Abstract WMP105: Gluteofemoral Fat Distribution Is Associated With Decreased Stroke Risk: A Mendelian Randomization Study

Abstract

Introduction: Previous studies have suggested that increased body fat is associated with stroke risk. Advances in imaging-based fat distribution measurements have uncovered distinct biological underpinnings of local fat depots. Here, we explored associations between biologically relevant local adiposity profiles and stroke risk, aiming to refine the association between body fat distribution and stroke. Methods: Utilizing data from Genome-Wide Association Studies of MRI-derived visceral (VAT), abdominal subcutaneous (ASAT) and gluteofemoral (GFAT) adipose tissue volumes in the UK Biobank (n= 37,750), we selected genome-wide (p<5x10 -8 ), independent (r 2 <0.01), BMI- and height-adjusted variants associated with each trait. We performed Mendelian Randomization (MR) analyses of each trait on ischemic stroke (n=34,217) and subtypes (large artery (LAS)=4,373; cardioembolic (CES)=7,193; small vessel (SVS)=5,386) in MEGASTROKE. We performed multivariable MR, adjusting for relevant cardiometabolic factors (low-density lipoprotein, systolic blood pressure, type 2 diabetes, coronary artery disease). Estimates were expressed as per liter increase in fat volume. Results: GFAT distribution was associated with an overall decreased risk of ischemic stroke (OR 0.89; 95% CI: 0.82-96; p=0.04), mainly driven by SVS risk (OR 0.76; 95% CI: 0.64-0.88; p<0.001) (Figure 1A). Associations were largely consistent in weighted-median and MR-Egger analyses. After adjusting for cardiometabolic factors, only the association between GFAT and SVS remained significant (Figure 1B) . Neither VAT nor ASAT volumes were associated with ischemic stroke risk (both p>0.05). Conclusions: GFAT distribution is associated with a favorable stroke risk profile, suggesting that increases in stroke risk in the setting of an unhealthy body fat distribution may potentially primarily be driven by relative decreases in GFAT rather than increases in VAT or ASAT.