Assessing the Independent and Joint Effects of GLP1R and GIPR on Liver Fat and BMI Using Mendelian Randomization

Metabolic dysfunction-associated steatotic liver disease (MASLD) occurs when extra fat accumulates in liver cells and is strongly linked to obesity and type 2 diabetes (T2D). While the FDA recently approved the first dual GLP1R/GIPR agonist (Tirzepatide) for T2D and obesity, the long-term genetic signaling through these pathways on MASLD is unclear. This study evaluated how naturally higher expression of GLP1R and GIPR affects liver fat and body weight in European populations, along with their combined effect using Mendelian randomization (MR) and multivariable MR. Cis-eQTLs for GLP1R and GIPR expression were obtained from eQTLGen and then clumped (r² < 0.001, 10,000 kb), used as instruments. Summary statistics on liver fat were extracted from the GWAS Catalog and the GIANT Consortium for BMI, serving as the outcomes. Data analysis was conducted with R packages TwoSampleMR and MVMR, using inverse-variance weighted MR. Result: Dual targeting of GLP1R/GIPR revealed a stronger positive effect of GIPR gene expression on liver fat compared to GLP1R alone (GLP1R: β = 0.0074, p = 0.595; GIPR: β = 0.121, p = 0.094), suggesting that GIPR antagonists may further reduce liver fat alongside GLP1R agonists. As for BMI, genetic evidence aligned with Tirzepatide clinical trial results, effectively lowering blood sugar and body weight loss (GLP1R: β = –0.098, p = 0.289; GIPR: β = –0.0009, p = 0.0118). Viewing this dual target through a genetics lens, unbiased evidence underscores its therapeutic potential to reduce body weight and mitigate MASLD.