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Int J Epidemiol. 2018 Oct 1. doi: 10.1093/ije/dyy201. [Epub ahead of print]

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

Collaborators (189)

Alicia BJ, 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 TY, Clarke CL, Conroy DM, Couch FJ, Cox DG, Cox A, 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 VM, 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.

Author information

1
Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
2
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
4
Department of Electron Microscopy/Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
5
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia.
6
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
7
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
8
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
9
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
10
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
11
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
12
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
13
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
14
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, Canada.

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.

PMID:
30277539
DOI:
10.1093/ije/dyy201

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