Abstract P613: Genetic Risk of Vascular Risk Factors and Severity of Leukoaraiosis in Patients With Ischemic Stroke: The MRI-GENIE Study

Abstract

Introduction: Severity of leukoaraiosis detected on T2 MRI scans as white matter hyperintensities (WMH) is associated with infarct growth and poor poststroke outcomes in patients with acute ischemic stroke (AIS). Traditional vascular risk factors (VRF) such as age, hypertension (HTN), type 2 diabetes mellitus (T2D), and cigarette smoking are linked to WMH in large population-based studies, yet casual inferences for WMH in AIS patients are limited. We sought to examine the VRFs for evidence of causal relationships with WMH burden in AIS patients using mendelian randomization principles and polygenic risk score (PRS) methods. Method: We examined FLAIR MRIs obtained within 48 hours of AIS onset in 4,362 European Caucasian patients from the MRI-GENetics Interface Exploration (MRI-GENIE) study. WMH volume (WMHv) was measured using a fully automated deep-learning trained algorithm. We considered 13 VRFs: blood pressure (HTN, SBP, DBP, Pulse Pressure), lipid (total cholesterol, HDL, LDL, TG), BMI, T2D, atrial fibrillation, alcohol use and smoking. For each factor, we calculated a weighted PRS for each individual based on the most recent GWAS with various GWAS p-value cutoff. We then used linear regression to estimate associations between each PRS and log transformed WMHv, controlling for age, gender and principal components of genetic ancestries. Strata-specific estimates were combined using inverse-variance weighting based meta-analysis. Results: PRS of both SBP and DBP were positively and robustly associated with WMHv in the meta-analysis (p value of the association ranging from <0.001 to 0.046 for various SNP selection strategies (GWAS p-value cutoff ranging from p<1E-5 to p<1E-8)), unlike the PRS of other risk factors, although stratum-specific significance was achieved for some factors. Conclusion: Using mendelian randomization, our results lend further evidence that high blood pressure is a causal risk factor for WMH in AIS patients. This result is consistent with previous epidemiological studies of leukoaraiosis in stroke-free populations, and it supports universal control of HTN as common contributor to WMH burden and the overall brain health.