Genetically proxied impaired GIPR signaling and risk of 6 cancers

Miranda Rogers; Tim Robinson; 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

Miranda Rogers, Tim Robinson, George Davey Smith, Richard M Martin, James Yarmolinsky^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

3 Citations (Scopus)

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.

Original language	English
Article number	106848
Journal	iScience
Volume	26
Issue number	6
Early online date	9 May 2023
DOIs	https://doi.org/10.1016/j.isci.2023.106848
Publication status	Published - 16 Jun 2023

Bibliographical note

Funding Information:
The breast cancer genome-wide association analyses for BCAC and CIMBA were supported by Cancer Research UK ( PPRPGM-Nov20\100002 , C1287/A10118 , C1287/A16563 , C1287/A10710 , C12292/A20861 , C12292/A11174 , C1281/A12014 , C5047/A8384 , C5047/A15007 , C5047/A10692 , C8197/A16565 ) and the Gray Foundation , The National Institutes of Health ( CA128978 , X01HG007492 -the DRIVE consortium ), the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344 ) and the Ministère de l’Économie , Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, the Quebec Breast Cancer Foundation , the European Community's Seventh Framework Programme under grant agreement n° 223175 ( HEALTH-F2-2009-223175 ) (COGS), the European Union's Horizon 2020 Research and Innovation Programme ( 634935 and 633784 ), the Post-Cancer GWAS initiative ( U19 CA148537 , CA148065 and CA148112 - the GAME-ON initiative ), the Department of Defence ( W81XWH-10-1-0341 ), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer ( CRN-87521 ), the Komen Foundation for the Cure , the Breast Cancer Research Foundation , and the Ovarian Cancer Research Fund. All studies and funders are listed in Zhang H et al. (Nat Genet, 2020).

Funding Information:
Funding: G.D.S., R.M.M., and J.Y. are supported by Cancer Research UK ( C18281/A29019 ) program grant (the Integrative Cancer Epidemiology Programme ). G.D.S., R.M.M., and J.Y. are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council ( MC_UU_00011/1 , MC_UU_00011/3 , MC_UU_00011/6 , and MC_UU_00011/4 ) and the University of Bristol . J.Y. is supported by a Cancer Research UK Population Research Postdoctoral Fellowship ( C68933/A28534 ). R.M.M. is also supported by the NIHR Bristol Biomedical Research Centre ( BRC-1215-20011 ) which is funded by the NIHR and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol . R.M.M. is a National Institute for Health Research Senior Investigator ( NIHR202411 ). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. T.R. is supported by a National Institute of Health Research Development and Skills Enhancement Award ( NIHR302363 ). M.R. is an Academic Foundation Doctor in the Severn Foundation School. E.A. was funded by the Swedish Research Council ( 2020-02191 ). Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization.

