Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis

Abstract

Background

In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.

Methods

We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.

Results

All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 × 10–4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 × 10–4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 × 10–19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 × 10–6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.

Conclusions

We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

Metadata

Item Type:	Article
Authors/Creators:	Shu, X Wu, L Khankari, NK Shu, X-O Wang, TJ Michailidou, K Bolla, MK Wang, Q Dennis, J Milne, RL Schmidt, MK Pharoah, PDP Andrulis, IL Hunter, DJ Simard, J Easton, DF Zheng, W Alicia, B-FJ Anton-Culver, H Antonenkova, NN Arndt, V Aronson, KJ Auer, PL Barrdahl, M Baynes, C Beane Freeman, LE Beckmann, MW Behrens, S Benitez, J Bermisheva, M Blomqvist, C Bogdanova, NV Bojesen, SE Brauch, H Brenner, H Brinton, L Broberg, P Brucker, SY Brüning, T Burwinkel, B Cai, Q Caldés, T Canzian, F Carter, BD Castelao, JE Chang-Claude, J Chenevix-Trench, G David Cheng, T-Y Clarke, CL Conroy, DM Couch, FJ Cox, DG Cox, A https://orcid.org/0000-0002-5138-1099 Cross, SS Cunningham, JM Czene, K Daly, MB Doheny, KF Dörk, T dos-Santos-Silva, I Dumont, M Dunning, AM Dwek, M Earp, HS Eccles, DM Heather Eliassen, A Engel, C Eriksson, M Gareth Evans, D Fachal, L Fasching, PA Figueroa, J Fletcher, O Flyger, H Fritschi, L Gabrielson, M Gago-Dominguez, M Gapstur, SM García-Closas, M Gaudet, MM Ghoussaini, M Giles, GG Goldberg, MS Goldgar, DE González-Neira, A Guénel, P Hahnen, E Haiman, CA Håkansson, N Hall, P Hallberg, E Hamann, U Harrington, P He, W Hein, A Hicks, B Hillemanns, P Hogervorst, FB Hollestelle, A Hoover, RN Hopper, JL Howell, A Huang, G Jakubowska, A Janni, W John, EM Johnson, N Jones, K Jung, A Kaaks, R Kabisch, M Kerin, MJ Khusnutdinova, E Kitahara, CM Kosma, V-M Koutros, S Kraft, P Kristensen, VN Lambrechts, D Le Marchand, L Lindström, S Linet, MS Lissowska, J Loibl, S Lubinski, J Luccarini, C Lux, MP Maishman, T Kostovska, IM Mannermaa, A Manoukian, S Manson, JE Margolin, S Mavroudis, D Meijers-Heijboer, H Meindl, A Menon, U Meyer, J Mulligan, AM Neuhausen, SL Nevanlinna, H Neven, P Newman, WT Nielsen, SF Nordestgaard, BG Olopade, OI Olshan, AF Olson, JE Olsson, H Olswold, C Orr, N Perou, CM Peto, J Plaseska-Karanfilska, D Prentice, R Presneau, N Pylkäs, K Rack, B Radice, P Rahman, N Rennert, G Rennert, HS Romero, A Romm, J Saloustros, E Sandler, DP Sawyer, EJ Schmutzler, RK Schneeweiss, A Scott, RJ Scott, C Seal, S Seynaeve, C Smeets, A Southey, MC Spinelli, JJ Stone, J Surowy, H Swerdlow, AJ Tamimi, R Tapper, W Taylor, JA Terry, MB Tessier, DC Thöne, K Tollenaar, RAEM Torres, D Troester, MA Truong, T Untch, M Vachon, C Van Den Berg, D van den Ouweland, AMW van Veen, EM Vincent, D Waisfisz, Q Weinberg, CR Wendt, C Whittemore, AS Wildiers, H Winqvist, R Wolk, A Xia, L Yang, XR Ziogas, A Ziv, E
Copyright, Publisher and Additional Information:	© 2018 The Authors. This is an author-produced version of a paper subsequently published in International Journal of Epidemiology. Uploaded in accordance with the publisher's self-archiving policy.
Keywords:	Breast cancer; insulin; glucose; obesity; genetics; Mendelian randomization analysis
Dates:	Published: 1 June 2019 Published (online): 1 October 2018 Accepted: 6 September 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield)
Funding Information:	Funder Grant number Cancer Research UK C9267/A25152 Breast Cancer Now TB2017SHEF
Depositing User:	Symplectic Sheffield
Date Deposited:	21 Oct 2019 09:33
Last Modified:	21 Oct 2019 09:33
Status:	Published
Publisher:	Oxford University Press (OUP)
Refereed:	Yes
Identification Number:	10.1093/ije/dyy201
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:152353

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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis

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