Combined effects of apoE-CI-CII cluster and LDL-R gene polymorphisms on chromosome 19 and coronary artery disease risk.
ABSTRACT 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.
SourceAvailable from: Puneetpal Singh[Show abstract] [Hide abstract]
ABSTRACT: The article by Versmissen et al1 revealed the mutual influences of both low-density lipoprotein receptor mutation and apoE4 homozygosity in attenuating coronary heart disease (CHD) risk, but individually, both of these did not show any association with the CHD risk. Alterations of serum apoE levels significantly modify the relationship between APOE polymorphism and lipid levels.2 This study could not observe the higher CHD risk in the apoE4/E4 carriers having the low-density lipoprotein receptor mutation, which may have been missed as a consequence of unexpected masking of the effect of the APOE polymorphism by serum apoE concentrations. This study did not adjust the models with apoE levels, which modulate lipid levels, confer a 2-fold higher risks of cardiovascular disease mortality, and account for 26.07% of total cholesterol variance independent of the APOE polymorphism.3 The finding of this study would seem more reasonable if single nucleotide polymorphisms within the regulatory region of APOE were also investigated and their coordinated effect was controlled. Individual APOE polymorphism (APOE4 [rs429358] and APOE2 [rs7412]) depicts a partial story because the interactive effect of apoE4/E4 and low-density lipoprotein receptor mutation on CHD risk may differ when the impact of rs429358 is mediated by rs449647, rs405509, and rs440446. These single-nucleotide polymorphisms of the regulatory region influence transcriptional efficacy and APOE expression,4 the functional repercussions of which have been overlooked in this study. With APOE being in a tight cluster with APOCI and APOCII at 19q13.2, there is significant linkage disequilibrium betweenCirculation Cardiovascular Genetics 04/2012; 5(2):e13; author reply e14. DOI:10.1161/CIRCGENETICS.111.962274 · 5.34 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Missing heritability is still a challenge for Genome Wide Association Studies (GWAS). Gene-gene interactions may partially explain this residual genetic influence and contribute broadly to complex disease. To analyze the gene-gene interactions in case-control studies of complex disease, we propose a simple, non-parametric method that utilizes the F-statistic. This approach consists of three steps. First, we examine the joint distribution of a pair of SNPs in cases and controls separately. Second, an F-test is used to evaluate the ratio of dependence in cases to that of controls. Finally, results are adjusted for multiple tests. This method was used to evaluate gene-gene interactions that are associated with risk of Type 2 Diabetes among African Americans in the Howard University Family Study. We identified 18 gene-gene interactions (P < 0.0001). Compared with the commonly-used logistical regression method, we demonstrate that the F-ratio test is an efficient approach to measuring gene-gene interactions, especially for studies with limited sample size.Bioinformatics and biology insights 07/2012; 6:169-76. DOI:10.4137/BBI.S9867
[Show abstract] [Hide abstract]
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.PLoS ONE 06/2013; 8(6):e66924. DOI:10.1371/journal.pone.0066924 · 3.53 Impact Factor