TY - JOUR
T1 - Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke
T2 - Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals
AU - Khan, Tauseef A.
AU - Shah, Tina
AU - Prieto, David
AU - Zhang, Weili
AU - Price, Jackie
AU - Fowkes, Gerald R.
AU - Cooper, Jackie
AU - Talmud, Philippa J.
AU - Humphries, Steve E.
AU - Sundstrom, Johan
AU - Hubacek, Jaroslav A.
AU - Ebrahim, Shah
AU - Lawlor, Debbie A.
AU - Ben-Shlomo, Yoav
AU - Abdollahi, Mohammad R.
AU - Slooter, Arjen J. C.
AU - Szolnoki, Zoltan
AU - Sandhu, Manjinder
AU - Wareham, Nicholas
AU - Frikke-Schmidt, Ruth
AU - Tybjaerg-Hansen, Anne
AU - Fillenbaum, Gerda
AU - Heijmans, Bastiaan T.
AU - Katsuya, Tomohiro
AU - Gromadzka, Grazyna
AU - Singleton, Andrew
AU - Ferrucci, Luigi
AU - Hardy, John
AU - Worrall, Bradford
AU - Rich, Stephen S.
AU - Matarin, Mar
AU - Whittaker, John
AU - Gaunt, Tom R.
AU - Whincup, Peter
AU - Morris, Richard
AU - Deanfield, John
AU - Donald, Ann
AU - Smith, George Davey
AU - Kivimaki, Mika
AU - Kumari, Meena
AU - Smeeth, Liam
AU - Khaw, Kay-Tee
AU - Nalls, Michael
AU - Meschia, James
AU - Sun, Kai
AU - Hui, Rutai
AU - Day, Ian
AU - Hingorani, Aroon D.
AU - Casas, Juan P.
PY - 2013/4/5
Y1 - 2013/4/5
N2 - 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LDL-C or other lipids and biomarkers of cardiovascular risk.Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke.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.
AB - 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.
KW - Stroke
KW - lipids
KW - apolipoprotein E
KW - cardiovascular disease
KW - systematic review
KW - meta-analysis
KW - biomarkers
KW - INTIMA-MEDIA THICKNESS
KW - GENOME-WIDE ASSOCIATION
KW - CORONARY-HEART-DISEASE
KW - C-REACTIVE PROTEIN
KW - ONSET ALZHEIMERS-DISEASE
KW - BRITISH WOMENS HEART
KW - GENE POLYMORPHISMS
KW - TRANSPORT PROTEIN
KW - LDL-CHOLESTEROL
KW - COMMON VARIANTS
U2 - 10.1093/ije/dyt034
DO - 10.1093/ije/dyt034
M3 - Article
VL - 42
SP - 475
EP - 492
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
SN - 0300-5771
IS - 2
ER -