Funding Information:
The authors would like to thank the participants of the individual studies contributing to the BCAC, CIMBA, GECCO, CORECT, CCFR, ILCCO, PANC4, MAGIC, DIAGRAM, and GIANT consortia and the UK Biobank and FinnGen study. The authors would also like to acknowledge the investigators of these consortia and studies for generating the data used for this analysis. Summary genetic association data for cancer included data from the following consortia: Breast Cancer Association Consortium (BCAC), Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), UK Biobank, the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Cancer Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), the International Lung Cancer Consortium (ILCCO), the Pancreatic Cancer Cohort Consortium (PanScan), and the Pancreatic Cancer Case-Control Consortium (PanC4). The breast cancer genome-wide association analyses for BCAC and CIMBA were supported by Cancer Research UK (PPRPGM-Nov20\100002, C1287/A10118, C1287/A16563, C1287/A10710, C12292/A20861, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565) and the Gray Foundation, The National Institutes of Health (CA128978, X01HG007492-the DRIVE consortium), the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, the Quebec Breast Cancer Foundation, the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), the European Union's Horizon 2020 Research and Innovation Programme (634935 and 633784), the Post-Cancer GWAS initiative (U19 CA148537, CA148065 and CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), the Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. All studies and funders are listed in Zhang H et al. (Nat Genet, 2020). The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. iCOGS: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. All studies and funders are listed in Milne et al. (Nat Genet, 2017) and Phelan et al. (Nat Genet, 2017). Funding: G.D.S. R.M.M. and J.Y. are supported by Cancer Research UK (C18281/A29019) program grant (the Integrative Cancer Epidemiology Programme). G.D.S. R.M.M. and J.Y. are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4) and the University of Bristol. J.Y. is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C68933/A28534). R.M.M. is also supported by the NIHR Bristol Biomedical Research Centre (BRC-1215-20011) which is funded by the NIHR and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. R.M.M. is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. T.R. is supported by a National Institute of Health Research Development and Skills Enhancement Award (NIHR302363). M.R. is an Academic Foundation Doctor in the Severn Foundation School. E.A. was funded by the Swedish Research Council (2020-02191). Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Conceptualization, J.Y. and R.M.M.; Methodology, J.Y. R.M.M. and D.G.; Investigation, M.R. and J.Y.; Writing – Original Draft, M.R. and J.Y.; Writing – Review & Editing, M.R. and J.Y.; Funding Acquisition, J.Y. and R.M.M.; Resources, E.A. M.J. R.C.C.P. L.D. M.G. and V.M.; Supervision, J.Y. and R.M. T.R. has received funding from Amgen and Daiichi-Sankyo to attend educational events unrelated to this work. All other authors declare no potential conflicts of interest. All other authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.

Funding Information:
The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 , C12292/A11174 . iCOGS: the European Community's Seventh Framework Programme under grant agreement n° 223175 ( HEALTH-F2-2009-223175 ) (COGS), Cancer Research UK ( C1287/A10118 , C1287/A 10710 , C12292/A11174 , C1281/A12014 , C5047/A8384 , C5047/A15007 , C5047/A10692 , C8197/A16565 ), the National Institutes of Health ( CA128978 ) and Post-Cancer GWAS initiative ( 1U19 CA148537 , 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative ), the Department of Defence ( W81XWH-10-1-0341 ), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer ( CRN-87521 ), and the Ministry of Economic Development , Innovation and Export Trade ( PSR-SIIRI-701 ), Komen Foundation for the Cure , the Breast Cancer Research Foundation , and the Ovarian Cancer Research Fund . The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research , the Ministry of Economy , Science and Innovation through Genome Québec , and The Quebec Breast Cancer Foundation . All studies and funders are listed in Milne et al. (Nat Genet, 2017) and Phelan et al. (Nat Genet, 2017).

Publisher Copyright:
© 2023 The Author(s)

Research Groups and Themes

ICEP
Bristol Population Health Science Institute

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.isci.2023.106848Licence: CC BY

Handle.net

Persistent link

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research
IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

@article{c86d241684014c7487e588f671c6d1a7,

title = "Genetically proxied impaired GIPR signaling and risk of 6 cancers",

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.",

author = "Miranda Rogers and Tim Robinson and \{Davey Smith\}, George and Martin, \{Richard M\} and James Yarmolinsky",

