Genetically Proxied GIP-GIPR Pathway Perturbation and Fracture Risk

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.

We conducted drug-target Mendelian randomisation using cis genetic variants near GIP, GIPR, GCG, GLP1R in 401 983 unrelated UK Biobank participants. Instruments were scaled to 1 kg/m² 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.

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).

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.