Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis-Reference-Cited by-同舟云学术

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

Published:2018-10-01 Issue:3 Volume:48 Page:795-806
ISSN:0300-5771
Container-title:International Journal of Epidemiology
language:en
Short-container-title:

Author:

Shu Xiang¹,Wu Lang¹,Khankari Nikhil K¹,Shu Xiao-Ou¹^ORCID,Wang Thomas J²,Michailidou Kyriaki³⁴,Bolla Manjeet K³,Wang Qin³,Dennis Joe³,Milne Roger L⁵⁶,Schmidt Marjanka K⁷⁸,Pharoah Paul D P³⁹,Andrulis Irene L¹⁰¹¹,Hunter David J¹²¹³,Simard Jacques¹⁴,Easton Douglas F³⁹,Zheng Wei¹^ORCID,Alicia Beeghly-Fadiel J,Anton-Culver Hoda,Antonenkova Natalia N,Arndt Volker,Aronson Kristan J,Auer Paul L,Barrdahl Myrto,Baynes Caroline,Beane Freeman Laura E,Beckmann Matthias W,Behrens Sabine,Benitez Javier,Bermisheva Marina,Blomqvist Carl,Bogdanova Natalia V,Bojesen Stig E,Brauch Hiltrud,Brenner Hermann,Brinton Louise,Broberg Per,Brucker Sara Y,Brüning Thomas,Burwinkel Barbara,Cai Qiuyin,Caldés Trinidad,Canzian Federico,Carter Brian D,Castelao Jose E,Chang-Claude Jenny,Chenevix-Trench Georgia,David Cheng Ting-Yuan,Clarke Christine L,Conroy Don M,Couch Fergus J,Cox David G,Cox Angela,Cross Simon S,Cunningham Julie M,Czene Kamila,Daly Mary B,Doheny Kimberly F,Dörk Thilo,dos-Santos-Silva Isabel,Dumont Martine,Dunning Alison M,Dwek Miriam,Earp H Shelton,Eccles Diana M,Heather Eliassen A,Engel Christoph,Eriksson Mikael,Gareth Evans D,Fachal Laura,Fasching Peter A,Figueroa Jonine,Fletcher Olivia,Flyger Henrik,Fritschi Lin,Gabrielson Marike,Gago-Dominguez Manuela,Gapstur Susan M,García-Closas Montserrat,Gaudet Mia M,Ghoussaini Maya,Giles Graham G,Goldberg Mark S,Goldgar David E,González-Neira Anna,Guénel Pascal,Hahnen Eric,Haiman Christopher A,Håkansson Niclas,Hall Per,Hallberg Emily,Hamann Ute,Harrington Patricia,He Wei,Hein Alexander,Hicks Belynda,Hillemanns Peter,Hogervorst Frans B,Hollestelle Antoinette,Hoover Robert N,Hopper John L,Howell Anthony,Huang Guanmengqian,Jakubowska Anna,Janni Wolfgang,John Esther M,Johnson Nichola,Jones Kristine,Jung Audrey,Kaaks Rudolf,Kabisch Maria,Kerin Michael J,Khusnutdinova Elza,Kitahara Cari M,Kosma Veli-Matti,Koutros Stella,Kraft Peter,Kristensen Vessela N,Lambrechts Diether,Le Marchand Loic,Lindström Sara,Linet Martha S,Lissowska Jolanta,Loibl Sibylle,Lubinski Jan,Luccarini Craig,Lux Michael P,Maishman Tom,Kostovska Ivana Maleva,Mannermaa Arto,Manoukian Siranoush,Manson JoAnn E,Margolin Sara,Mavroudis Dimitrios,Meijers-Heijboer Hanne,Meindl Alfons,Menon Usha,Meyer Jeffery,Mulligan Anna Marie,Neuhausen Susan L,Nevanlinna Heli,Neven Patrick,Newman William T,Nielsen Sune F,Nordestgaard Børge G,Olopade Olufunmilayo I,Olshan Andrew F,Olson Janet E,Olsson Håkan,Olswold Curtis,Orr Nick,Perou Charles M,Peto Julian,Plaseska-Karanfilska Dijana,Prentice Ross,Presneau Nadege,Pylkäs Katri,Rack Brigitte,Radice Paolo,Rahman Nazneen,Rennert Gadi,Rennert Hedy S,Romero Atocha,Romm Jane,Saloustros Emmanouil,Sandler Dale P,Sawyer Elinor J,Schmutzler Rita K,Schneeweiss Andreas,Scott Rodney J,Scott Christopher,Seal Sheila,Seynaeve Caroline,Smeets Ann,Southey Melissa C,Spinelli John J,Stone Jennifer,Surowy Harald,Swerdlow Anthony J,Tamimi Rulla,Tapper William,Taylor Jack A,Terry Mary Beth,Tessier Daniel C,Thöne Kathrin,Tollenaar Rob A E M,Torres Diana,Troester Melissa A,Truong Thérèse,Untch Michael,Vachon Celine,Van Den Berg David,van den Ouweland Ans M W,van Veen Elke M,Vincent Daniel,Waisfisz Quinten,Weinberg Clarice R,Wendt Camilla,Whittemore Alice S,Wildiers Hans,Winqvist Robert,Wolk Alicja,Xia Lucy,Yang Xiaohong R,Ziogas Argyrios,Ziv Elad,

Affiliation:

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

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.

Funder

Vanderbilt University Medical Center

National Cancer Institute

National Institutes of Health

Government of Canada

Canadian Institutes of Health Research

Genome Québec

Quebec Breast Cancer Foundation

National Cancer Institute Genetic Associations and Mechanisms in Oncology

Discovery, Biology and Risk of Inherited Variants in Breast Cancer

Cancer Research UK

BCAC