Natural variation in the genes that encode protein drug targets can offer insight into mechanism-based efficacy and safety.14 Such genetic instrumental variable analysis, or Mendelian randomization (MR), is more robust against confounding than traditional epidemiologic designs.15 Since genetic variants are randomly allocated at conception, MR can be conceptualized as a quasi-randomized natural experiment comparing NAFLD risk according to levels of genetically proxied SGLT-1 activity. This evidence concerns the gene SLC5A1 and metabolic dysfunction-associated steatotic liver disease.