Associations of Visceral Adipose Tissue, Circulating Protein Biomarkers, and Risk of Cardiovascular Diseases: A Mendelian Randomization Analysis

Abstract

Aim: To evaluate the genetic associations of visceral adipose tissue (VAT) mass with metabolic risk factors and cardiovascular disease (CVD) endpoints and to construct a network analysis about the underlying mechanism using Mendelian randomization (MR) analysis. Methods and Results: Using summary statistics from genome-wide association studies (GWAS), we conducted the two-sample MR to assess the effects of VAT mass on 10 metabolic risk factors and 53 CVD endpoints. Genetically predicted VAT mass was associated with metabolic risk factors, including triglyceride (odds ratio, OR, 1.263 [95% confidence interval, CI, 1.203-1.326]), high-density lipoprotein cholesterol (OR, 0.719 [95% CI, 0.678-0.763]), type 2 diabetes (OR, 2.397 [95% CI, 1.965-2.923]), fasting glucose (OR, 1.079 [95% CI, 1.046-1.113]), fasting insulin (OR, 1.194 [95% CI, 1.16-1.229]), and insulin resistance (OR, 1.204 [95% CI, 1.16-1.25]). Genetically predicted VAT mass was associated with CVD endpoints, including atrial fibrillation (OR, 1.414 [95% CI, 1.332 = 1.5]), coronary artery disease (OR, 1.573 [95% CI, 1.439 = 1.72]), myocardial infarction (OR, 1.633 [95% CI, 1.484 =1.796]), heart failure (OR, 1.711 [95% CI, 1.599-1.832]), any stroke (OR, 1.29 [1.193-1.394]), ischemic stroke (OR, 1.292 [1.189-1.404]), large artery stroke (OR, 1.483 [1.206-1.823]), cardioembolic stroke (OR, 1.261 [1.096-1.452]), and intracranial aneurysm (OR, 1.475 [1.235-1.762]). In the FinnGen study, the relevance of VAT mass to coronary heart disease, stroke, cardiac arrhythmia, vascular diseases, hypertensive heart disease, and cardiac death was found. In network analysis to identify the underlying mechanism between VAT and CVDs, VAT mass was positively associated with 23 cardiovascular-related proteins (e.g., Leptin, Hepatocyte growth factor, interleukin-16), and inversely with 6 proteins (e.g., Galanin peptides, Endothelial cell-specific molecule 1). These proteins were further associated with 32 CVD outcomes. Conclusion: Mendelian randomization analysis has shown that VAT mass was associated with a wide range of CVD outcomes including coronary heart disease, cardiac arrhythmia, vascular diseases, and stroke. A few circulating proteins may be the mediators between VAT and CVDs.

Keywords: cardiovascular disease; mendelian randomization; obesity; two-sample MR; visceral adipose tissue.

FIGURE 1

The causal effect of visceral adiposity on 10 metabolic risk factors. Odds ratios are expressed per 1-SD increase in genetically determined VAT mass. CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.

FIGURE 2

The causal effect of visceral adiposity on 10 independent CVD endpoints. Odds ratios are expressed per 1-SD increase in genetically determined VAT mass. CI, confidence interval.

FIGURE 3

The causal effect of visceral adiposity on 43 CVD endpoints from the FinnGen analysis. Odds ratios are expressed per 1-SD increase in genetically determined VAT mass. CI, confidence interval; PAD, peripheral arterial disease; AV-block, atrioventricular block; DVT, deep vein thrombosis; SAH, subarachnoid haemmorrhage.

FIGURE 4

Network analysis of VAT-proteins-CVDs. AGRP, Agouti-related protein; TNF-R2, Tumor necrosis factor receptor 2; TRAIL-R2, TNF-related apoptosis-inducing ligand receptor 2; GDF-15, Growth/differentiation factor 15; REN, Renin; SELE, E-selectin; TNFSF14, Tumor necrosis factor ligand superfamily member 14; TRANCE, TNF-related activation-induced cytokine; KIM-1, Kidney injury molecule 1; GAL, Galanin peptides; MPO, Myeloperoxidase; U-PAR, Urokinase plasminogen activator surface receptor; MB, Myoglobin; PSGL-1, P-selectin glycoprotein ligand 1; IL-1ra, Interleukin-1 receptor antagonist protein; t-PA, Tissue-type plasminogen activator; CSF-1, Macrophage colony-stimulating factor 1; FAS, Tumor necrosis factor receptor superfamily member 6; RAGE, Receptor for advanced glycosylation end products; VEGF-D, Vascular endothelial growth factor D; KLK6, Kallikrein-6; IL16, Pro-interleukin-16; HGF, Hepatocyte growth factor; ESM-1, Endothelial cell-specific molecule 1; VEGF-A, Vascular endothelial growth factor A; LEP, Leptin; FGF-23, Fibroblast growth factor 23; Gal-3, Galectin-3; MMP-7, Matrix metalloproteinase-7; TG, Triglycerides; T2D, Type 2 diabetes; IA, Intracranial aneurysm; HDL-C, High-density lipoprotein cholesterol; PULMHEART, Pulmonary heart disease, diseases of pulmonary circulation; INTRACRA, Nontraumatic intracranial haemmorrhage; HYPTENSHD, Hypertensive Heart Disease; HEARTFAIL, All-cause Heart Failure; FG, fasting glucose; AFL, atrial fibrillation and flutter; PAROXTAC, Paroxysmal tachycardia; CONDUCTION, Conduction disorders; AVBLOCK, AV-block; AF, Atrial fibrillation; CORATHER, Coronary atherosclerosis; CHD, Major coronary heart disease event; MI, myocardial infarction; UAP, Unstable angina pectoris; ANGINA, Angina pectoris; CAD, coronary artery disease; STR_SAH, Stroke, including SAH; CES, Cardioembolic stroke; AS, Any stroke; AIS, Ischemic stroke; PAD, Peripheral artery disease; VTE, Venous thromboembolism; PULMEMB, Pulmonary embolism; PHLETHROMBDVTLOW, DVT of lower extremities; PHLETHROM, Phlebitis and thrombophlebitis (not including DVT); DVTANDPULM, DVT of lower extremities and pulmonary embolism; ATHSCLE, Atherosclerosis, excluding cerebral, coronary and PAD; AORTANEUR, Aortic aneurysm.