Mendelian Randomization analyses between body mass index and atrioventricular block: underweight is a risky state

Abstract Background Atrioventricular block (AVB) is a prevalent cardiac conduction disorder among the elderly population. Body mass index (BMI) is a crucial indicator of nutritional status, and underweight individuals face elevated risks of various health conditions, including cardiovascular diseases. Previous observational studies have reported an association between BMI and AVB risk, but causality remains uncertain due to potential confounding factors and reverse causation. Methods To investigate the causal relationship between BMI and AVB risk, we employed a Two-Sample Mendelian Randomization (TSMR) approach, utilizing data from two independent Genome-Wide Association Studies (GWAS). We obtained genetic variants associated with BMI from a meta-analysis comprising 694,649 individuals of European descent and AVB summary statistics from the FinnGen project, including 5536 AVB cases and 286109 controls of European ancestry. We selected instrumental variables (IVs) for BMI based on strict criteria and validated their strength through F statistics. In our study, Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, and Simple Mode were used for causal relationship analysis. Results Our TSMR analysis, using the inverse variance weighted (IVW) method, revealed a significant negative causal effect of BMI on AVB risk. One standard deviation genetically determined rise in BMI was associated with a 38% reduction in relative AVB risk (N = 373 SNPs; OR = 0.62; 95% CI = 0.53–0.73; p = 3.74 × 10 − 9). Supplementary analyses using MR-Egger regression, weighted mode, simple mode, and weighted median provided consistent support for these findings. Conclusions Our study supports the genetic causality between lower BMI and increased AVB risk, indicating that maintaining a healthy BMI is crucial, especially for individuals who are underweight. These findings may help unravel the underlying mechanisms linking BMI and AVB, potentially contributing to improved prevention and management strategies for this cardiac disorder.