Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry
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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.
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.
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).
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.
KeywordsType 2 diabetes Genetic susceptibility GWAS Breast cancer Epidemiology
We thank all the individuals who took part in these studies and all the researchers, study staff, clinicians and other healthcare providers, technicians, and administrative staff who have enabled this work to be carried out. In particular, we thank: Andrew Berchuck (OCAC); Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL); Antonis Antoniou, Lesley McGuffog, Ken Offit (CIMBA); Joe Dennis, Andrew Lee, Ed Dicks, Craig Luccarini, and the staff of the Centre for Genetic Epidemiology Laboratory; Javier Benitez, Anna Gonzalez-Neira, and the staff of the CNIO genotyping unit; Jacques Simard, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière, Frederic Robidoux, and the staff of the McGill University and Génome Québec Innovation Centre; Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory; and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer, and the staff of Mayo Clinic Genotyping Core Facility; Maggie Angelakos, Judi Maskiell, Gillian Dite (ABCFS), Ellen van der Schoot, Femake Atsma (Sanquin Bloodbank); Emiel Rutgers, Senno Verhoef, Frans Hogervorst, the Thai Ministry of Public Health (MOPH); Dr. Prat Boonyawongviroj (former Permanent Secretary of MOPH); Dr. Pornthep Siriwanarungsan (Department Director-General of Disease Control); Michael Schrauder, Matthias Rübner, Sonja Oeser, Silke Landrith, Eileen Williams, Elaine Ryder-Mills, Kara Sargus, Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones, Christof Sohn, Andeas Schneeweiß, and Peter Bugert (the Danish Breast Cancer Group); Núria Álvarez; the CTS Steering Committee (including Leslie Bernstein, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu, and Jessica Clague DeHart at the Beckman Research Institute of the City of Hope; Dennis Deapen, Rich Pinder, Eunjung Lee and Fred Schumacher at the University of Southern California; Pam Horn-Ross, Peggy Reynolds, and David Nelson at the Cancer Prevention Institute of California; and Hannah Park at the University of California Irvine); Hartwig Ziegler; Sonja Wolf; Volker Hermann; the GENICA network [Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany; (HB, Wing-Yee Lo, Christina Justenhoven), Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Yon-Dschun Ko, Christian Baisch), Institute of Pathology, University of Bonn, Germany (Hans-Peter Fischer), Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Germany (UH), Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Germany (Thomas Brüning, Beate Pesch, Sylvia Rabstein, Anne Lotz), Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany (Volker Harth)]; Tuomas Heikkinen; Irja Erkkilä; Kirsimari Aaltonen; Karl von Smitten; Natalia Antonenkova; Peter Hillemanns; Hans Christiansen; Eija Myöhänen; Helena Kemiläinen; Heather Thorne; Eveline Niedermayr; the AOCS Management Group (D Bowtell, G Chenevix-Trench, A deFazio, D Gertig, A Green, P Webb); the ACS Management Group (A Green, P Parsons, N Hayward, P Webb, D Whiteman); the LAABC data collection team, especially Annie Fung and June Yashiki; Gilian Peuteman; Dominiek Smeets; Thomas Van Brussel; Kathleen Corthouts; Nadia Obi; Judith Heinz; Sabine Behrens; Ursula Eilber; Muhabbet Celik; Til Olchers; the Mayo Clinic Breast Cancer Patient Registry; Martine Tranchant; Marie-France Valois; Annie Turgeon; Lea Heguy; Phuah Sze Yee; Peter Kang; Kang In Nee; Shivaani Mariapun; Yoon Sook-Yee; Daphne Lee; Teh Yew Ching; Nur Aishah Mohd Taib; Meeri Otsukka; Kari Mononen; Teresa Selander; Nayana Weerasooriya; OFBCR staff: E Krol-Warmerdam, J Molenaar, J Blom; Louise Brinton; Neonila Szeszenia-Dabrowska; Beata Peplonska; Witold Zatonski; Pei Chao; Michael Stagner; Petra Bos; Jannet Blom; Ellen Crepin; Anja Nieuwlaat; Annette Heemskerk; the Erasmus MC Family Cancer Clinic; Sue Higham; Simon Cross; Helen Cramp; Dan Connley; Sabapathy Balasubramanian; Ian Brock; the Eastern Cancer Registration and Information Centre; the SEARCH and EPIC teams; Michael Kerin, Nicola Miller, Niall McInerney, Gabrielle Colleran (BIGGS), and Pierre Kerbrat; Patrick Arveux; Romuald Le Scodan; Yves Raoul; Pierre Laurent-Puig; Claire Mulot (CECILE), Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier and Katja Butterbach (ESTHER), Taru A. Muranen (HEBCS), Natalia Antonenkova, Peter Hillemanns, Hans Christiansen and Johann H. Karstens (HMBCS), Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts (LMBC), Petra Seibold, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels (MARIE). MBCSG wish to thank Paolo Radice, Bernard Peissel, and Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT); Bernardo Bonanni, Monica Barile, and Irene Feroce of the Istituto Europeo di Oncologia (IEO) and Loris Bernard and the personnel of the Cogentech Cancer Genetic Test Laboratory. Cancer Council Victoria acknowledges the Traditional Owners of the land and waters throughout Victoria and pays respect to them, their culture and their Elders past, present, and future. We would like to thank Martine Tranchant (Cancer Genomics Laboratory, CHU de Québec Research Center), Marie-France Valois, Annie Turgeon, and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management, and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. OBCS thanks Arja Jukkola-Vuorinen, Mervi Grip, Saila Kauppila, Kari Mononen, and Meeri Otsukka for data collection and sample preparation. Craig Luccarini; Don Conroy; Caroline Baynes; Kimberley Chua; the Ohio State University Human Genetics Sample Bank; and Robert Pilarski. Data on SCCS cancer cases used in this publication were provided by the: Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; and Arkansas Department of Health, Cancer Registry. DFBBCS thank Muriel Adank for selecting the samples and Margreet Ausems, Christi van Asperen, Senno Verhoef, and Rogier van Oldenburg for providing samples from their Clinical Genetic centers. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists.
