• Tauseef A Khan, Tina Shah, David Prieto, Weili Zhang, Jackie Price, Gerald R Fowkes, Jackie Cooper, Philippa J Talmud, Steve E Humphries, Johan Sundstrom, Jaroslav A Hubacek, Shah Ebrahim, Debbie A Lawlor, Yoav Ben-Shlomo, Mohammad R Abdollahi, Arjen J C Slooter, Zoltan Szolnoki, Manjinder Sandhu, Nicholas Wareham, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen, Gerda Fillenbaum, Bastiaan T Heijmans, Tomohiro Katsuya, Grazyna Gromadzka, Andrew Singleton, Luigi Ferrucci, John Hardy, Bradford Worrall, Stephen S Rich, Mar Matarin, John Whittaker, Tom R Gaunt, Peter Whincup, Richard Morris, John Deanfield, Ann Donald, George Davey Smith, Mika Kivimaki, Meena Kumari, Liam Smeeth, Kay-Tee Khaw, Michael Nalls, James Meschia, Kai Sun, Rutai Hui, Ian Day, Aroon D Hingorani, and Juan P Casas.
• Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
• Int J Epidemiol. 2013 Apr 1; 42 (2): 475-92.

BackgroundAt the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 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on LDL-C or other lipids and biomarkers of cardiovascular risk.MethodsWe conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke.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).ResultsThe ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for ε2/ε2; 0.85 (95% CrI: 0.78-0.92) for ε2/ε3; 1.05 (95% CrI: 0.89-1.24) for ε2/ε4; 1.05 (95% CrI: 0.99-1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94-1.33) for ε4/ε4 using the ε3/ε3 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 × 10(-152)), apolipoprotein B (P-trend: 8.7 × 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10(-26)) and HDL-C (P-trend: 1.6 × 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.ConclusionsIn 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 ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.

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