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 and 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 2189 ICH cases and 4041 controls from 7 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, 357 controls) had available genome-wide data to adjust for population stratification.

Results: Alleles 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 cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele 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.

Figure 1. Forest plots of meta-analysis of APOE in Lobar and Deep ICH

GERFHS = Genetic and Environmental Risk Factors for Hemorrhagic Stroke Study at the University of Cincinnati (Cincinnati, OH, USA), GOCHA = Multi-center North American (USA) Genetics of Cerebral Hemorrhage on Anticoagulation Study, HM-ICH = Hospital del Mar (Barcelona, Spain) ICH Study, JUHSS = Jagiellonian University (Krakow, Poland) Hemorrhagic Stroke Study, LUHSS = Lund University (Lund, Sweden) Hemorrhagic Stroke Study, MUG-ICH = Medical University of Graz (Graz, Austria) ICH Study, VHH-ICH = Val d’Hebron Hospital (Barcelona, Spain) ICH Study. ICH = Intracerebral Hemorrhage

Figure 2. Effect of APOE genotype on predicted probability of ICH status vs. Control

A: Lobar ICH probability, B: Deep ICH Probability. Box plots display the median (solid line), interquartile range (box) and total range (whiskers) of probability distribution for each genotype. Disease status probability based on meta-analysis of logistic regression analyses from individual studies under the assumption of the additive model, including adjustment for age, gender, hypertension and principal components (where available).