholar 

  38. Balcerzyk A, Zak I, Krauze J. Synergistic effects of apolipoprotein E gene epsilon polymorphism and some conventional risk factors on premature ischaemic heart disease development. Kardiol Pol. 2007;65(9):1058–65. discussion 1066 – 7.

    PubMed  Google Scholar 

  39. Mehta A, Dhindsa DS, Hooda A, Nayak A, Massad CS, Rao B, Makue LF, Rajani RR, Alabi O, Quyyumi AA, et al. Premature atherosclerotic peripheral artery disease: an underrecognized and undertreated disorder with a rising global prevalence. Trends Cardiovasc Med. 2021;31(6):351–8.

    Article  CAS  PubMed  Google Scholar 

  40. Jahangiry L, Abbasalizad Farhangi M, Najafi M, Sarbakhsh P. Clusters of the risk markers and the pattern of premature Coronary Heart Disease: an application of the latent class analysis. Front Cardiovasc Med. 2021;8:707070.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Fallahzadeh A, Mehraban S, Mahmoodi T. Risk factor profile and outcomes of premature acute coronary syndrome after percutaneous coronary intervention: a 1-year prospective design. Clin Cardiol. 2024;47(1):e24170.

    Article  PubMed  Google Scholar 

  42. Wei A, Liu J, Wang L, Zheng S. Correlation of triglyceride-glucose index and dyslipidaemia with premature coronary heart diseases and multivessel disease: a cross-sectional study in Tianjin, China. BMJ Open. 2022;12(9):e065780.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Du Y, Chen K, Liu E, Wang X, Li F, Liu T, Zheng X, Li G, Che J. Gender-specific associations of CD36 polymorphisms with the lipid profile and susceptibility to premature multi-vessel coronary artery heart disease in the Northern Han Chinese. Gene. 2020;753:144806.

    Article  CAS  PubMed  Google Scholar 

  44. Poorzand H, Tsarouhas K. Risk factors of premature coronary artery disease in Iran: a systematic review and meta-analysis. Eur J Clin Invest. 2019;49(7):e13124.

    Article  PubMed  Google Scholar 

  45. Patil RS, Shetty LH, Krishnan S, Trivedi AS, Raghu TR, Manjunath CN. Profile of coronary artery disease in Indian rural youth (< 35 yrs). Indian Heart J. 2020;72(5):394–7.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Tian R, Zhang LN, Zhang TT, Pang HY, Chen LF, Shen ZJ, Liu Z, Fang Q, Zhang SY. Association between Oxidative Stress and peripheral leukocyte telomere length in patients with premature coronary artery disease. Med Sci Monit. 2017;23:4382–90.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Reynolds HR, Shaw LJ, Min JK, Spertus JA, Chaitman BR, Berman DS, Picard MH, Kwong RY, Bairey-Merz CN, Cyr DD, et al. Association of Sex with Severity of Coronary Artery Disease, Ischemia, and Symptom Burden in patients with moderate or severe ischemia: secondary analysis of the ISCHEMIA Randomized Clinical Trial. JAMA Cardiol. 2020;5(7):773–86.

    Article  PubMed  Google Scholar 

  48. Kryczka KE, Kruk M, Demkow M, Lubiszewska B. Fibrinogen and a Triad of thrombosis, inflammation, and the renin-angiotensin system in premature coronary artery disease in women: a new insight into sex-related differences in the pathogenesis of the Disease. Biomolecules. 2021;11(7):1036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Babahajiani M, Zarepur E, Khosravi A, Mohammadifard N, Noohi F, Alikhasi H, Nasirian S, Moezi Bady SA, Janjani P, Solati K, et al. Ethnic differences in the lifestyle behaviors and premature coronary artery disease: a multi-center study. BMC Cardiovasc Disord. 2023;23(1):170.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Sharma SK, Makkar JS, Bana A, Sharma K, Kasliwal A, Sidana SK, Degawat PR, Bhagat KK, Chaurasia AK, Natani V, et al. Premature coronary artery disease, risk factors, clinical presentation, angiography and interventions: Hospital based registry. Indian Heart J. 2022;74(5):391–7.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Khoja A, Andraweera PH, Lassi ZS, Padhani ZA, Ali A, Zheng M, Pathirana MM, Aldridge E, Wittwer MR, Chaudhuri DD, et al. Modifiable and non-modifiable risk factors for premature Coronary Heart Disease (PCHD): systematic review and Meta-analysis. Heart Lung Circ. 2024;33(3):265–80.

    Article  PubMed  Google Scholar 

  52. Nazli SA, Chua YA. Familial hypercholesterolaemia and coronary risk factors among patients with angiogram-proven premature coronary artery disease in an Asian cohort. PLoS ONE. 2022;17(9):e0273896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Paquette M, Dufour R, Baass A. Scavenger receptor LOX1 genotype predicts coronary artery disease in patients with familial hypercholesterolemia. Can J Cardiol. 2017;33(10):1312–8.

    Article  PubMed  Google Scholar 

  54. Zhang Y, Dron JS, Bellows BK, Khera AV, Liu J, Balte PP, Oelsner EC, Amr SS, Lebo MS, Nagy A, et al. Familial hypercholesterolemia variant and Cardiovascular Risk in individuals with elevated cholesterol. JAMA Cardiol. 2024;9(3):263–71.

    Article  PubMed  Google Scholar 

  55. Abdel-Aziz TA, Mohamed RH. Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease. Mol Biol Rep. 2013;40(4):3065–71.

    Article  CAS  PubMed  Google Scholar 

  56. Zhao X, Zhang HW, Xu RX, Guo YL, Zhu CG, Wu NQ, Gao Y, Li JJ. Oxidized-LDL is a useful marker for predicting the very early coronary artery disease and cardiovascular outcomes. Per Med. 2018;15(6):521–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author would like to thank other colleagues whom were not listed in the authorship of Center for Cardiovascular Diseases, Meizhou People’s Hospital, for their helpful comments on the manuscript.

Funding

This study was supported by the Science and Technology Program of Meizhou (Grant No.: 2019B0202001).

Author information

Authors and Affiliations

Authors

Contributions

YL and WZ designed the study. YL, WZ, CH, JP and HL collected clinical data. YL and CH analyzed the data. YL prepared the manuscript. All authors were responsible for critical revisions, and all authors read and approved the final version of this work.

Corresponding author

Correspondence to Youqian Li.

Ethics declarations

Ethics approval and consent to participate

All participants were informed on the study procedures and goals and the study obtained written informed consent from all the participants. We confirm that all methods were performed in accordance with relevant guidelines and regulations. This study was approved by the Human Ethics Committees of Meizhou People’s Hospital.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Zhong, W., Huang, C. et al. Apolipoprotein E E3/E4 genotype is associated with an increased risk of premature coronary artery disease. BMC Cardiovasc Disord 24, 353 (2024). https://doi.org/10.1186/s12872-024-04021-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12872-024-04021-8

Keywords