APOE ε4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage

Abstract

Objective: Genetic variants e2/e4 within the APOE gene are established risk factors for lobar intracerebral hemorrhage (ICH). Published preliminary data suggest a potential role for APOE e4 in risk of nonlobar ICH. We therefore investigated the role of APOE in recurrent nonlobar ICH, and sought to clarify whether effects of APOE on circulating lipids mediate this association.Methods: Three hundred sixty-three survivors of nonlobar ICH were followed prospectively for ICH recurrence, with APOE genotype determined at enrollment. All participants had clinical, demographic, and laboratory data captured at time of index ICH and during follow-up. Using a multivariate model, we performed association and interaction analyses of the relationships among APOE genotype, lipid levels, and recurrent nonlobar ICH. Results:We observed 29 nonlobar ICH recurrences among 363 survivors. APOE e4 was associated with recurrent nonlobar ICH (hazard ratio 5 1.31; 95% confidence interval 5 1.02-2.69; p 5 0.038) after adjustment for age/sex/ethnicity and cardiovascular risk factors. Increasing lowdensity lipoprotein (LDL) levels were associated with decreased risk of recurrent nonlobar ICH (p 5 0.027), as were decreasing HDL levels (p 5 0.046). LDL levels modified the association of APOE e4 with recurrent nonlobar ICH (mediation p , 0.05). No associations were identified between APOE e2 and recurrent nonlobar ICH.Conclusion: APOE e4 is associated with recurrent ICH in nonlobar brain regions, providing further evidence for its causal role in ICH unrelated to cerebral amyloid angiopathy. LDL levels modulated this effect, suggesting that circulating lipid levels may mediate a portion of the role of APOE e4 in nonlobar ICH. Neurology ® 2015;85:349-356 GLOSSARY CAA 5 cerebral amyloid angiopathy; CI 5 confidence interval; EMR 5 electronic medical record; HDL 5 high-density lipoprotein; HR 5 hazard ratio; ICH 5 intracerebral hemorrhage; IQR 5 interquartile range; LDL 5 low-density lipoprotein; TC 5 total cholesterol.Primary intracerebral hemorrhage (ICH) is the most lethal acute cerebrovascular disorder, its mortality rate ranging from 40% to 50% at 90 days from the initial bleeding event.1 Survivors are often burdened with substantial disability and face a high risk of recurrent ICH.2 Previous studies demonstrated that survivors of ICH in the lobar brain regions are at higher risk of recurrence, and multiple predictors of recurrent lobar ICH have been identified.3,4 Among these, the e2/e4 variants of the APOE gene are presumed to modify lobar ICH recurrence risk via their role in small vessel disease associated with cerebral amyloid angiopathy (CAA). 3,5 A recent, large meta-analysis of case-control studies conclusively demonstrated that APOE e2 and e4 increase risk of ICH in the lobar brain regions. 6 An intriguing preliminary finding that emerged as well was an association between APOE e4, but not e2, and nonlobar ICH.6 This finding warrants further exploration of its potential underlying biology, as nonlobar ICH is typically associate...

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity

“…Previously demonstrated associations between APOE ε4 and nonlobar ICH risk, also seen in nonlobar ICH recurrence, 17 , 53 were not replicated in this study. Potential explanations include a higher rate of participants affected by hypertension and an overall younger age of participants in this study.…”

ApoE Polymorphisms and the Risk of Different Subtypes of Stroke in the Chinese Population: A Comprehensive Meta-Analysis

“…ApoE polymorphisms have been reported to be associated with various diseases, including type II diabetes, coronary artery disease [86,87] , hypertension [15] , Alzheimer's disease [88,89] , and dementia in Parkinson disease [90] . Recently, the associations between ApoE gene polymorphisms and the risk of different subtypes of stroke have been studied extensively [91][92][93] , but the results remain inconclusive, particularly in different ethnic groups and geographical locations. Therefore, this study summarized the published evidence on the association between ApoE gene polymorphisms and stroke risk in the Chinese population.…”

Association of Apolipoprotein E Polymorphisms with White Matter Lesions and Brain Atrophy

“…Since APOE gene polymorphism plays a key role in the reg-ulation of plasma lipid levels, 26,27 APOE isoforms are thought to play an important role in the pathogenesis of vascular disease. 28,29 The results show that, First, serum ApoB and urea levels of patients with WML are different among allele groups. In addition, ApoB level of E2 allele carriers was higher than others.…”