Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals
Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals
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DOI：
10.1093/ije/dyt034
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发表时间：
2013-04-01
影响因子：
7.7
通讯作者：
Casas, Juan P.
中科院分区：
文献类型：
--
作者：
Khan, Tauseef A.;Shah, Tina;Casas, Juan P.
在编码载脂蛋白E的载脂蛋白E基因中，与高LDL-胆固醇（LDL-C）水平相关的等位基因F12/F13/F14的基因型也与高冠状动脉风险相关。然而，APOE基因型与其他心血管生物标志物和缺血性卒中风险的关系尚不清楚。我们评估了APOE基因型与缺血性卒中风险的相关性，并评估了所观察到的效果是否与APOE基因型对LDL-C或其他血脂和心血管风险生物标志物的影响一致。我们使用贝叶斯荟萃分析汇总了41项研究（共9027例病例和61730例对照），以计算APOE基因型与缺血性卒中的比值比（OR）。为了更好地评估任何观察到的效应的潜在机制，我们还使用了16项欧洲血统研究（多达60883人）的原始数据进行了汇总分析。我们评估了APOE基因型与血脂、其他心血管风险的循环生物标志物和颈动脉内膜中层厚度（C-IMT）的相关性。结果APOE基因型与缺血性脑卒中相关的OR值为：1.09（95%可信区间（CrI）：0.84 - 1.43），对于≤ 2/≤ 2; 0.85（95%CrI：0.78 - 0.92），对于Cr2/Cr3; 1.05（95%CrI：0.89 - 1.24），对于Cr2/Cr4; 1.05（95%CrI：0.99 - 1.12）和1.12（95%CrI：0.94 - 1.33）。一项研究LDL-C（使用APOE作为工具）对缺血性卒中影响的回归分析显示，LDL-C每增加1 mmol/l，OR为1.33（95% CrI：1.17，1.52），具有正剂量-反应相关性。在单独的合并分析中，APOE基因型与LDL-C水平呈线性正相关（P趋势：2 x 10（-152）），载脂蛋白B（P趋势：8.7 x 10（-06））和C-IMT（P趋势：0.001），与载脂蛋白E（P趋势：6 x 10（-26））和HDL-C（P趋势：1.6 x 10（-12））呈负线性相关。结论在欧洲血统人群中，APOE基因型与LDL-C、C-IMT和缺血性卒中呈剂量-反应正相关。然而，APOE β 2/β 2基因型与缺血性脑卒中的相关性需要进一步研究。这种跨领域一致性支持LDL-C对缺血性卒中的因果作用。
Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for epsilon 2/epsilon 2; 0.85 (95% CrI: 0.78-0.92) for epsilon 2/epsilon 3; 1.05 (95% CrI: 0.89-1.24) for epsilon 2/epsilon 4; 1.05 (95% CrI: 0.99-1.12) for epsilon 3/epsilon 4; and 1.12 (95% CrI: 0.94-1.33) for epsilon 4/epsilon 4 using the epsilon 3/epsilon 3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 x 10(-152)), apolipoprotein B (P-trend: 8.7 x 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 x 10(-26)) and HDL-C (P-trend: 1.6 x 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE epsilon 2/epsilon 2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.