Genetically proxied impaired GIPR signaling and risk of 6 cancers

Miranda Rogers; Dipender Gill; Emma Ahlqvist; Tim Robinson; Daniela Mariosa; Mattias Johansson; Ricardo Cortez Cardoso Penha; Laure Dossus; Marc J Gunter; Victor Moreno; George Davey Smith; Richard M Martin; James Yarmolinsky

doi:10.1016/j.isci.2023.106848

Genetically proxied impaired GIPR signaling and risk of 6 cancers

iScience. 2023 May 9;26(6):106848. doi: 10.1016/j.isci.2023.106848. eCollection 2023 Jun 16.

Authors

Miranda Rogers^{1

2}, Dipender Gill^{3

4}, Emma Ahlqvist⁵, Tim Robinson^{1

2}, Daniela Mariosa⁶, Mattias Johansson⁶, Ricardo Cortez Cardoso Penha⁶, Laure Dossus⁷, Marc J Gunter⁷, Victor Moreno^{8

9

10

11}, George Davey Smith^{1

2}, Richard M Martin^{1

2

12}, James Yarmolinsky^{1

2}

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, BS8 2BN Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2PS Bristol, UK.
³ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, W2 1PG London, UK.
⁴ Chief Scientific Office, Research and Early Development, Novo Nordisk, 2300 Copenhagen, Denmark.
⁵ Department of Clinical Sciences, Lund University, Lund, 22362 Malmö, Sweden.
⁶ Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), 69007 Lyon, France.
⁷ Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), 69007 Lyon, France.
⁸ Biomarkers and Susceptibility Unit, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
⁹ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute(IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁰ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
¹¹ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, 08036 Barcelona, Spain.
¹² University Hospitals Bristol and Weston NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, BS8 2BN Bristol, UK.

Abstract

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.

Keywords: Cancer; Genetics; Health sciences.

Abstract

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