Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis
Authors: Yarmolinsky James , Bouras Emmanouil , Constantinescu Andrei , Burrows Kimberley , Bull Caroline J. , Vincent Emma E. , Martin Richard M. , Dimopoulou Olympia , Lewis Sarah J. , Moreno Victor , Vujkovic Marijana , Chang Kyong-Mi , Voight Benjamin F. , Tsao Philip S. , Gunter Marc J. , Hampe Jochen , Pellatt Andrew J. , Pharoah Paul D. P. , Schoen Robert E. , Gallinger Steven , Jenkins Mark A. , Pai Rish K. ,   the PRACTICAL consortium, Eeles Rosalind A. , Haiman Christopher A. , Kote-Jarai Zsofia , Schumacher Fredrick R. , Benlloch Sara , Al Olama Ali Amin , Muir Kenneth , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen , Wang Ying , Stevens Victoria L. , Tangen Catherine M. , Batra Jyotsna , Clements Judith A. ,   APCB BioResource (Australian Prostate Cancer BioResource), Grönberg Henrik , Pashayan Nora , Schleutker Johanna , Albanes Demetrius , Weinstein Stephanie , Wolk Alicja , West Catharine M. L. , Mucci Lorelei A. , Cancel-Tassin Géraldine , Koutros Stella , Sørensen Karina Dalsgaard , Grindedal Eli Marie , Neal David E. , Hamdy Freddie C. , Donovan Jenny L. , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry S. , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Nielsen Sune F. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Castelao Jose Esteban , Roobol Monique J. , Menegaux Florence , Khaw Kay-Tee , Cannon-Albright Lisa , Pandha Hardev , Thibodeau Stephen N. , Hunter David J. , Kraft Peter , Blot William J. , Riboli Elio ,   VA Million Veteran Program, Gill Dipender , Tsilidis Kostas K. 
Published: May 2023

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 HbA1c: 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).

Graphical Abstract