{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:55:58Z","timestamp":1790744158483,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014653","name":"Manchester Biomedical Research Centre","doi-asserted-by":"publisher","award":["NIHR203308"],"award-info":[{"award-number":["NIHR203308"]}],"id":[{"id":"10.13039\/100014653","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","award":["21173"],"award-info":[{"award-number":["21173"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","award":["21754"],"award-info":[{"award-number":["21754"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","award":["21755"],"award-info":[{"award-number":["21755"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>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\u2010based therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      We conducted drug\u2010target Mendelian randomisation using cis genetic variants near GIP, GIPR, GCG, GLP1R in 401\u2009983 unrelated UK Biobank participants. Instruments were scaled to 1\u2009kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      lower BMI or 1\u2009mmol\/mol lower HbA1c. Outcomes included fractures at major osteoporotic sites, combined spine\u2010and\u2010hip fractures, site\u2010specific fractures and estimated bone mineral density (eBMD). We compared these estimates with genome\u2010wide liability to lower BMI or HbA1c to contextualise the fracture associations observed for the target\u2010proximal instruments. We used Cox models to estimate time\u2010to\u2010fracture associations per SD of target genetic risk score aligned to lower BMI or HbA1c.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>GIP\u2010GIPR perturbation was associated with lower odds of fractures at major osteoporotic sites when scaled to lower BMI (OR 0.80, 95% CI 0.66\u20130.98) or lower HbA1c. Associations were similar for combined spine\u2010and\u2010hip fractures under both scaling approaches (OR 0.68, 0.49\u20130.94). Genome\u2010wide liability to lower BMI or HbA1c did not show the same fracture associations as GIP\u2010GIPR perturbation. GCG\u2010GLP1R estimates were imprecise. Genetically proxied incretin pathway perturbation was not associated with eBMD. In Cox analyses, GIP\u2010GIPR genetic risk score was associated with lower risk of fractures at major osteoporotic sites (HR 0.976, 0.959\u20130.992) and combined spine\u2010and\u2010hip fractures (HR 0.971, 0.946\u20130.996).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Human genetic evidence suggests an association between genetically proxied GIP\u2010GIPR pathway perturbation and lower fracture risk, supporting fracture\u2010focused evaluation of GIPR\u2010targeting therapies in clinical and post\u2010marketing studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71378","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:49:17Z","timestamp":1790740157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetically Proxied\n                    <scp>GIP<\/scp>\n                    \u2010\n                    <scp>GIPR<\/scp>\n                    Pathway Perturbation and Fracture Risk"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0999-0934","authenticated-orcid":false,"given":"Wenjie","family":"Cheng","sequence":"first","affiliation":[{"name":"Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health The University of Manchester, Manchester Academic Health Science Centre  Manchester UK"},{"name":"Dermatology Center Xinhua Hospital, Shanghai Jiaotong University School of Medicine  Shanghai Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Liu","sequence":"additional","affiliation":[{"name":"Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health The University of Manchester, Manchester Academic Health Science Centre  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3510-8241","authenticated-orcid":false,"given":"Jie","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics, Xiangya School of Public Health Central South University  Changsha Hunan China"},{"name":"Health Management Center Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0128-0062","authenticated-orcid":false,"given":"Houchen","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Chinese PLA General Hospital  Beijing Beijing China"},{"name":"National Clinical Research Center for Orthopedics and Sports Medicine The Chinese PLA General Hospital  Beijing Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sizheng Steven","family":"Zhao","sequence":"additional","affiliation":[{"name":"Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health The University of Manchester, Manchester Academic Health Science Centre  Manchester UK"},{"name":"NIHR Manchester Biomedical Research Centre Manchester University NHS Foundation Trust  Manchester 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