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, Z. Szolnoki, Manjinder Sandhu, Nicholas Wareham, Ruth Frikke-Schmidt & 29 others 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, Juan P. Casas

Research output: Article

72 Citations (Scopus)

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 Methods: We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke.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

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

Fingerprint

Apolipoproteins E
Meta-Analysis
Biomarkers
Stroke
Genotype
LDL Cholesterol
Carotid Intima-Media Thickness
Odds Ratio
Apolipoprotein E2
Lipids
Lipoprotein(a)
Bayes Theorem
Apolipoproteins B
Hypercholesterolemia
C-Reactive Protein
Triglycerides
Alleles
Regression Analysis

ASJC Scopus subject areas

  • Epidemiology

Cite this

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. / Khan, Tauseef A.; Shah, Tina; Prieto, David; Zhang, Weili; Price, Jackie; Fowkes, Gerald R.; Cooper, Jackie; Talmud, Philippa J.; Humphries, Steve E.; Sundstrom, Johan; Hubacek, Jaroslav A.; Ebrahim, Shah; Lawlor, Debbie A.; Ben-Shlomo, Yoav; Abdollahi, Mohammad R.; Slooter, Arjen J C; Szolnoki, Z.; Sandhu, Manjinder; Wareham, Nicholas; Frikke-Schmidt, Ruth; Tybjærg-Hansen, Anne; Fillenbaum, Gerda; Heijmans, Bastiaan T.; Katsuya, Tomohiro; Gromadzka, Grazyna; Singleton, Andrew; Ferrucci, Luigi; Hardy, John; Worrall, Bradford; Rich, Stephen S.; Matarin, Mar; Whittaker, John; Gaunt, Tom R.; Whincup, Peter; Morris, Richard; Deanfield, John; Donald, Ann; Smith, George Davey; Kivimaki, Mika; Kumari, Meena; Smeeth, Liam; Khaw, Kay Tee; Nalls, Michael; Meschia, James; Sun, Kai; Hui, Rutai; Day, Ian; Hingorani, Aroon D.; Casas, Juan P.

In: International Journal of Epidemiology, Vol. 42, No. 2, 04.2013, p. 475-492.

Research output: Article

Khan, TA, Shah, T, Prieto, D, Zhang, W, Price, J, Fowkes, GR, Cooper, J, Talmud, PJ, Humphries, SE, Sundstrom, J, Hubacek, JA, Ebrahim, S, Lawlor, DA, Ben-Shlomo, Y, Abdollahi, MR, Slooter, AJC, Szolnoki, Z, Sandhu, M, Wareham, N, Frikke-Schmidt, R, Tybjærg-Hansen, A, Fillenbaum, G, Heijmans, BT, Katsuya, T, Gromadzka, G, Singleton, A, Ferrucci, L, Hardy, J, Worrall, B, Rich, SS, Matarin, M, Whittaker, J, Gaunt, TR, Whincup, P, Morris, R, Deanfield, J, Donald, A, Smith, GD, Kivimaki, M, Kumari, M, Smeeth, L, Khaw, KT, Nalls, M, Meschia, J, Sun, K, Hui, R, Day, I, Hingorani, AD & Casas, JP 2013, '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', International Journal of Epidemiology, vol. 42, no. 2, pp. 475-492. https://doi.org/10.1093/ije/dyt034
Khan, Tauseef A. ; Shah, Tina ; Prieto, David ; Zhang, Weili ; Price, Jackie ; Fowkes, Gerald R. ; Cooper, Jackie ; Talmud, Philippa J. ; Humphries, Steve E. ; Sundstrom, Johan ; Hubacek, Jaroslav A. ; Ebrahim, Shah ; Lawlor, Debbie A. ; Ben-Shlomo, Yoav ; Abdollahi, Mohammad R. ; Slooter, Arjen J C ; Szolnoki, Z. ; Sandhu, Manjinder ; Wareham, Nicholas ; Frikke-Schmidt, Ruth ; Tybjærg-Hansen, Anne ; Fillenbaum, Gerda ; Heijmans, Bastiaan T. ; Katsuya, Tomohiro ; Gromadzka, Grazyna ; Singleton, Andrew ; Ferrucci, Luigi ; Hardy, John ; Worrall, Bradford ; Rich, Stephen S. ; Matarin, Mar ; Whittaker, John ; Gaunt, Tom R. ; Whincup, Peter ; Morris, Richard ; Deanfield, John ; Donald, Ann ; Smith, George Davey ; Kivimaki, Mika ; Kumari, Meena ; Smeeth, Liam ; Khaw, Kay Tee ; Nalls, Michael ; Meschia, James ; Sun, Kai ; Hui, Rutai ; Day, Ian ; Hingorani, Aroon D. ; Casas, Juan P. / 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. In: International Journal of Epidemiology. 2013 ; Vol. 42, No. 2. pp. 475-492.
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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 Z. 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.}",
year = "2013",
month = "4",
doi = "10.1093/ije/dyt034",
language = "English",
volume = "42",
pages = "475--492",
journal = "International Journal of Epidemiology",
issn = "0300-5771",
publisher = "Oxford University Press",
number = "2",

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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, Z.

AU - Sandhu, Manjinder

AU - Wareham, Nicholas

AU - Frikke-Schmidt, Ruth

AU - Tybjærg-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

Y1 - 2013/4

N2 - 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.

AB - 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.

KW - Apolipoprotein E

KW - Biomarkers

KW - Cardiovascular disease

KW - Lipids

KW - Meta-analysis

KW - Stroke

KW - Systematic review

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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 -