Variants at APOE influence risk of deep and lobar intracerebral hemorrhage

Abstract

Objective Prior studies investigating the association between APOE alleles ε2 / ε4 and risk of Intracerebral Hemorrhage (ICH) have been inconsistent, limited to small sample sizes and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2,189 ICH cases and 4,041 controls from seven cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases and 357 controls) had available genome-wide data to adjust for population stratification. Results ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (Odds Ratio (OR) = 1.82, 95% Confidence Interval (CI) 1.50 – 2.23, p = 6.6 × 10−10 and OR = 2.20, 95%CI 1.85 – 2.63, p = 2.4 × 10−11 respectively). Restriction of analysis to definite / probable CAA ICH uncovered a stronger effect. ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI 1.08 – 1.36, p = 2.6 × 10−4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.

The APOE E4 Allele Confers Increased Risk of Ischemic Stroke Among Greek Carriers

“…Although there are conflicting results, it is perhaps not surprising that the consensus from the majority of well-designed studies, involving a more uniform patient cohort, appears to support a causal role for the E4 allele in stroke [14,18,31]. Since many other genetic and environmental factors obviously contribute to the expression of IS and CHD, it is logical to expect that a single variant may only explain a small proportion of cases.…”

“…For example, recent reviews and a large scale meta-analysis point to a possible association between certain common gene polymorphisms and ischemic stroke [6][7][8]. In particular, polymorphisms of the apolipoprotein-E (APOE) gene have been associated with cardiovascular disease (CVD) risk, with the APOE E4 allele being implicated in lipid disorders, CHD and stroke [8][9][10][11][12][13][14]. Nonetheless, other studies have failed to demonstrate a statistically significant association between carriers of the E4 allele and IS, adding further to the confusion related to the precise role of this gene polymorphism [15][16][17][18][19].…”

Treatment Targets in Intracerebral Hemorrhage

“…Individuals who have both alleles have an earlier onset of disease and an increased risk of recurrence [16,21,23]. Both APOE ε2 and ε4 are independent risk factors for lobar ICH, however, in the same large-scale genetic association study, APOE ε4 was also found to be associated with deep ICH [24]. Finally, there is now evidence that APOE ε2 may be associated with increased hematoma volumes at presentation, as well as subsequent hematoma expansion, which has important prognostic implications [25].…”

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

“…The e2 allele is protective in Alzheimer's disease but associated with an increased risk of cerebral amyloid angiopathy-related lobar ICH. 61,62 The relationship between markers of SVD and APOE genotype was assessed by a meta-analysis of 42 cross-sectional or longitudinal studies. APOE e4 was associated with an increased burden of both WMH and microbleeds, and APOE e2 was associated with an increased WMH burden.…”