Abstract WMP107: Exploration of the Inflammatory Profile of Gluteofemoral Adipose Tissue Distribution Supports Role of Targeting Inflammation to Further Decrease Cardiovascular Risk

Abstract

Introduction: Recent evidence suggests that body fat distribution is associated with cardiovascular risk. We have previously shown that gluteofemoral adipose tissue (GFAT) distribution is associated with a favorable cardiovascular risk profile. Given the emerging role of inflammation in cardiovascular health, we explored the inflammatory profile of GFAT and the possible mediatory role of inflammatory cytokines underlying the association between GFAT and cardiovascular risk. Methods: As previously described, utilizing GWAS data and univariable Mendelian Randomization (MR) analyses we explored the association between genetically proxied GFAT (n= 37,750) and 6 vascular outcomes [ischemic stroke (IS) (n=62,100), large artery stroke (LAS) (n=6,399), small vessel stroke (SVS) (n=6,811), coronary artery disease (CAD) (n=181,522), lacunar stroke (n=6,030), and carotid intima media thickness (cIMT) (n=45,185)]. We also performed univariable MR between GFAT and 40 circulating inflammatory markers (n=75,000) and derived the significant profile after FDR correction. We then explored the mediatory effect of the inflammatory profile on the cardiovascular outcomes after performing two-step mediation MR. Cytokines that showed significant univariable MR associations with both GFAT and the vascular outcomes were considered candidate mediators. Results: Genetically proxied GFAT was associated with decreased risk of IS (p=0.006), LAS (p=0.016), SVS (p<0.001), CAD (p<0.001), and lacunar stroke (p=0.001), and lower mean cIMT (p=0.001). GFAT showed significant association with 9 inflammatory cytokines (Figure) . HGF was a candidate mediator underlying the GFAT-CAD association and IL-2 showed significant suppression effect in the GFAT-cIMT axis (β GFAT-cIMT =-0.07, p=0.001; β IL-2-cIMT =0.01, p=0.0126). Conclusion: In the context of a favorable body fat distribution, targeting IL-2 may further enhance the protective role of GFAT on cardiovascular risk.