The causal relationships between body composition and heart failure: A two-sample mendelian randomization study

Abstract

Abstract The objective of this study was to assess the causal relationships between various body composition indicators, including body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and specific measures of fat mass (right arm, right leg, trunk, and whole-body fat mass) and fat-free mass, and the risk of heart failure (HF) using a two-sample Mendelian randomization (MR) approach. We used genome-wide significant single nucleotide polymorphisms (SNPs) related to body composition from the UK Biobank, GIANT, and FinnGen as instrumental variables. To estimate causal associations, we applied multiple methods, including inverse variance weighted (IVW), IVW with multiplicative random effects (IVW_mre), MR-PRESSO, and maximum likelihood. The results demonstrated that each standard deviation (SD) increase in BMI (OR = 1.48; 95% CI: 1.37–1.60; P = 1.24E-23), WC (OR = 1.60; 95% CI: 1.45–1.77; P = 1.72E-20), and WHR (OR = 1.25; 95% CI: 1.01–1.54; P = 3.70E-02) was significantly associated with increased HF risk. Comparable associations were observed for fat mass in the right arm (OR = 1.42; P = 6.60E-17), right leg (OR = 1.57; P = 5.80E-18), trunk (OR = 1.31; P = 3.02E-11), and the whole body (OR = 1.34; P = 2.24E-12). Fat-free mass—both whole-body (OR = 1.34; P = 4.77E-10) and regional measurements (right arm, right leg, trunk)—also exhibited positive associations with HF risk. Leave-one-out analyses confirmed the stability of these findings and underscored the significance of multiple body composition indicators in HF risk assessment and prevention.