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.

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 METHODS: We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke.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

Five Factor Model personality traits and all-cause mortality in the Edinburgh Artery Study cohort.

OBJECTIVE: To examine whether personality traits are related to all-cause mortality in a general adult population in Scotland. METHODS: The Edinburgh Artery Study began in 1987 to 1988 by recruiting 1592 men and women aged 55 to 74 years to be followed-up for atherosclerotic diseases. The NEO Five-Factor Inventory (NEO-FFI) was completed by 1035 surviving participants in 1995 to 1996. Deaths from all causes were examined in relation to personality traits and social and physical risk factors for mortality. RESULTS: During follow-up, 242 (37.1%) men and 165 (24.6%) women died. For the whole sample, there was a 28% lower rate of all-cause mortality for each 1 SD increase in NEO-FFI openness (95% CI, 0.61-0.84) and a 18% lower rate of all-cause mortality for each 1 SD increase in NEO-FFI conscientiousness (95% CI, 0.70-0.97). In men, the risk of all-cause mortality was 0.63 (95% CI, 0.5-10.78) for a 1 SD increase in openness and 0.75 (95% CI, 0.61-0.91) for a 1 SD increase in conscientiousness. In women, none of the personality domains were significantly associated with all-cause mortality. Well fitting structural equation models in men (n = 652) showed that the relationships between conscientiousness and openness and all-cause mortality were not substantially explained by smoking, or other variables in the models. CONCLUSION: High conscientiousness and openness may be protective against all-cause mortality in men. Further investigations are needed on the mechanisms of these associations, and the influence of personality traits on specific causes of death.