note = "Funding Information: The breast cancer genome-wide association analyses for BCAC and CIMBA were supported by Cancer Research UK ( PPRPGM-Nov20\textbackslash{}100002 , C1287/A10118 , C1287/A16563 , C1287/A10710 , C12292/A20861 , C12292/A11174 , C1281/A12014 , C5047/A8384 , C5047/A15007 , C5047/A10692 , C8197/A16565 ) and the Gray Foundation , The National Institutes of Health ( CA128978 , X01HG007492 -the DRIVE consortium ), the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344 ) and the Minist{\`e}re de l{\textquoteright}{\'E}conomie , Science et Innovation du Qu{\'e}bec through Genome Qu{\'e}bec and the PSRSIIRI-701 grant, the Quebec Breast Cancer Foundation , the European Community's Seventh Framework Programme under grant agreement n° 223175 ( HEALTH-F2-2009-223175 ) (COGS), the European Union's Horizon 2020 Research and Innovation Programme ( 634935 and 633784 ), the Post-Cancer GWAS initiative ( U19 CA148537 , CA148065 and CA148112 - the GAME-ON initiative ), the Department of Defence ( W81XWH-10-1-0341 ), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer ( CRN-87521 ), the Komen Foundation for the Cure , the Breast Cancer Research Foundation , and the Ovarian Cancer Research Fund. All studies and funders are listed in Zhang H et al. (Nat Genet, 2020). Funding Information: Funding: G.D.S., R.M.M., and J.Y. are supported by Cancer Research UK ( C18281/A29019 ) program grant (the Integrative Cancer Epidemiology Programme ). G.D.S., R.M.M., and J.Y. are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council ( MC\_UU\_00011/1 , MC\_UU\_00011/3 , MC\_UU\_00011/6 , and MC\_UU\_00011/4 ) and the University of Bristol . J.Y. is supported by a Cancer Research UK Population Research Postdoctoral Fellowship ( C68933/A28534 ). R.M.M. is also supported by the NIHR Bristol Biomedical Research Centre ( BRC-1215-20011 ) which is funded by the NIHR and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol . R.M.M. is a National Institute for Health Research Senior Investigator ( NIHR202411 ). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. T.R. is supported by a National Institute of Health Research Development and Skills Enhancement Award ( NIHR302363 ). M.R. is an Academic Foundation Doctor in the Severn Foundation School. E.A. was funded by the Swedish Research Council ( 2020-02191 ). Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: The authors would like to thank the participants of the individual studies contributing to the BCAC, CIMBA, GECCO, CORECT, CCFR, ILCCO, PANC4, MAGIC, DIAGRAM, and GIANT consortia and the UK Biobank and FinnGen study. The authors would also like to acknowledge the investigators of these consortia and studies for generating the data used for this analysis. Summary genetic association data for cancer included data from the following consortia: Breast Cancer Association Consortium (BCAC), Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), UK Biobank, the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Cancer Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), the International Lung Cancer Consortium (ILCCO), the Pancreatic Cancer Cohort Consortium (PanScan), and the Pancreatic Cancer Case-Control Consortium (PanC4). The breast cancer genome-wide association analyses for BCAC and CIMBA were supported by Cancer Research UK (PPRPGM-Nov20\textbackslash{}100002, C1287/A10118, C1287/A16563, C1287/A10710, C12292/A20861, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565) and the Gray Foundation, The National Institutes of Health (CA128978, X01HG007492-the DRIVE consortium), the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and the Minist{\`e}re de l{\textquoteright}{\'E}conomie, Science et Innovation du Qu{\'e}bec through Genome Qu{\'e}bec and the PSRSIIRI-701 grant, the Quebec Breast Cancer Foundation, the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), the European Union's Horizon 2020 Research and Innovation Programme (634935 and 633784), the Post-Cancer GWAS initiative (U19 CA148537, CA148065 and CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), the Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. All studies and funders are listed in Zhang H et al. (Nat Genet, 2020). The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. iCOGS: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Qu{\'e}bec, and The Quebec Breast Cancer Foundation. All studies and funders are listed in Milne et al. (Nat Genet, 2017) and Phelan et al. (Nat Genet, 2017). Funding: G.D.S. R.M.M. and J.Y. are supported by Cancer Research UK (C18281/A29019) program grant (the Integrative Cancer Epidemiology Programme). G.D.S. R.M.M. and J.Y. are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC\_UU\_00011/1, MC\_UU\_00011/3, MC\_UU\_00011/6, and MC\_UU\_00011/4) and the University of Bristol. J.Y. is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C68933/A28534). R.M.M. is also supported by the NIHR Bristol Biomedical Research Centre (BRC-1215-20011) which is funded by the NIHR and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. R.M.M. is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. T.R. is supported by a National Institute of Health Research Development and Skills Enhancement Award (NIHR302363). M.R. is an Academic Foundation Doctor in the Severn Foundation School. E.A. was funded by the Swedish Research Council (2020-02191). Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Conceptualization, J.Y. and R.M.M.; Methodology, J.Y. R.M.M. and D.G.; Investigation, M.R. and J.Y.; Writing – Original Draft, M.R. and J.Y.; Writing – Review \& Editing, M.R. and J.Y.; Funding Acquisition, J.Y. and R.M.M.; Resources, E.A. M.J. R.C.C.P. L.D. M.G. and V.M.; Supervision, J.Y. and R.M. T.R. has received funding from Amgen and Daiichi-Sankyo to attend educational events unrelated to this work. All other authors declare no potential conflicts of interest. All other authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 , C12292/A11174 . iCOGS: the European Community's Seventh Framework Programme under grant agreement n° 223175 ( HEALTH-F2-2009-223175 ) (COGS), Cancer Research UK ( C1287/A10118 , C1287/A 10710 , C12292/A11174 , C1281/A12014 , C5047/A8384 , C5047/A15007 , C5047/A10692 , C8197/A16565 ), the National Institutes of Health ( CA128978 ) and Post-Cancer GWAS initiative ( 1U19 CA148537 , 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative ), the Department of Defence ( W81XWH-10-1-0341 ), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer ( CRN-87521 ), and the Ministry of Economic Development , Innovation and Export Trade ( PSR-SIIRI-701 ), Komen Foundation for the Cure , the Breast Cancer Research Foundation , and the Ovarian Cancer Research Fund . The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research , the Ministry of Economy , Science and Innovation through Genome Qu{\'e}bec , and The Quebec Breast Cancer Foundation . All studies and funders are listed in Milne et al. (Nat Genet, 2017) and Phelan et al. (Nat Genet, 2017). Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jun,

