Genetically proxied impaired GIPR signaling and risk of 6 cancers

Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of...

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Published in:iScience 2023-06, Vol.26 (6), p.106848, Article 106848
Main Authors: Rogers, Miranda, Gill, Dipender, Ahlqvist, Emma, Robinson, Tim, Mariosa, Daniela, Johansson, Mattias, Cortez Cardoso Penha, Ricardo, Dossus, Laure, Gunter, Marc J., Moreno, Victor, Davey Smith, George, Martin, Richard M., Yarmolinsky, James
Format: Article
Language:English
Subjects:
Cancer
Cancer and Oncology
Cancer och onkologi
Clinical Medicine
Genetics
Health sciences
Klinisk medicin
Medical and Health Sciences
Medicin och hälsovetenskap
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Summary:Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention. [Display omitted] •GIPR signaling may influence cancer risk•We tested the effect of a functional variant in GIPR (E354Q) on risk of 6 cancers•E354Q was associated with increased risk of overall and luminal A-like breast cancer•Further evaluation of GIPR signaling in breast cancer prevention is warranted Health sciences; Genetics; Cancer
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.106848