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

2018; Oxford University Press; Volume: 48; Issue: 3 Linguagem: Inglês

10.1093/ije/dyy201

1464-3685

Xiang Shu, Lang Wu, Nikhil K. Khankari, Xiao‐Ou Shu, Thomas J. Wang, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Roger L. Milne, Marjanka K. Schmidt, Paul D.P. Pharoah, Irene L. Andrulis, David J. Hunter, Jacques Simard, Douglas F. Easton, Wei Zheng, Beeghly-Fadiel Alicia, Hoda Anton‐Culver, Natalia Antonenkova, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Myrto Barrdahl, Caroline Baynes, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benı́tez, Marina Bermisheva, Carl Blomqvist, Natalia Bogdanova, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Louise A. Brinton, Per Broberg, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Qiuyin Cai, Trinidad Caldés, Federico Canzian, Brian D. Carter, Jose E. Castelao, Jenny Chang‐Claude, Georgia Chenevix‐Trench, Ting‐Yuan David Cheng, Christine L. Clarke, Don Conroy, Fergus J. Couch, David G. Cox, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Kimberly F. Doheny, Thilo Dörk, Isabel dos‐Santos‐Silva, Martine Dumont, Alison M. Dunning, Miriam Dwek, H. Shelton Earp, Diana Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Laura Fachal, Peter A. Fasching, Jonine D. Figueroa, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago‐Dominguez, Susan M. Gapstur, Montserrat García‐Closas, Mia M. Gaudet, Maya Ghoussaini, Graham G. Giles, Mark S. Goldberg, David E. Goldgar, Anna González‐Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Emily Hallberg, Ute Hamann, Patricia Harrington, Wei He, Alexander Hein, Belynda Hicks, Peter Hillemanns, Frans B.L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Kristine Jones, Audrey Jung, Rudolf Kaaks, Maria Kabisch, Michael J. Kerin, Э. К. Хуснутдинова, Cari M. Kitahara, Veli‐Matti Kosma, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Diether Lambrechts, Loı̈c Le Marchand, Sara Lindström, Martha S. Linet, Jolanta Lissowska, Sibylle Loibl, Jan Lubiński, Craig Luccarini, Michael P. Lux, Tom Maishman, Ivana Maleva Kostovska, Graham J. Mann, Siranoush Manoukian, JoAnn E. Manson, Sara Margolin, Dimitrios Mavroudis, Hanne Meijers‐Heijboer, Alfons Meindl, Usha Menon, Jeffery Meyer, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Olufunmilayo I. Olopade, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Curtis Olswold, Nick Orr, Charles M. Perou, Julian Peto, Dijana Plaseska-Karanfilska, Ross Prentice, Nadège Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Gad Rennert, Hedy S. Rennert, Atocha Romero, Jane Romm, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Rita K. Schmutzler, Andreas Schneeweiß, Rodney J. Scott, Christopher G. Scott, Sheila Seal, Caroline Seynaeve, Ann Smeets, Melissa C. Southey, John J. Spinelli, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William Tapper, Jack A. Taylor, Mary Beth Terry, Daniel C. Tessier, Kathrin Thöne, Rob A.�E.�M. Tollenaar, Diana Torres, Melissa A. Troester, Thérèse Truong, Michael Untch, Celine M. Vachon, David Van Den Berg, Ans M.W. van den Ouweland, Elke M. van Veen, Daniel Vincent, Quinten Waisfisz, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Alicja Wolk, Lucy Xia, Xiaohong R. Yang, Argyrios Ziogas, Elad Ziv,

Cancer Risks and Factors

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.