Adipokines May Partly Mediate the Favorable Effect of Gluteofemoral Adipose Tissue Distribution on Cardiovascular Risk: A Mediation Mendelian Randomization Analysis
Evangelos Pavlos Myserlis1, Marios Georgakis2, Livia Parodi3, Ernst Mayerhofer4, Jonathan Rosand5, Christopher Anderson6
1Department of Neurology, Medical University of South Carolina, 2Institute for Stroke and Dementia Research, 3L'Oreal, 4Regeneron Genetics Center, 5Massachusetts General Hospital, 6Brigham and Women's Hospital
Objective:
To explore the role of gluteofemoral adipose tissue (GFAT) distribution in relevant vascular phenotypes and investigate the mediatory role of cardiovascular, inflammatory, glycemic, and adipose-specific factors underlying these associations.
Background:
Recent evidence suggests that body fat distribution is associated with cardiovascular risk. Previously, we have shown that GFAT is associated with a favorable stroke risk profile, mainly driven by reduced large artery (LAS) and small vessel (SVS) stroke risk.
Design/Methods:
Utilizing data from Genome-Wide Association Studies (GWAS) of MRI-derived GFAT (n= 37,750), we selected genome-wide, independent, BMI- and height-adjusted single nucleotide polymorphisms (SNPs). We performed univariable Mendelian Randomization (MR) of genetically proxied GFAT on ischemic stroke (IS) (n=62,100), LAS (n=6,399), 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 then explored the mediatory effect of common cardiovascular (systolic blood pressure (SBP), diabetes (T2DM), LDL), insulin resistance (fasting insulin), inflammatory (C-reactive protein (CRP)), and adipose tissue-specific (adiponectin, leptin) factors by performing two-step mediation MR analyses. Factors that showed significant univariable MR associations with both GFAT and the vascular phenotypes 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). While common vascular risk factors were predominant mediators across outcomes, neither CRP nor insulin resistance were significant mediators. Both adiponectin (15% (2-57%) in IS, 4% (1-14%) in CAD) and leptin were mediators or candidate mediators, respectively.
Conclusions:
In the setting of an unhealthy body fat distribution, targeting adipose-tissue specific pathways may provide additional benefit to reducing vascular risk, beyond addressing traditional risk factors.