A Beneficial Role for Gluteofemoral Adipose Tissue in Cerebrovascular Disease: Causal Pathway and Mediation Analysis

Previous studies have shown that increased body fat is associated with stroke risk, with evidence suggesting that body fat distribution, rather than total body fat, exerts a more prominent role in cerebrovascular risk prediction. In this study, we explore causal associations between body mass index (BMI)-independent adipose tissue distribution profiles and cerebrovascular disease (CVD) risk, aiming to refine the association between body fat distribution and stroke.

We selected variants associated with BMI-independent visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT) volumes in UK Biobank, and performed univariable and multivariable Mendelian randomization (MR) analyses with ischemic stroke (IS) and subtypes (large artery stroke [LAS], cardioembolic stroke [CES], and small vessel stroke [SVS]). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and MRI-confirmed lacunar stroke as positive controls. We explored the mediatory role of common cardiovascular (systolic blood pressure, diabetes, and low-density lipoprotein), insulin resistance, inflammatory (C-reactive protein), and adipose tissue-specific (adiponectin, leptin) factors by performing 2-step mediation MR analyses. Estimates were expressed per standard deviation increase in adjusted adipose tissue volume.

Genetic predisposition to higher GFAT volume was associated with lower risk of IS (odds ratio [OR] 0.92, 95% CI 0.86-0.98), LAS (OR 0.80, 95% CI 0.66-0.96), and SVS (OR 0.77, 95% CI 0.67-0.88), but not CES, consistent in multivariable analyses. Genetic predisposition to higher GFAT volume was also associated with lower risk of CAD (OR 0.82, 95% CI 0.76-0.88), lacunar stroke (OR 0.78, 95% CI 0.67-0.92), and mean cIMT (β = -0.073, 95% CI -0.114 to -0.031). Associations were largely consistent in sensitivity analyses. No association was observed between genetic predisposition to ASAT or VAT and IS risk. Although common vascular risk factors were the predominant mediators in the GFAT-CVD axis, adiponectin and leptin mediated a proportion of IS and CAD risk (∼15% (1.8%-57%) and ∼4.6% (0.8%-13.5%) mediated by adiponectin, respectively).

This study supports a protective role of gluteofemorally distributed fat volume in CVD risk. Although this role is predominantly mediated by common vascular risk factor modification, adipose tissue-specific factors may exert a mediatory effect, suggesting a possible novel target for attenuating adiposity-related CVD risk.