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[Preprint]. 2024 Aug 9:2024.08.08.24311685.
doi: 10.1101/2024.08.08.24311685.

The role of the gluteofemoral adipose tissue in cerebrovascular disease risk: evidence from a mendelian randomization and mediation analysis

Evangelos Pavlos Myserlis  1 , Marios K Georgakis  2   3 , Livia Parodi  3   4   5 , Ernst Mayerhofer  5 , Jonathan Rosand  3   5   6   7 , Chirantan Banerjee  1 , Christopher D Anderson  3   4   5   7
Affiliations

The role of the gluteofemoral adipose tissue in cerebrovascular disease risk: evidence from a mendelian randomization and mediation analysis

Evangelos Pavlos Myserlis et al. medRxiv. .

Update in

Abstract

Objective: To explore causal associations between BMI-independent body fat distribution profiles and cerebrovascular disease risk, and to investigate potential mediators underlying these associations.

Methods: Leveraging data from genome wide association studies of BMI-independent gluteofemoral (GFAT), abdominal subcutaneous (ASAT), and visceral (VAT) adipose tissue volumes in UK Biobank, we selected variants associated with each trait, and performed univariable and multivariable mendelian randomization (MR) analyses on ischemic stroke and subtypes (large artery (LAS), cardioembolic (CES), small vessel (SVS)). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and an MRI-confirmed lacunar stroke as positive controls. For significant associations, we explored the mediatory role of four possible mediator categories in mediation MR analyses.

Results: Higher genetically proxied, BMI-independent GFAT volume was associated with decreased risk of ischemic stroke (FDR-p=0.0084), LAS (FDR-p=0.019), SVS (FDR-p<0.001), CAD (FDR-p<0.001), MRI-confirmed lacunar stroke (FDR-p=0.0053), and lower mean cIMT (FDR-p=0.0023), but not CES (FDR-p=0.749). Associations were largely consistent in pleiotropy- and sample structure-robust analyses. No association was observed between genetically proxied ASAT or VAT volumes and ischemic stroke/subtypes risk. In multivariable MR analyses, GFAT showed the most consistent independent association with ischemic stroke, LAS, and SVS. Common vascular risk factors were the predominant mediators in the GFAT-cerebrovascular disease axis, while adipose-tissue-specific adiponectin and leptin mediated a proportion of ischemic stroke and CAD risk.

Interpretation: Genetically proxied, BMI-independent higher GFAT volume is associated with reduced cerebrovascular disease risk. Although this is largely mediated by common vascular risk factor modification, targeting adipose-tissue specific pathways may provide additional cardiovascular benefit.

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Conflict of interest statement

L.P. is an employee of L’Oreal as of October 2023. E.M. is an employee of Regeneron as of July 2023. J.R. receives payments for consulting and expert testimony from the National Football League and Elli Lilly, and has a leadership or fiduciary role with Columbia University, European Stroke Journal, and Lancet Neurology. C.D.A. has received sponsored research support from Bayer AG, Massachusetts General Hospital, and the American Heart Association, is a member of the Editorial Board for Neurology, and has consulted for ApoPharma Inc. The rest of the authors have nothing to disclose.

Figures

Figure 1.
Figure 1.. Study design.
SNPs single-nucleotide polymorphisms; ASAT abdominal subcutaneous adipose tissue; VAT visceral adipose tissue; GFAT gluteofermoral adipose tissue; CAD coronary artery disease; cIMT carotid intima media thickness; SBP systolic blood pressure; T2DM type 2 diabetes mellitus; LDL low-density lipoprotein; CRP c-reactive protein
Figure 2.
Figure 2.
(A) Univariable and (B) multivariable inverse-variance weighted MR associations between BMI-adjusted local adiposity profiles and ischemic stroke and stroke subtypes.
Figure 3.
Figure 3.. Association between BMI-independent GFAT volume and relevant vascular phenotypes.
IMT carotid intima media thickness; IVW inverse-variance weighted; CI confidence interval; GFAT gluteofemoral adipose tissue
Figure 4.
Figure 4.. Percentage mediated by suggestive or significant mediators across outcomes.
IMT intima media thickness
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