Abstract 51: Apoe Epsilon 4 And Risk Of Bleeding Patients With Brain Arteriovenous Malformations. A Combined Genetic Study In The Uk Biobank And All Of Us

Abstract

Background: Patients with brain arteriovenous malformation (AVM) are at risk of intracranial hemorrhage (ICH). The epsilon 2 and 4 alleles within the APOE gene are well-described genetic risk factors for spontaneous, non-traumatic intraparenchymal hemorrhages. We tested the hypothesis that the APOE epsilon variants lead to higher risk of ICH in patients with AVMs. Methods: We conducted a two-stage (discovery and replication) genetic association study using individual-level data from the UK Biobank and the All of Us Research Program. We ascertained AVMs and ICH using validated ICD-9/10 codes. Genome-wide array genotyping was completed using the UK Biobank Axiom Array in the UK Biobank, and Illumina’s Global Diversity Array in All of Us. We used genotypic data on the APOE variants rs429358 and rs7412 to ascertain the epsilon 2 and 4 status. Within each study, we tested for association between APOE epsilon variants and ICH risk using multivariable logistic regression. Results: The discovery phase included 189 UK Biobank participants with an AVM (mean age 57 years, female sex 49%), including 37 (19.6%) that sustained an ICH. After adjusting by age, sex, and race/ethnicity, APOE epsilon 4 was associated with a higher risk of ICH (OR 4.20; 95%CI 1.99-9.25; p<0.001) whereas epsilon 2 was not (p>0.05). These results were replicated in 228 participants with AVMs enrolled in All of Us (mean age 56 years, female sex 66%), including 31 (13.6%) who sustained an ICH, where APOE epsilon 4 was associated with a higher risk of ICH (OR 2.73; 95%CI 1.05-7.22; p=0.038) whereas epsilon 2 was not (p>0.05). Conclusion: Among study participants with AVMs enrolled in two large population studies, the APOE epsilon 4 variants were associated higher risk of sustaining a brain bleed. These results point to shared pathophysiology with spontaneous intraparenchymal hemorrhages and provide support for further research focused on evaluating the role of APOE in risk stratification strategies.