Combined effects of apoE-CI-CII cluster and LDL-R gene polymorphisms on chromosome 19 and coronary artery disease risk

Department of Hygiene, School of Medicine, Wuhan University, DongHu Road 115, Wuhan 430071, PR China.
International Journal of Hygiene and Environmental Health (Impact Factor: 3.83). 05/2006; 209(3):265-73. DOI: 10.1016/j.ijheh.2005.12.005
Source: PubMed


To investigate associations of gene polymorphisms of the apoE-CI-CII gene cluster and the LDL-R gene on coronary artery disease (CAD) and their interactions with alcohol drinking and smoking in the Chinese Han population.
A questionnaire survey of the behaviors of smoking and drinking, dietary patterns and anamnesis was conducted among 203 patients of CAD, aged 65.0 +/- 11.1 years, and 365 controls, aged 63.6 +/- 12.0 years. Peripheral blood samples were colleted and the total DNA was extracted. The apoE genotypes were identified by multiplex amplification refractory mutation system (multi-AMRS), the apoCI promoter polymorphisms and AvaII polymorphisms of the apoCII and LDL-R gene were detected by using PCR-RFLP. Pairwise linkage disequilibrium coefficients (D, D') were estimated by the LINKAGE program. The interactions between genes with alcohol drinking and smoking were analyzed by using multivariate logistic regression models.
The differences of systolic/diastolic blood pressure, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations, smoking and drinking were significant between subjects with CAD and controls. The frequencies of apoE gene epsilon 3/4 genotype (25.9%) and epsilon 4 (13.9%) in CAD were significantly higher than those in controls (12.5% and 6.9%, respectively, p < 0.05). A significant difference was also found for the apoCI locus, the frequencies of H2 allele were 20.5% in the CAD and 11.3% in the control. Linkage disequilibrium coefficient D' was 0.672 (p < 0.01) between apoE and apoCI genes. Significant differences for a deficit of epsilon 3-H1-T1 and excess of epsilon 4-H2-T1 was found in CAD by estimation of the haplotype frequencies. After control for possible confounding factors, the multivariate logistic analysis showed that epsilon 4, H2 allele, smoking and drinking were risk factors of CAD. A significant interaction among epsilon 4, H2 and smoking was observed (OR 18.3, 95% CI: 2.35-150.81, p < 0.05), it was a multiplicative model. An additive model was shown among epsilon 4, H2 and drinking (OR12.7, 95% CI: 2.8-58.6, p < 0.05).
The results suggested that both apoE and apoCI on chromosome 19 were the susceptibility locus for CAD, their linkage disequilibrium should be responsible for the development of CAD. Drinking and smoking enhance the genetic predisposition to CAD.

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    • "These eligible studies were from 17 provinces of China including Anhui, Beijing, Fujian, Gansu, Guangdong, Heilongjiang, Hubei, Hunan, Jiangsu, Jilin, Shandong, Shanghai, Sichuan, Tianjin, Xinjiang, Yunnan and Zhejiang. Controls were population-based in 34 studies [14]–[30], [32]–[39], [42]–[46], [48]–[50], [52], hospital-based in six studies [31], [40], [41], [47], [51], [53]. There were 10 studies did not follow the HWE [17], [26], [29], [31], [37], [39], [46], [47], [49], [51]. "
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    ABSTRACT: Epidemiological studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphism and coronary artery disease (CAD) risk which developed inconsistent conclusions. To derive a more precise estimation of the relationship in Chinese population, we performed this meta-analysis. Databases, including PubMed, EMbase, Web of Science, CBMdisc and CNKI, were searched to get the genetic association studies. Additionally, hand searching of the references of identified articles were performed. All the statistical tests were performed using Review Manager 5.1.2 and Stata 11.0. We identified a total of 40 studies, including 4,564 CAD cases and 3,985 controls. The results showed evidence for significant association between ApoE ε4 allele and CAD risk (for ε2/ε4 vs. ε3/ε3: OR = 1.86, 95% CI = 1.42-2.43, p<0.00001; for ε3/ε4 vs. ε3/ε3: OR = 2.34, 95% CI = 2.07-2.65, p<0.00001; for ε4/ε4 vs. ε3/ε3: OR = 2.89, 95% CI = 1.87-4.47, p<0.00001; for ε4 allele vs. ε3 allele: OR = 2.11, 95% CI = 1.91-2.35, p<0.00001). The present meta-analysis suggests an association between ApoE ε4 allele and increased risk of CAD in Chinese population. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.
    Preview · Article · Jun 2013 · PLoS ONE
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    • "The restriction site of APO CI has been associated with a significant increase of APO CI gene transcription [14]. Since these three genes are located in the same chromosome, the effect of the APO E, CI and CII gene cluster on serum lipid levels has been studied, particularly in Chinese Han samples of CAD patients [15,16]. The results suggest that the linkage disequilibrium between APO E and APO CI should be, in part, responsible for the development of CAD. "
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    ABSTRACT: To analyze apolipoprotein gene polymorphisms in the Tunisian population and to check the relation of these polymorphisms and homocysteine, lipid and apolipoprotein levels to the coronary artery disease (CAD). In healthy blood donors and in patients with CAD complicated by myocardial infarction (MI) four apolipoprotein gene polymorphisms [APO (a) PNR, APO E, APO CI and APO CII] were determined and plasma levels of total homocysteine, total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HLD-C) and apolipoproteins (apo A-I, Apo B, Apo E) were measured. Analysis of the four apolipoprotein gene polymorphisms shows a relative genetic homogeneity between Tunisian population and those on the other side of Mediterranean basin. Compared to controls, CAD patients have significantly higher main concentrations of TC, TG, LDL-C, apo B and homocysteine, and significantly lower ones of HDL-C, apo A-I and apo E. The four apolipoprotein gene polymorphisms have not showed any significant differences between patients and controls. However, the APO E4 allele appears to be associated to the severity of CAD and to high levels of atherogenic parameters and low level of apo E, which has very likely an anti-atherogenic role. Although APO (a) PNR, APO CI and APO CII genes are analyzed in only few populations, they show a frequency distribution, which is not at variance with that of APO E gene and other widely studied genetic markers. In the Tunisian population the APO E 4 appears to be only indirectly involved in the severity of CAD. In the routine practice, in addition of classic parameters, it will be useful to measure the concentration of apo E and that of Homocysteine and if possible to determine the APO E gene polymorphism.
    Full-text · Article · Dec 2008 · Lipids in Health and Disease
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    ABSTRACT: Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases. To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk. We conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies. Eighty-two studies of lipid levels (86,067 healthy participants) and 121 studies of coronary outcomes (37,850 cases and 82,727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes. Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators. In the most extreme comparison, people with the epsilon2/epsilon2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean low-density lipoprotein cholesterol (LDL-C) values than those with the epsilon4/epsilon4 genotype. There were approximately linear relationships of apoE genotypes (when ordered epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon3, epsilon3/epsilon4, epsilon4/epsilon4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the epsilon2/epsilon2 genotype. Compared with epsilon3/epsilon3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in epsilon2 carriers and was 1.06 (95% CI, 0.99-1.13) in epsilon4 carriers. There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the epsilon3/epsilon3 genotype, epsilon2 carriers have a 20% lower risk of coronary heart disease and epsilon4 carriers have a slightly higher risk.
    Full-text · Article · Oct 2007 · JAMA The Journal of the American Medical Association
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