Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis
Authors: Shu Xiang , Wu Lang , Khankari Nikhil K , Shu Xiao-Ou , Wang Thomas J , Michailidou Kyriaki , Bolla Manjeet K , Wang Qin , Dennis Joe , Milne Roger L , Schmidt Marjanka K , Pharoah Paul D P , Andrulis Irene L , Hunter David J , Simard Jacques , Easton Douglas F , Zheng Wei ,   Breast Cancer Association Consortium, 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 
Published: September 2018

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.