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

Zhiguo Zhao; Wanqing Wen; Kyriaki Michailidou; Manjeet K. Bolla; Qin Wang; Ben Zhang; Jirong Long; Xiao Ou Shu; Marjanka K. Schmidt; Roger L. Milne; Montserrat García-Closas; Jenny Chang-Claude; Sara Lindstrom; Stig E. Bojesen; Habibul Ahsan; Kristiina Aittomäki; Irene L. Andrulis; Hoda Anton-Culver; Volker Arndt; Matthias W. Beckmann; Alicia Beeghly-Fadiel; Javier Benitez; Carl Blomqvist; Natalia V. Bogdanova; Anne Lise Børresen-Dale; Judith Brand; Hiltrud Brauch; Hermann Brenner; Barbara Burwinkel; Qiuyin Cai; Graham Casey; Georgia Chenevix-Trench; Fergus J. Couch; Angela Cox; Simon S. Cross; Kamila Czene; Thilo Dörk; Martine Dumont; Peter A. Fasching; Jonine Figueroa; Dieter Flesch-Janys; Olivia Fletcher; Henrik Flyger; Florentia Fostira; Marilie Gammon; Graham G. Giles; Pascal Guénel; Christopher A. Haiman; Ute Hamann; Patricia Harrington; Mikael Hartman; Maartje J. Hooning; John L. Hopper; Anna Jakubowska; Farzana Jasmine; Esther M. John; Nichola Johnson; Maria Kabisch; Sofia Khan; Muhammad Kibriya; Julia A. Knight; Veli Matti Kosma; Mieke Kriege; Vessela Kristensen; Loic Le Marchand; Eunjung Lee; Jingmei Li; Annika Lindblom; Artitaya Lophatananon; Robert Luben; Jan Lubinski; Kathleen E. Malone; Arto Mannermaa; Siranoush Manoukian; Sara Margolin; Frederik Marme; Catriona McLean; Hanne Meijers-Heijboer; Alfons Meindl; Hui Miao; Kenneth Muir; Susan L. Neuhausen; Heli Nevanlinna; Patrick Neven; Janet E. Olson; Barbara Perkins; Paolo Peterlongo; Kelly Anne Phillips; Katri Pylkäs; Anja Rudolph; Regina Santella; Elinor J. Sawyer; Rita K. Schmutzler; Minouk Schoemaker; Mitul Shah; Martha Shrubsole; Melissa C. Southey; Anthony J. Swerdlow; Amanda E. Toland; Ian Tomlinson; Diana Torres; Thérèse Truong; Giske Ursin; Rob B. Van Der Luijt; Senno Verhoef; Shan Wang-Gohrke; Alice S. Whittemore; Robert Winqvist; M. Pilar Zamora; Hui Zhao; Alison M. Dunning; Jacques Simard; Per Hall; Peter Kraft; Paul Pharoah; David Hunter; Douglas F. Easton; Wei Zheng

doi:10.1007/s10552-016-0741-6

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

Zhiguo Zhao, Wanqing Wen, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Ben Zhang, Jirong Long, Xiao Ou Shu, Marjanka K. Schmidt, Roger L. Milne, Montserrat García-Closas, Jenny Chang-Claude, Sara Lindstrom, Stig E. Bojesen, Habibul Ahsan, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W. BeckmannAlicia Beeghly-Fadiel, Javier Benitez, Carl Blomqvist, Natalia V. Bogdanova, Anne Lise Børresen-Dale, Judith Brand, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Qiuyin Cai, Graham Casey, Georgia Chenevix-Trench, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Thilo Dörk, Martine Dumont, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Marilie Gammon, Graham G. Giles, Pascal Guénel, Christopher A. Haiman, Ute Hamann, Patricia Harrington, Mikael Hartman, Maartje J. Hooning, John L. Hopper, Anna Jakubowska, Farzana Jasmine, Esther M. John, Nichola Johnson, Maria Kabisch, Sofia Khan, Muhammad Kibriya, Julia A. Knight, Veli Matti Kosma, Mieke Kriege, Vessela Kristensen, Loic Le Marchand, Eunjung Lee, Jingmei Li, Annika Lindblom, Artitaya Lophatananon, Robert Luben, Jan Lubinski, Kathleen E. Malone, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Frederik Marme, Catriona McLean, Hanne Meijers-Heijboer, Alfons Meindl, Hui Miao, Kenneth Muir, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Janet E. Olson, Barbara Perkins, Paolo Peterlongo, Kelly Anne Phillips, Katri Pylkäs, Anja Rudolph, Regina Santella, Elinor J. Sawyer, Rita K. Schmutzler, Minouk Schoemaker, Mitul Shah, Martha Shrubsole, Melissa C. Southey, Anthony J. Swerdlow, Amanda E. Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Giske Ursin, Rob B. Van Der Luijt, Senno Verhoef, Shan Wang-Gohrke, Alice S. Whittemore, Robert Winqvist, M. Pilar Zamora, Hui Zhao, Alison M. Dunning, Jacques Simard, Per Hall, Peter Kraft, Paul Pharoah, David Hunter, Douglas F. Easton, Wei Zheng

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Pages (from-to)	679-693
Number of pages	15
Journal	Cancer Causes and Control
Volume	27
Issue number	5
DOIs	https://doi.org/10.1007/s10552-016-0741-6
State	Published - May 1 2016

Keywords

Breast cancer
Epidemiology
GWAS
Genetic susceptibility
Type 2 diabetes

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1007/s10552-016-0741-6

Cite this

Zhao, Z., Wen, W., Michailidou, K., Bolla, M. K., Wang, Q., Zhang, B., Long, J., Shu, X. O., Schmidt, M. K., Milne, R. L., García-Closas, M., Chang-Claude, J., Lindstrom, S., Bojesen, S. E., Ahsan, H., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., ... Zheng, W. (2016). Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry. Cancer Causes and Control, 27(5), 679-693. https://doi.org/10.1007/s10552-016-0741-6

Zhao, Z, Wen, W, Michailidou, K, Bolla, MK, Wang, Q, Zhang, B, Long, J, Shu, XO, Schmidt, MK, Milne, RL, García-Closas, M, Chang-Claude, J, Lindstrom, S, Bojesen, SE, Ahsan, H, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Blomqvist, C, Bogdanova, NV, Børresen-Dale, AL, Brand, J, Brauch, H, Brenner, H, Burwinkel, B, Cai, Q, Casey, G, Chenevix-Trench, G, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dörk, T, Dumont, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fostira, F, Gammon, M, Giles, GG, Guénel, P, Haiman, CA, Hamann, U, Harrington, P, Hartman, M, Hooning, MJ, Hopper, JL, