Shiu Lun Au Yeung1, Shan Luo2, C Mary Schooling2,3. 1. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 7 Sassoon Road, Pokfulam, Hong Kong SAR, China. ayslryan@hku.hk. 2. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 7 Sassoon Road, Pokfulam, Hong Kong SAR, China. 3. Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA.
Abstract
AIMS/HYPOTHESIS: Growth differentiation factor 15 (GDF-15), a suggested biomarker for metformin use, may explain the potential cardioprotective and anti-cancer properties of metformin. We conducted a Mendelian randomisation study to examine the role of GDF-15 in risk of coronary artery disease (CAD) and breast and colorectal cancer. Secondary analyses included examination of the association of GDF-15 with type 2 diabetes, glycaemic traits, BP, lipids and BMI. METHODS: We obtained SNPs strongly (p value <5 × 10-8) predicting GDF-15 from a genome-wide association study (GWAS) (n = 5440) and applied them to genetic studies of CAD (CARDIoGRAMplusC4D 1000 Genomes-based GWAS [n = 184,305]), type 2 diabetes (DIAGRAM [DIAbetes Genetics Replication And Meta-analysis; n = 898,130]), glycaemic traits (MAGIC [the Meta-Analyses of Glucose and Insulin-related traits Consortium; HbA1c: n = 123,665; fasting glucose: n = 46,186]), BP, breast cancer and colorectal cancer (UK Biobank [n ≤ 401,447]), lipids (GLGC [Global Lipids Genetic Consortium; n ≤ 92,820]) and adiposity (GIANT [Genetic Investigation of ANthropometric Traits Consortium; n = 681,275]). Causal estimates were obtained using inverse variance weighting, taking into account correlations between SNPs. Sensitivity analyses included focusing on the lead SNP (rs888663) and validation for CAD in the UK Biobank and for breast cancer in the Breast Cancer Association Consortium. RESULTS: Using 5 SNPs, increased GDF-15 was associated with lower CAD (OR 0.93 per SD increase, 95% CI 0.87, 0.99) and breast cancer (OR 0.89 per SD increase, 95% CI 0.82, 0.96), with similar results from lead SNP analysis. However, the associations with CAD (OR 0.99 per SD increase, 95% CI 0.93, 1.04) and breast cancer (OR 0.97 per SD increase, 95% CI 0.94, 1.01) in the validation studies were not as apparent. GDF-15 was not associated with type 2 diabetes, glycaemic traits, CAD risk factors or colorectal cancer. CONCLUSIONS/ INTERPRETATION: There is no convincing evidence that GDF-15 reduces risk of CAD or breast or colorectal cancer. Whether the observed inverse association of metformin use with cancer risk is via other unexplored mechanistic pathways warrants further investigation.
RCT Entities:
AIMS/HYPOTHESIS: Growth differentiation factor 15 (GDF-15), a suggested biomarker for metformin use, may explain the potential cardioprotective and anti-cancer properties of metformin. We conducted a Mendelian randomisation study to examine the role of GDF-15 in risk of coronary artery disease (CAD) and breast and colorectal cancer. Secondary analyses included examination of the association of GDF-15 with type 2 diabetes, glycaemic traits, BP, lipids and BMI. METHODS: We obtained SNPs strongly (p value <5 × 10-8) predicting GDF-15 from a genome-wide association study (GWAS) (n = 5440) and applied them to genetic studies of CAD (CARDIoGRAMplusC4D 1000 Genomes-based GWAS [n = 184,305]), type 2 diabetes (DIAGRAM [DIAbetes Genetics Replication And Meta-analysis; n = 898,130]), glycaemic traits (MAGIC [the Meta-Analyses of Glucose and Insulin-related traits Consortium; HbA1c: n = 123,665; fasting glucose: n = 46,186]), BP, breast cancer and colorectal cancer (UK Biobank [n ≤ 401,447]), lipids (GLGC [Global Lipids Genetic Consortium; n ≤ 92,820]) and adiposity (GIANT [Genetic Investigation of ANthropometric Traits Consortium; n = 681,275]). Causal estimates were obtained using inverse variance weighting, taking into account correlations between SNPs. Sensitivity analyses included focusing on the lead SNP (rs888663) and validation for CAD in the UK Biobank and for breast cancer in the Breast Cancer Association Consortium. RESULTS: Using 5 SNPs, increased GDF-15 was associated with lower CAD (OR 0.93 per SD increase, 95% CI 0.87, 0.99) and breast cancer (OR 0.89 per SD increase, 95% CI 0.82, 0.96), with similar results from lead SNP analysis. However, the associations with CAD (OR 0.99 per SD increase, 95% CI 0.93, 1.04) and breast cancer (OR 0.97 per SD increase, 95% CI 0.94, 1.01) in the validation studies were not as apparent. GDF-15 was not associated with type 2 diabetes, glycaemic traits, CAD risk factors or colorectal cancer. CONCLUSIONS/ INTERPRETATION: There is no convincing evidence that GDF-15 reduces risk of CAD or breast or colorectal cancer. Whether the observed inverse association of metformin use with cancer risk is via other unexplored mechanistic pathways warrants further investigation.
Authors: Andrea Natali; Lorenzo Nesti; Elena Venturi; Angela C Shore; Faisel Khan; Kim Gooding; Phillip E Gates; Helen C Looker; Fiona Dove; Isabel Goncalves; Margaretha Persson; Jan Nilsson Journal: Diabetes Obes Metab Date: 2018-10-02 Impact factor: 6.577
Authors: Charlotte Andersson; Danielle Enserro; Lisa Sullivan; Thomas J Wang; James L Januzzi; Emelia J Benjamin; Joseph A Vita; Naomi M Hamburg; Martin G Larson; Gary F Mitchell; Ramachandran S Vasan Journal: Atherosclerosis Date: 2016-02-18 Impact factor: 5.162
Authors: Cathie Sudlow; John Gallacher; Naomi Allen; Valerie Beral; Paul Burton; John Danesh; Paul Downey; Paul Elliott; Jane Green; Martin Landray; Bette Liu; Paul Matthews; Giok Ong; Jill Pell; Alan Silman; Alan Young; Tim Sprosen; Tim Peakman; Rory Collins Journal: PLoS Med Date: 2015-03-31 Impact factor: 11.069
Authors: William J Astle; Heather Elding; Tao Jiang; Dave Allen; Dace Ruklisa; Alice L Mann; Daniel Mead; Heleen Bouman; Fernando Riveros-Mckay; Myrto A Kostadima; John J Lambourne; Suthesh Sivapalaratnam; Kate Downes; Kousik Kundu; Lorenzo Bomba; Kim Berentsen; John R Bradley; Louise C Daugherty; Olivier Delaneau; Kathleen Freson; Stephen F Garner; Luigi Grassi; Jose Guerrero; Matthias Haimel; Eva M Janssen-Megens; Anita Kaan; Mihir Kamat; Bowon Kim; Amit Mandoli; Jonathan Marchini; Joost H A Martens; Stuart Meacham; Karyn Megy; Jared O'Connell; Romina Petersen; Nilofar Sharifi; Simon M Sheard; James R Staley; Salih Tuna; Martijn van der Ent; Klaudia Walter; Shuang-Yin Wang; Eleanor Wheeler; Steven P Wilder; Valentina Iotchkova; Carmel Moore; Jennifer Sambrook; Hendrik G Stunnenberg; Emanuele Di Angelantonio; Stephen Kaptoge; Taco W Kuijpers; Enrique Carrillo-de-Santa-Pau; David Juan; Daniel Rico; Alfonso Valencia; Lu Chen; Bing Ge; Louella Vasquez; Tony Kwan; Diego Garrido-Martín; Stephen Watt; Ying Yang; Roderic Guigo; Stephan Beck; Dirk S Paul; Tomi Pastinen; David Bujold; Guillaume Bourque; Mattia Frontini; John Danesh; David J Roberts; Willem H Ouwehand; Adam S Butterworth; Nicole Soranzo Journal: Cell Date: 2016-11-17 Impact factor: 41.582
Authors: Jiyang Jiang; Anbupalam Thalamuthu; Jennifer E Ho; Anubha Mahajan; Weronica E Ek; David A Brown; Samuel N Breit; Thomas J Wang; Ulf Gyllensten; Ming-Huei Chen; Stefan Enroth; James L Januzzi; Lars Lind; Nicola J Armstrong; John B Kwok; Peter R Schofield; Wei Wen; Julian N Trollor; Åsa Johansson; Andrew P Morris; Ramachandran S Vasan; Perminder S Sachdev; Karen A Mather Journal: Front Genet Date: 2018-03-23 Impact factor: 4.599
Authors: Ching-Lung Cheung; Kathryn C B Tan; Philip C M Au; Gloria H Y Li; Bernard M Y Cheung Journal: EBioMedicine Date: 2019-02-13 Impact factor: 8.143
Authors: Jie Zheng; Min Xu; Venexia Walker; Jinqiu Yuan; Roxanna Korologou-Linden; Jamie Robinson; Peiyuan Huang; Stephen Burgess; Shiu Lun Au Yeung; Shan Luo; Michael V Holmes; George Davey Smith; Guang Ning; Weiqing Wang; Tom R Gaunt; Yufang Bi Journal: Diabetologia Date: 2022-07-29 Impact factor: 10.460
Authors: Justin B Echouffo-Tcheugui; Natalie Daya; Kunihiro Matsushita; Dan Wang; Chiadi E Ndumele; Mahmoud Al Rifai; Ron C Hoogeveen; Christie M Ballantyne; Elizabeth Selvin Journal: Clin Chem Date: 2021-03-31 Impact factor: 8.327
Authors: Valborg Gudmundsdottir; Shaza B Zaghlool; Valur Emilsson; Thor Aspelund; Marjan Ilkov; Elias F Gudmundsson; Stefan M Jonsson; Nuno R Zilhão; John R Lamb; Karsten Suhre; Lori L Jennings; Vilmundur Gudnason Journal: Diabetes Date: 2020-05-08 Impact factor: 9.461