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Significant interaction of APOE rs4420638 polymorphism with HDL-C and APOA-I levels in coronary heart disease in Han Chinese men.
Huang, Y, Ye, HD, Gao, X, Nie, S, Hong, QX, Ji, HH, Sun, J, Zhou, SJ, Fei, B, Li, KQ, et al
Genetics and molecular research : GMR. 2015;(4):13414-24
Abstract
Apolipoprotein E (APOE) is recognized for its importance in lipoprotein metabolism and cardiovascular disease. We evaluated the association between APOE rs4420638 genotypes and circulating lipid concentrations along with the risk of coronary heart disease (CHD). We conducted a case-control study involving 1508 individuals to investigate the contribution of rs4420638 to the risk of CHD in Han Chinese. In addition, we performed a meta-analysis to evaluate the association between rs4420638 and CHD in Europeans and Asians. The results show that rs4420638 is significantly correlated with increased CHD risk in male Han Chinese [P = 0.040, odds ratio (OR) = 1.34, 95% confidential interval (95%CI) = 1.01-1.78] and is likely to increase the risk of CHD under the dominant model in males (P = 0.036, OR = 1.38, 95%CI = 1.02-1.88). A further subgroup analysis by rs4420638 genotype found a significant association of rs4420638 AA with high-density lipoprotein cholesterol (HDL-C) (P = 0.012) and APOA-I levels (P = 0.0001) in males. The meta-analysis suggests that rs4420638 significantly increases the risk of CHD (OR = 1.18, 95%CI = 1.14-1.22, P < 0.0001, fixed-effect method). Our case-control study shows that rs4420638 genotype AA has a significant association with the concentrations of circulating HDL-C and APOA-I in CHD in Han Chinese males. The meta-analysis suggests that rs4420638 is associated with CHD risk in Europeans and Asians.
2.
Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.
Boekholdt, SM, Arsenault, BJ, Hovingh, GK, Mora, S, Pedersen, TR, Larosa, JC, Welch, KM, Amarenco, P, Demicco, DA, Tonkin, AM, et al
Circulation. 2013;(14):1504-12
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Abstract
BACKGROUND It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. METHODS AND RESULTS We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81-0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72-0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels <50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR, 0.98; 95% CI, 0.94-1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR, 0.93; 95% CI, 0.90-0.97). CONCLUSIONS Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.
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Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions.
Heijmans, BT, Beekman, M, Putter, H, Lakenberg, N, van der Wijk, HJ, Whitfield, JB, Posthuma, D, Pedersen, NL, Martin, NG, Boomsma, DI, et al
European journal of human genetics : EJHG. 2005;(10):1143-53
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Abstract
Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.