Genetically Proxied GIP ‐ GIPR Pathway Perturbation and Fracture Risk

AIMS: To determine whether genetic proxies for incretin pathway perturbation are associated with fracture risk and bone mineral density, providing human genetic evidence relevant to the skeletal safety of incretin-based therapies. MATERIALS AND METHODS: lower BMI or 1 mmol/mol lower HbA1c. Outcomes included fractures at major osteoporotic sites, combined spine-and-hip fractures, site-specific fractures and estimated bone mineral density (eBMD). We compared these estimates with genome-wide liability to lower BMI or HbA1c to contextualise the fracture associations observed for the target-proximal instruments. We used Cox models to estimate time-to-fracture associations per SD of target genetic risk score aligned to lower BMI or HbA1c. RESULTS: GIP-GIPR perturbation was associated with lower odds of fractures at major osteoporotic sites when scaled to lower BMI (OR 0.80, 95% CI 0.66-0.98) or lower HbA1c. Associations were similar for combined spine-and-hip fractures under both scaling approaches (OR 0.68, 0.49-0.94). Genome-wide liability to lower BMI or HbA1c did not show the same fracture associations as GIP-GIPR perturbation. GCG-GLP1R estimates were imprecise. Genetically proxied incretin pathway perturbation was not associated with eBMD. In Cox analyses, GIP-GIPR genetic risk score was associated with lower risk of fractures at major osteoporotic sites (HR 0.976, 0.959-0.992) and combined spine-and-hip fractures (HR 0.971, 0.946-0.996). CONCLUSIONS: Human genetic evidence suggests an association between genetically proxied GIP-GIPR pathway perturbation and lower fracture risk, supporting fracture-focused evaluation of GIPR-targeting therapies in clinical and post-marketing studies.