Genetically Proxied GIP-GIPR Pathway Perturbation and Fracture Risk.

Authors

Wenjie Cheng, Weijie Liu, Jie Wei, Chao Zeng, Houchen Lyu, Sizheng Steven Zhao

Published in

Diabetes, obesity & metabolism. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

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.

PMID:
42811415
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.