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PLoS Med. 2016 Aug 23;13(8):e1002105. doi: 10.1371/journal.pmed.1002105. eCollection 2016 Aug.

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Guo Y1, Warren Andersen S2, Shu XO2, Michailidou K3, Bolla MK3, Wang Q3, Garcia-Closas M4,5, Milne RL6,7, Schmidt MK8, Chang-Claude J9,10, Dunning A11, Bojesen SE12,13,14, Ahsan H15, Aittomäki K16, Andrulis IL17,18, Anton-Culver H19, Arndt V20, Beckmann MW15, Beeghly-Fadiel A2, Benitez J21,22, Bogdanova NV23, Bonanni B24, Børresen-Dale AL25,26, Brand J27, Brauch H28,29,30, Brenner H20,28,31, Brüning T32, Burwinkel B33,34, Casey G35, Chenevix-Trench G36, Couch FJ37, Cox A38, Cross SS11, Czene K27, Devilee P39, Dörk T40, Dumont M41, Fasching PA42,43, Figueroa J44, Flesch-Janys D45,46, Fletcher O5, Flyger H47, Fostira F48, Gammon M49, Giles GG6,7, Guénel P50,51, Haiman CA35, Hamann U52, Hooning MJ53, Hopper JL7, Jakubowska A54, Jasmine F15, Jenkins M7, John EM55,56, Johnson N5, Jones ME4, Kabisch M52, Kibriya M15, Knight JA57,58, Koppert LB53, Kosma VM59,60,61, Kristensen V25,26,62, Le Marchand L63, Lee E35, Li J27, Lindblom A64, Luben R65, Lubinski J54, Malone KE66, Mannermaa A59,60,61, Margolin S67, Marme F68,69, McLean C70, Meijers-Heijboer H71, Meindl A72, Neuhausen SL73, Nevanlinna H74, Neven P75, Olson JE76, Perez JI77, Perkins B78, Peterlongo P79, Phillips KA80,81,82, Pylkäs K83, Rudolph A9, Santella R84,85, Sawyer EJ86, Schmutzler RK87,88,89,90, Seynaeve C53, Shah M78, Shrubsole MJ2, Southey MC91, Swerdlow AJ4,92, Toland AE93, Tomlinson I94, Torres D52, Truong T50,51, Ursin G95, Van Der Luijt RB96, Verhoef S8, Whittemore AS56, Winqvist R83,97, Zhao H98,99, Zhao S1, Hall P27, Simard J41, Kraft P100,101, Pharoah P3,78, Hunter D100,101, Easton DF3,78, Zheng W2.

Author information

1
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
2
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
4
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
5
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
6
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
7
Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia.
8
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
9
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
11
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
12
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
13
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
14
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
15
Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America.
16
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
17
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
18
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
19
Department of Epidemiology, University of California Irvine, Irvine, California, United States of America.
20
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
21
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
22
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
23
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
24
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
25
Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway.
26
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
27
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
28
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
29
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
30
University of Tübingen, Tübingen, Germany.
31
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
32
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
33
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
34
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
35
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
36
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
37
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
38
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
39
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
40
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
41
Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
42
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
43
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, United States of America.
44
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.
45
Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
46
Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
47
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
48
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
49
Departments of Epidemiology, University of North Carolina Chapel-Hill, Chapel Hill, North Carolina, United States of America.
50
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
51
University Paris-Sud, Villejuif, France.
52
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
53
Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
54
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
55
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America.
56
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America.
57
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
58
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
59
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
60
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
61
Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
62
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
63
University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
64
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
65
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
66
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
67
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
68
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
69
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
70
Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
71
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
72
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
73
Beckman Research Institute of City of Hope, Duarte, California, United States of America.
74
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
75
Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
76
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
77
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
78
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
79
IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
80
Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
81
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
82
Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.
83
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
84
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
85
Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, New York, United States of America.
86
Research Oncology, Guy's Hospital, King's College London, London, United Kingdom.
87
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
88
Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
89
Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.
90
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
91
Department of Pathology, The University of Melbourne, Melbourne, Australia.
92
Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
93
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
94
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
95
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
96
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
97
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
98
Vesalius Research Center, Leuven, Belgium.
99
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
100
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
101
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.

Abstract

BACKGROUND:

Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.

METHODS:

We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.

RESULTS:

In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.

CONCLUSIONS:

BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

PMID:
27551723
PMCID:
PMC4995025
DOI:
10.1371/journal.pmed.1002105
[Indexed for MEDLINE]
Free PMC Article

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