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Cancer Causes Control. 2016 May;27(5):679-93. doi: 10.1007/s10552-016-0741-6. Epub 2016 Apr 6.

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Zhao Z1,2, Wen W1, Michailidou K3, Bolla MK3, Wang Q3, Zhang B1, Long J1, Shu XO1, Schmidt MK4, Milne RL5,6, García-Closas M7,8, Chang-Claude J9,10, Lindstrom S11,12, Bojesen SE13,14,15, Ahsan H16, Aittomäki K17, Andrulis IL18,19, Anton-Culver H20, Arndt V21, Beckmann MW22, Beeghly-Fadiel A1, Benitez J23,24, Blomqvist C25, Bogdanova NV26, Børresen-Dale AL27,28, Brand J29, Brauch H30,31,32, Brenner H21,32,33, Burwinkel B34,35, Cai Q1, Casey G36, Chenevix-Trench G37, Couch FJ38, Cox A39, Cross SS40, Czene K29, Dörk T41, Dumont M42, Fasching PA22,43, Figueroa J44, Flesch-Janys D45,46, Fletcher O8, Flyger H47, Fostira F48, Gammon M49, Giles GG5,6, Guénel P50,51, Haiman CA36, Hamann U52, Harrington P53, Hartman M54, Hooning MJ55, Hopper JL6, Jakubowska A56, Jasmine F16, John EM57,58, Johnson N8, Kabisch M52, Khan S59, Kibriya M16, Knight JA18,60, Kosma VM61,62,63, Kriege M55, Kristensen V27,28,64, Le Marchand L65, Lee E36, Li J29, Lindblom A66, Lophatananon A67, Luben R68, Lubinski J56, Malone KE69, Mannermaa A61,62,63, Manoukian S70, Margolin S71, Marme F72,73, McLean C74, Meijers-Heijboer H75, Meindl A76, Miao H54, Muir K67,77, Neuhausen SL78, Nevanlinna H59, Neven P79, Olson JE80, Perkins B81, Peterlongo P82, Phillips KA83,84,85, Pylkäs K86, Rudolph A9, Santella R87,88, Sawyer EJ89, Schmutzler RK90,91,92,93, Schoemaker M7, Shah M81, Shrubsole M1, Southey MC94, Swerdlow AJ7,95, Toland AE96, Tomlinson I97, Torres D52, Truong T50,51, Ursin G98,99, Van Der Luijt RB100, Verhoef S4, Wang-Gohrke S10, Whittemore AS58, Winqvist R86,101, Pilar Zamora M102, Zhao H103,104, Dunning AM81, Simard J42, Hall P29, Kraft P11,12, Pharoah P3,81, Hunter D11,12, Easton DF3,81, Zheng W105.

Author information

1
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
2
Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.
3
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
4
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
5
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
6
Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
7
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
8
Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
9
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
10
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
11
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA.
12
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
13
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
14
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
15
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
16
Department of Health Studies, The University of Chicago, Chicago, IL, USA.
17
Department of Clinical Genetics, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
18
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
19
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
20
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
21
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
22
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
23
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
24
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
25
Department of Oncology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
26
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
27
Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo, Norway.
28
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
29
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
30
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
31
University of Tübingen, Tübingen, Germany.
32
German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
33
Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany.
34
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
35
Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
36
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
37
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
38
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
39
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
40
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
41
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
42
Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
43
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
44
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
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, NC, USA.
50
Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, 94807, Villejuif, France.
51
University Paris-Sud, UMRS 1018, 94807, Villejuif, France.
52
Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.
53
Strangeways Research Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK.
54
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
55
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
56
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
57
Cancer Prevention Institute of California, Fremont, CA, USA.
58
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA.
59
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
60
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
61
Department of Clinical Pathology, Imaging Center, Kuopio University Hospital, Kuopio, Finland.
62
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
63
Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
64
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
65
University of Hawaii Cancer Center, Honolulu, HI, USA.
66
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
67
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
68
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
69
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
70
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
71
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
72
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
73
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
74
Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
75
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
76
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
77
Institute of Population Health, University of Manchester, Manchester, UK.
78
Beckman Research Institute of City of Hope, Duarte, CA, USA.
79
Department of Oncology, Multidisciplinary Breast Centre and Gynaecological Oncology, KU Leuven - University of Leuven, University Hospitals Leuven, 3000, Louvain, Belgium.
80
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
81
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
82
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
83
Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
84
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
85
Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.
86
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
87
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
88
Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY, USA.
89
Research Oncology, Guy's Hospital, King's College London, London, UK.
90
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
91
Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
92
Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.
93
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
94
Department of Pathology, The University of Melbourne, Melbourne, Australia.
95
Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
96
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
97
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
98
Cancer Registry of Norway, Oslo, Norway.
99
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
100
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
101
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
102
Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
103
Vesalius Research Center, Louvain, Belgium.
104
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Louvain, Belgium.
105
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA. wei.zheng@vanderbilt.edu.

Abstract

PURPOSE:

Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.

METHODS:

We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.

RESULTS:

The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).

CONCLUSIONS:

We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

KEYWORDS:

Breast cancer; Epidemiology; GWAS; Genetic susceptibility; Type 2 diabetes

PMID:
27053251
PMCID:
PMC5029371
DOI:
10.1007/s10552-016-0741-6
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Compliance with Ethical Standards Conflict of Interest: The authors declare that they have no conflict of interest.

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