@article{6a3d24dbee9c4ad8b195409457d91c44,
title = "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",
abstract = "Background: At 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. Methods: We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke.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 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 doseresponse 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-o6) 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. 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 ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.",
keywords = "Apolipoprotein E, Biomarkers, Cardiovascular disease, Lipids, Meta-analysis, Stroke, Systematic review",
author = "Khan, {Tauseef A.} and Tina Shah and David Prieto and Weili Zhang and Jackie Price and Fowkes, {Gerald R.} and Jackie Cooper and Talmud, {Philippa J.} and Humphries, {Steve E.} and Johan Sundstrom and Hubacek, {Jaroslav A.} and Shah Ebrahim and Lawlor, {Debbie A.} and Yoav Ben-Shlomo and Abdollahi, {Mohammad R.} and Slooter, {Arjen J.C.} and Zoltan Szolnoki and Manjinder Sandhu and Nicholas Wareham and Ruth Frikke-Schmidt and Anne Tybj{\ae}rg-Hansen and Gerda Fillenbaum and Heijmans, {Bastiaan T.} and Tomohiro Katsuya and Grazyna Gromadzka and Andrew Singleton and Luigi Ferrucci and John Hardy and Bradford Worrall and Rich, {Stephen S.} and Mar Matarin and John Whittaker and Gaunt, {Tom R.} and Peter Whincup and Richard Morris and John Deanfield and Ann Donald and Smith, {George Davey} and Mika Kivimaki and Meena Kumari and Liam Smeeth and Khaw, {Kay Tee} and Michael Nalls and James Meschia and Kai Sun and Rutai Hui and Ian Day and Hingorani, {Aroon D.} and Casas, {Juan P.}",
note = "Funding Information: T.A.K. is funded by a Graduate Teaching Assistantship of London School of Hygiene & Tropical Medicine. A.D.H. was funded by a British Heart Foundation Senior Fellowship (FS/05/125). S.E.H, J.C. and P.J.T. are supported by the British Heart Foundation (PG2008/015). L.S. is funded by a Wellcome Trust Senior Fellowship in Clinical Science. T.R.G. was the recipient of a British Heart Foundation Intermediate Fellowship FS/05/065/19497 and T.R.G., I.D., S.E., D.A.L. and Y.B.S. are the recipients of a British Heart Foundation project grant PG/07/131/24254. D.A.L., G.D.S., T.R.G. and I.D. work in a UK Medical Research Council-supported centre. M.R.A. as funded by postdoctoral support from the University of Bristol which funded some set-up costs of Bristol Genetic Epidemiology Laboratory (M.R.A., T.R.G., I.D.). RCUK funding to I.D. and G.D.S. supported a Collaboration Development Workshop in Cardiovascular Genetics held in Beijing in March 2010. Tamuno Alfred is thanked for statistical support. J.S. is funded by the Swedish Research Council (2007-5942) and the Swedish Heart Lung Foundation (20041151). J.A.H. is funded by Centre for Cardiovascular Research and Institute for Clinical and Experimental Medicine project 00023001 (IKEM CR). A.J.S. is supported by the NESTOR stimulation programme for geriatric research in The Netherlands (Ministry of Health and Ministry of Education), the Netherlands Organization for Scientific Research (NWO), the Netherlands Prevention fund, the municipality of Rotterdam, the International Alzheimer Research Foundation (IARF), and the Fund for Scientific Research (FWO-F), Flanders, Belgium. T.K. (Tomohiro Katsuya) was supported by Grants-in-Aid for Scientific Research (18590265, 18590811, 19650188, 21390223) from the Ministry of Education, Science, Sports and Culture of Japan. R.H. is supported by the grants from the Ministry of Science and Technology of China (2011CB503900, 2009DFB30050 and 2006CB503805). M.A.N., A.B.S., J.H., B.B.W., S.R., T.G.B., R.D.B., J.F.M.: ISGS and SWISS received funding from grants from the National Institute of Neurological Disorders and Stroke (US), R01 NS39987 and R01 NS42733. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000954-06. This work used samples and clinical data from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.cor-iell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000015-50, human subjects protocol number 2003-078. The ISGS study was funded by a grant from the National Institute for Neurological Disorders and Stroke (US; R01 NS42733) (J Meschia, P.I.). The SWISS study was funded by a grant from the National Institute for Neurological Disorders and Stroke (US; R01 NS39987 (J Meschia, P.I.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http:// biowulf.nih.gov). Funding Information: Samples from the English Longitudinal Study of Ageing (ELSA) DNA Repository (EDNAR), received support under a grant (AG1764406S1) awarded by the National Institute on Aging (NIA). ELSA was developed by a team of researchers based at the National Centre for Social Research, University College London and the Institute of Fiscal Studies, UK. The data were collected by the National Centre for Social Research. Northwick Park Heart Study II (NPHS-II) was supported by the British Medical Research Council, the US National Institutes of Health (NHLBI 33014) and Du Pont Pharma, Wilmington, USA. The Whitehall II study (is supported by the US National Institutes of Health (NHLBl R01HL036310-20A2, NIA R01AG013196 and R01AG034454), the British Heart Foundation (RG/ 02/005) and the Medical Research Council, UK. Edinburgh Artery Study (EAS) was funded by the British Heart Foundation. The British Regional Heart Study (BRHS) is a British Heart Foundation Research Group and is supported by British Heart Foundation (RG/04/003). The views expressed in this publication are those of the authors and not necessarily those of the funding bodies. The British Women{\textquoteright}s Heart and Health Study (BWHHS) was funded by the Department of Health Policy Research Programme and the British Heart Foundation (BHF Project Grant No: PG/06/002 and DoH Project Grant No: 0090041). The Caerphilly Prospective Study (CaPS) was established by the former MRC Epidemiology Unit in Cardiff. Diabetes UK supported the creation of UDACS. The AAA Trial (AAAT) was funded by the British Heart Foundation, Chief Scientist Office in Scotland, Chest Heart and Stroke Scotland and Wellcome Trust. The EARSI study was supported by the European Community Concerted Action MRH4 COMAC Epidemiology, and the EARSII study was supported by the European Commission Contract BMH1-CT92-0206. Analyses in the Czech-MONICA study were supported by project grants No. 00023001 (I.K.E.M., C.R.) and 1M0510 (M.S.M.T., C.R.). The Uppsala Longitudinal Study of Adult Men (ULSAM) study was supported by the Swedish Research Council (2006–6555), Swedish Heart-Lung Foundation, Erik, Karin och G{\"o}sta Selanders Foundation, Thur{\'e}us Foundation, Lisa och Johan Gr{\"o}nbergs Foundation, Loo och Hans Ostermans Foundation and Uppsala University.",
year = "2013",
month = apr,
doi = "10.1093/ije/dyt034",
language = "English (US)",
volume = "42",
pages = "475--492",
journal = "International journal of epidemiology",
issn = "0300-5771",
publisher = "Oxford University Press",
number = "2",
}