The work conducted for this project at the Vanderbilt Epidemiology Center is supported in part by NIH Grant R37CA070867 and endowment funds for the Ingram Professorship and Anne Potter Wilson Chair in Medicine. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community’s Seventh Framework Programme under Grant agreement no 223175 (HEALTH-F2–2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C8197/A16565 and C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (PSR-SIIRI-701). Additional support for the iCOGS infrastructure was provided by the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112—the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australia, California, and Ontario sites of the Breast Cancer Family Registry were supported by Grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS (Australia site of the BCFR) was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. John L. Hopper is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow and M.C.S. is a NHMRC Senior Research Fellow. Work at the OFBCR (Ontario site of the BCFR) was also supported by the Canadian Institutes of Health Research ‘CIHR Team in Familial Risks of Breast Cancer’ program. The ABCS study was supported by the Dutch Cancer Society [Grants NKI 2007-3839; 2009 4363] and BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). Elinor J. Sawyer is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, UK. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). Ian Tomlinson is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society, and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire (ANSES), and Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital. The CNIO-BCS was supported by the Genome Spain Foundation, the Red Temática de Investigación Cooperativa en Cáncer, and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit, CNIO is supported by the Instituto de Salud Carlos III. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany Grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany. The HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation. The HMBCS was supported by the Rudolf Bartling Foundation. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute, the Stockholm Cancer Foundation, and the Swedish Cancer Society. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation, the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC (145684, 288704, 454508). Kelly-Anne Phillips is a National Breast Cancer Foundation Fellow (Australia). Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania and Cancer Foundation of Western Australia, and the NHMRC (199600). Georgia Chenevix-Trench and P.W. are supported by the NHMRC. LMBC is supported by the ‘Stichting tegen Kanker’ (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII and by a ERC consolidator grant. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center, and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated a 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1,000’). The MCBCS was supported by the NIH Grants (CA122340, CA128978) and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC Grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was supported by NIH Grants CA63464, CA54281, CA098758, and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program—Grant No CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—Grant No PSR-SIIRI-701. The NBCS was supported by grants from the Norwegian Research council (155218/V40, 175240/S10 to A.L.B.D., FUGE-NFR 181600/V11 to V.N.K. and a Swizz Bridge Award to A.L.B.D.). The NBHS was supported by NIH Grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. OBCS was supported by the Academy of Finland (Grant Number 250083, 122715 and Center of Excellence Grant Number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. This OFBCR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH), and the Susan G. Komen Breast Cancer Foundation. KC was financed by the Swedish Cancer Society (5128-B07-01PAF). The SBCS was supported by Yorkshire Cancer Research S305PA, S299, and S295. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, DBBR (a CCSG Share Resource by National Institutes of Health Grant P30 CA016056), the Hellenic Cooperative Oncology Group research Grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund—ESF), and Greek national funds through the Operational Program ‘Education and Lifelong Learning’ of the National Strategic Reference Framework (NSRF)—ARISTEIA. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The DFBBCS GWAS was funded by the Netherlands Organisation for Scientific Research (NWO) as part of a ZonMw/VIDI Grant number 91756341. The generation and management of GWAS genotype data for the Rotterdam Study (control samples) are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810.
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Conflict of interest
The authors declare that they have no conflict of interest.
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