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

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-SchmidtAnne Tybjaerg-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*, Juan P. Casas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke.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.

Original languageEnglish
Pages (from-to)475-492
Number of pages18
JournalInternational Journal of Epidemiology
Volume42
Issue number2
DOIs
Publication statusPublished - 5 Apr 2013

Keywords

  • Stroke
  • lipids
  • apolipoprotein E
  • cardiovascular disease
  • systematic review
  • meta-analysis
  • biomarkers
  • INTIMA-MEDIA THICKNESS
  • GENOME-WIDE ASSOCIATION
  • CORONARY-HEART-DISEASE
  • C-REACTIVE PROTEIN
  • ONSET ALZHEIMERS-DISEASE
  • BRITISH WOMENS HEART
  • GENE POLYMORPHISMS
  • TRANSPORT PROTEIN
  • LDL-CHOLESTEROL
  • COMMON VARIANTS

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