. 2023 Aug;66(8):1481-1500.

doi: 10.1007/s00125-023-05925-4. Epub 2023 May 12.

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis

James Yarmolinsky^#^{1

2}, Emmanouil Bouras^#³, Andrei Constantinescu^{4

5}, Kimberley Burrows^{4

5}, Caroline J Bull^{4

5

6}, Emma E Vincent^{4

5

6}, Richard M Martin^{4

5

7}, Olympia Dimopoulou^{4

5}, Sarah J Lewis^{4

5}, Victor Moreno^{8

9

10

11}, Marijana Vujkovic^{12

13}, Kyong-Mi Chang^{12

13}, Benjamin F Voight^{12

14

15

16}, Philip S Tsao^{17

18

19}, Marc J Gunter²⁰, Jochen Hampe²¹, Andrew J Pellatt²², Paul D P Pharoah²³, Robert E Schoen²⁴, Steven Gallinger²⁵, Mark A Jenkins²⁶, Rish K Pai²⁷; PRACTICAL consortium; VA Million Veteran Program; Dipender Gill²⁸, Kostas K Tsilidis^{3

28}

Collaborators, Affiliations

Collaborators

Rosalind A Eeles, Christopher A Haiman, Zsofia Kote-Jarai, Fredrick R Schumacher, Sara Benlloch, Ali Amin Al Olama, Kenneth Muir, Sonja I Berndt, David V Conti, Fredrik Wiklund, Stephen Chanock, Ying Wang, Victoria L Stevens, Catherine M Tangen, Jyotsna Batra, Judith A Clements, Henrik Grönberg, Nora Pashayan, Johanna Schleutker, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Catharine M L West, Lorelei A Mucci, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sørensen, Eli Marie Grindedal, David E Neal, Freddie C Hamdy, Jenny L Donovan, Ruth C Travis, Robert J Hamilton, Sue Ann Ingles, Barry S Rosenstein, Yong-Jie Lu, Graham G Giles, Adam S Kibel, Ana Vega, Manolis Kogevinas, Kathryn L Penney, Jong Y Park, Janet L Stanford, Cezary Cybulski, Børge G Nordestgaard, Sune F Nielsen, Hermann Brenner, Christiane Maier, Jeri Kim, Esther M John, Manuel R Teixeira, Susan L Neuhausen, Kim De Ruyck, Azad Razack, Lisa F Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A Townsend, Jose Esteban Castelao, Monique J Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Stephen N Thibodeau, David J Hunter, Peter Kraft, William J Blot, Elio Riboli

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. james.yarmolinsky@bristol.ac.uk.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. james.yarmolinsky@bristol.ac.uk.
³ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁶ School of Translational Health Sciences, University of Bristol, Bristol, UK.
⁷ NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
⁸ Biomarkers and Susceptibility Unit, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
⁹ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁰ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
¹¹ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
¹² Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
¹³ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ VA Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
²¹ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
²² University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²³ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁴ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
²⁵ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
²⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
²⁷ Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
²⁸ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK.

^# Contributed equally.

PMID: 37171501
PMCID: PMC10317892
DOI: 10.1007/s00125-023-05925-4

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis

James Yarmolinsky et al. Diabetologia. 2023 Aug.

. 2023 Aug;66(8):1481-1500.

doi: 10.1007/s00125-023-05925-4. Epub 2023 May 12.

Authors

Collaborators

Rosalind A Eeles, Christopher A Haiman, Zsofia Kote-Jarai, Fredrick R Schumacher, Sara Benlloch, Ali Amin Al Olama, Kenneth Muir, Sonja I Berndt, David V Conti, Fredrik Wiklund, Stephen Chanock, Ying Wang, Victoria L Stevens, Catherine M Tangen, Jyotsna Batra, Judith A Clements, Henrik Grönberg, Nora Pashayan, Johanna Schleutker, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Catharine M L West, Lorelei A Mucci, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sørensen, Eli Marie Grindedal, David E Neal, Freddie C Hamdy, Jenny L Donovan, Ruth C Travis, Robert J Hamilton, Sue Ann Ingles, Barry S Rosenstein, Yong-Jie Lu, Graham G Giles, Adam S Kibel, Ana Vega, Manolis Kogevinas, Kathryn L Penney, Jong Y Park, Janet L Stanford, Cezary Cybulski, Børge G Nordestgaard, Sune F Nielsen, Hermann Brenner, Christiane Maier, Jeri Kim, Esther M John, Manuel R Teixeira, Susan L Neuhausen, Kim De Ruyck, Azad Razack, Lisa F Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A Townsend, Jose Esteban Castelao, Monique J Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Stephen N Thibodeau, David J Hunter, Peter Kraft, William J Blot, Elio Riboli

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. james.yarmolinsky@bristol.ac.uk.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. james.yarmolinsky@bristol.ac.uk.
³ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁶ School of Translational Health Sciences, University of Bristol, Bristol, UK.
⁷ NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
⁸ Biomarkers and Susceptibility Unit, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
⁹ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁰ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
¹¹ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
¹² Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
¹³ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ VA Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
²¹ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
²² University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²³ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁴ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
²⁵ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
²⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
²⁷ Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
²⁸ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK.

^# Contributed equally.

PMID: 37171501
PMCID: PMC10317892
DOI: 10.1007/s00125-023-05925-4

Abstract

Aims/hypothesis: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk.

Methods: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10^-8) SNPs permitted to be in weak linkage disequilibrium (r²<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence.

Results: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA_1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10^-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints.

Conclusions/interpretation: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis.

Data availability: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Keywords: ABCC8; Breast cancer; Colorectal cancer; GLP1R; Glucose-lowering drug targets; Mendelian randomisation; PPARG; Prostate cancer.

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Figures

**Fig. 1**
Regional Manhattan plot of associations of SNPs with type 2 diabetes ±500 kb from the *PPARG* locus. rs17036160 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *PPARG* locus

**Fig. 2**
Regional Manhattan plot of associations of SNPs with ALT concentrations ±500 kb from the *PPARG* locus. rs17036160 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *PPARG* locus. SNPs in unclear linkage disequilibrium with sentinel SNP are in grey

**Fig. 3**
Regional Manhattan plot of associations of SNPs with AST concentrations ±500 kb from the *PPARG* locus. rs17036160 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *PPARG* locus

**Fig. 4**
Regional Manhattan plot of associations of SNPs with type 2 diabetes ±500 kb from the *ABCC8* locus. rs5219 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *ABCC8* locus

**Fig. 5**
Regional Manhattan plot of associations of SNPs with BMI ±500 kb from the *ABCC8* locus. rs5219 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *ABCC8* locus

**Fig. 6**
Regional Manhattan plot of associations of SNPs with type 2 diabetes ±500 kb from the *GLP1R* locus. rs10305420 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *GLP1R* locus

**Fig. 7**
Regional Manhattan plot of associations of SNPs with BMI ±500 kb from the *GLP1R* locus. rs10305420 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *GLP1R* locus

**Fig. 8**
Regional Manhattan plot of associations of SNPs with prostate cancer risk ±500 kb from the *PPARG* locus. rs17036160 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *PPARG* locus

**Fig. 9**
Regional Manhattan plot of associations of SNPs with ER⁺ breast cancer risk ±500 kb from the *PPARG* locus. rs17036160 (purple dot) represents the sentinel SNP associated with genetic liability to type 2 diabetes in the *PPARG* locus

See this image and copyright information in PMC

References

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Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis

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Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis

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