day = "16",

doi = "10.1016/j.isci.2023.106848",

language = "English",

volume = "26",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier Inc.",

number = "6",

}

TY - JOUR

T1 - Genetically proxied impaired GIPR signaling and risk of 6 cancers

AU - Rogers, Miranda

AU - Robinson, Tim

AU - Davey Smith, George

AU - Martin, Richard M

AU - Yarmolinsky, James

N1 - Funding Information: The breast cancer genome-wide association analyses for BCAC and CIMBA were supported by Cancer Research UK ( PPRPGM-Nov20\100002 , C1287/A10118 , C1287/A16563 , C1287/A10710 , C12292/A20861 , C12292/A11174 , C1281/A12014 , C5047/A8384 , C5047/A15007 , C5047/A10692 , C8197/A16565 ) and the Gray Foundation , The National Institutes of Health ( CA128978 , X01HG007492 -the DRIVE consortium ), the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344 ) and the Ministère de l’Économie , Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, the Quebec Breast Cancer Foundation , the European Community's Seventh Framework Programme under grant agreement n° 223175 ( HEALTH-F2-2009-223175 ) (COGS), the European Union's Horizon 2020 Research and Innovation Programme ( 634935 and 633784 ), the Post-Cancer GWAS initiative ( U19 CA148537 , CA148065 and CA148112 - the GAME-ON initiative ), the Department of Defence ( W81XWH-10-1-0341 ), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer ( CRN-87521 ), the Komen Foundation for the Cure , the Breast Cancer Research Foundation , and the Ovarian Cancer Research Fund. All studies and funders are listed in Zhang H et al. (Nat Genet, 2020). Funding Information: Funding: G.D.S., R.M.M., and J.Y. are supported by Cancer Research UK ( C18281/A29019 ) program grant (the Integrative Cancer Epidemiology Programme ). G.D.S., R.M.M., and J.Y. are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council ( MC_UU_00011/1 , MC_UU_00011/3 , MC_UU_00011/6 , and MC_UU_00011/4 ) and the University of Bristol . J.Y. is supported by a Cancer Research UK Population Research Postdoctoral Fellowship ( C68933/A28534 ). R.M.M. is also supported by the NIHR Bristol Biomedical Research Centre ( BRC-1215-20011 ) which is funded by the NIHR and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol . R.M.M. is a National Institute for Health Research Senior Investigator ( NIHR202411 ). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. T.R. is supported by a National Institute of Health Research Development and Skills Enhancement Award ( NIHR302363 ). M.R. is an Academic Foundation Doctor in the Severn Foundation School. E.A. was funded by the Swedish Research Council ( 2020-02191 ). Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: The authors would like to thank the participants of the individual studies contributing to the BCAC, CIMBA, GECCO, CORECT, CCFR, ILCCO, PANC4, MAGIC, DIAGRAM, and GIANT consortia and the UK Biobank and FinnGen study. The authors would also like to acknowledge the investigators of these consortia and studies for generating the data used for this analysis. Summary genetic association data for cancer included data from the following consortia: Breast Cancer Association Consortium (BCAC), Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), UK Biobank, the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Cancer Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), the International Lung Cancer Consortium (ILCCO), the Pancreatic Cancer Cohort Consortium (PanScan), and the Pancreatic Cancer Case-Control Consortium (PanC4). The breast cancer genome-wide association analyses for BCAC and CIMBA were supported by Cancer Research UK (PPRPGM-Nov20\100002, C1287/A10118, C1287/A16563, C1287/A10710, C12292/A20861, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565) and the Gray Foundation, The National Institutes of Health (CA128978, X01HG007492-the DRIVE consortium), the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, the Quebec Breast Cancer Foundation, the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), the European Union's Horizon 2020 Research and Innovation Programme (634935 and 633784), the Post-Cancer GWAS initiative (U19 CA148537, CA148065 and CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), the Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. All studies and funders are listed in Zhang H et al. (Nat Genet, 2020). The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. iCOGS: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. All studies and funders are listed in Milne et al. (Nat Genet, 2017) and Phelan et al. (Nat Genet, 2017). Funding: G.D.S. R.M.M. and J.Y. are supported by Cancer Research UK (C18281/A29019) program grant (the Integrative Cancer Epidemiology Programme). G.D.S. R.M.M. and J.Y. are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4) and the University of Bristol. J.Y. is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C68933/A28534). R.M.M. is also supported by the NIHR Bristol Biomedical Research Centre (BRC-1215-20011) which is funded by the NIHR and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. R.M.M. is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. T.R. is supported by a National Institute of Health Research Development and Skills Enhancement Award (NIHR302363). M.R. is an Academic Foundation Doctor in the Severn Foundation School. E.A. was funded by the Swedish Research Council (2020-02191). Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Conceptualization, J.Y. and R.M.M.; Methodology, J.Y. R.M.M. and D.G.; Investigation, M.R. and J.Y.; Writing – Original Draft, M.R. and J.Y.; Writing – Review & Editing, M.R. and J.Y.; Funding Acquisition, J.Y. and R.M.M.; Resources, E.A. M.J. R.C.C.P. L.D. M.G. and V.M.; Supervision, J.Y. and R.M. T.R. has received funding from Amgen and Daiichi-Sankyo to attend educational events unrelated to this work. All other authors declare no potential conflicts of interest. All other authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 , C12292/A11174 . iCOGS: the European Community's Seventh Framework Programme under grant agreement n° 223175 ( HEALTH-F2-2009-223175 ) (COGS), Cancer Research UK ( C1287/A10118 , C1287/A 10710 , C12292/A11174 , C1281/A12014 , C5047/A8384 , C5047/A15007 , C5047/A10692 , C8197/A16565 ), the National Institutes of Health ( CA128978 ) and Post-Cancer GWAS initiative ( 1U19 CA148537 , 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative ), the Department of Defence ( W81XWH-10-1-0341 ), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer ( CRN-87521 ), and the Ministry of Economic Development , Innovation and Export Trade ( PSR-SIIRI-701 ), Komen Foundation for the Cure , the Breast Cancer Research Foundation , and the Ovarian Cancer Research Fund . The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research , the Ministry of Economy , Science and Innovation through Genome Québec , and The Quebec Breast Cancer Foundation . All studies and funders are listed in Milne et al. (Nat Genet, 2017) and Phelan et al. (Nat Genet, 2017). Publisher Copyright: © 2023 The Author(s)

PY - 2023/6/16

Y1 - 2023/6/16

N2 - 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.

AB - 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.

U2 - 10.1016/j.isci.2023.106848

DO - 10.1016/j.isci.2023.106848

M3 - Article (Academic Journal)

C2 - 37250804

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 6

M1 - 106848

ER -

Genetically proxied impaired GIPR signaling and risk of 6 cancers

Abstract

Bibliographical note

Research Groups and Themes

UN SDGs

Access to Document

Handle.net

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this