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.
Highlights
Obesity is an established risk factor of cardiovascular disease (CVD) (Powell-Wiley et al, 2021)
We assessed the impact of visceral adiposity on metabolic risk factors including lipid profile (HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), TG), blood pressure (SBP, DBP), glycemic traits, and T2D (Figure 1)
In primary inverse variance–weighted (IVW) analysis, genetically predicted increased visceral adipose tissue (VAT) mass was associated with decreased high-density lipoprotein cholesterol (HDL-C), increased TG (OR, 1.263; 95% CI, 1.203–1.326; p = 5.7e−21), increased T2D (OR, 2.397; 95% CI, 1.965–2.923; p = 6.1e−18), increased fasting glucose (OR, 1.079; 95% CI, 1.046–1.113; p = 1.5e−6), increased fasting insulin (OR, 1.194; 95% CI, 1.16–1.229; p = 2.2e−33), and increased insulin resistance (OR, 1.204; 95% CI, 1.16–1.25; p = 1.5e−22)
Summary
Obesity is an established risk factor of cardiovascular disease (CVD) (Powell-Wiley et al, 2021). Some epidemiological studies revealed the protective effect of obesity, classified by body mass index (BMI), on CVD outcomes and questioned the nature of the relationship between obesity and CVDs (Antonopoulos et al, 2016a). This paradoxical phenomenon, known as the “obesity paradox” or “BMI paradox,” indicates that BMI or other general adiposity measurements cannot assess the actual metabolic status and body fat distribution. The associations between VAT area, measured by bioelectrical impedance analysis (BIA), and metabolic risk factors were observed among obese and non-obese participants (Tatsumi et al, 2017)
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