Obesity, Visceral Adipose Tissue, and Essential Hypertension: Evidence From a Mendelian Randomization Study and Mediation Analysis

Abstract

This study aims to investigate the causal relationship between obesity and essential hypertension, and evaluate the mediation effect of visceral adipose tissue (VAT) by Mendelian randomization (MR) analysis. We included body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), WC adjusted for BMI (WCadjbmi), and WHR adjusted for BMI (WHRadjbmi) as obesity-related anthropometric traits. In the bidirectional MR analyses, we found that higher BMI (OR, 1.638; p = 3.97 × 10^-19), WC (OR, 1.702; p = 1.45 × 10^-12), and WHR (OR, 1.863; p = 1.84 × 10^-8) were significantly associated with increased risk of essential hypertension, while no evidence of reverse causality was observed. Then, in the two-step MR analyses, all five anthropometric traits had a positive and significant association with VAT mass, especially WC (OR, 2.315; p = 1.00 × 10^-210). Meanwhile, higher predicted VAT mass was significantly associated with increased risk of essential hypertension (OR, 1.713; p = 1.18 × 10^-38). Furthermore, the mediation analyses revealed that VAT had a significant mediation effect on the causal relationship between obesity-related anthropometric traits and essential hypertension, and mediated proportions in BMI, WC, and WHR were 77.8%, 80.1%, and 41.4%, respectively. Finally, the sensitivity analyses using two other datasets showed a similar result. In conclusion, our results showed that BMI, WC, and WHR have a positive and significant association with increased risk of essential hypertension. Moreover, VAT has a significant mediation effect on the causal relationship between obesity-related anthropometric traits and essential hypertension. Our study provided important statistical evidence suggesting that VAT may play a crucial meditation role in the occurrence and development of obesity-related hypertension.

Keywords: Mendelian randomization; body mass index; essential hypertension; mediation analysis; obesity; visceral adipose tissue; waist circumference; waist‐hip ratio.

FIGURE 1

The flow chart of our study design. DF11, data freeze 11; GCST, GWAS catalog study; GIANT, The Genetic Investigation of ANthropometric Traits; GWAS, genome‐wide association study; IVW, inverse‐variance weighted; MR, Mendelian randomization; MR‐PRESSO, Mendelian randomization‐pleiotropy residual sum and outlier; VAT, Visceral adipose tissue.

FIGURE 2

The mediation triangle of obesity‐related anthropometric traits, VAT, and essential hypertension. The causal effect is presented as the beta‐value of the MR‐PRESSO results or the IVW results when there were no outliers detected. The mediation effect of VAT was estimated using “Rmediation” package with “Distribution of the Product” method, and the mediated proportion was calculated as “a*b”–“c.” BMI, body mass index; IVW, inverse‐variance weighted; MR‐PRESSO, Mendelian randomization‐pleiotropy residual sum and outlier; VAT, visceral adipose tissue; WC, waist circumference; WHR, waist‐hip ratio.

FIGURE 3

The bidirectional MR analyses for the associations of obesity‐related anthropometric traits with essential hypertension. (A) The two‐sample MR analyses for the causal effect of anthropometric traits on essential hypertension and (B) The two‐sample MR analyses for the causal effect of essential hypertension on anthropometric traits. The IVW method was set as the primary method, while MR‐Egger and MR‐PRESSO methods set as the complementary methods. BMI, body mass index; CI, confidence interval; HTN, hypertension; IVW, inverse‐variance weighted; MR, Mendelian randomization; MR‐PRESSO, Mendelian randomization‐pleiotropy residual sum and outlier; OR, odds ratio; SNP, single‐nucleotide polymorphism; WC, waist circumference; WCadjbmi, WC adjusted for BMI; WHR, waist‐hip ratio; WHRadjbmi, WHR adjusted for BMI.

FIGURE 4

The two‐step MR analyses for the associations among obesity‐related anthropometric traits, VAT, and essential hypertension. (A) The two‐sample MR analyses for the causal effect of anthropometric traits on VAT; (B) The two‐sample MR analyses for the causal effect of VAT on essential hypertension. The IVW method was set as the primary method, while the MR‐PRESSO method was set as the complementary method. “‐” indicates that no outlier was detected and the result of the MR‐PRESSO method was the same as the IVW method. BMI, body mass index; CI, confidence interval; HTN, hypertension; IVW, inverse‐variance weighted; MR, Mendelian randomization; MR‐PRESSO, Mendelian randomization‐pleiotropy residual sum and outlier; OR, odds ratio; SNP, single‐nucleotide polymorphism; VAT, visceral adipose tissue; WC, waist circumference; WCadjbmi, WC adjusted for BMI; WHR, waist‐hip ratio; WHRadjbmi, WHR adjusted for BMI.

FIGURE 5

Sensitivity analyses using two different datasets of obesity‐related anthropometric traits. (A) The two‐sample MR analyses for the causal effect of anthropometric traits on essential hypertension; (B) The two‐sample MR analyses for the causal effect of anthropometric traits on VAT. The IVW method was set as the primary method, while MR‐Egger and MR‐PRESSO methods set as the complementary methods. “‐” indicates that no outlier was detected and the result of the MR‐PRESSO method was the same as the IVW method. BMI, body mass index; CI, confidence interval; HTN, hypertension; IVW, inverse‐variance weighted; MR, Mendelian randomization; MR‐PRESSO, Mendelian randomization‐pleiotropy residual sum and outlier; OR, odds ratio; SNP, single‐nucleotide polymorphism; VAT, visceral adipose tissue; WC, waist circumference; WCadjbmi, WC adjusted for BMI; WHR, waist‐hip ratio; WHRadjbmi, WHR adjusted for BMI.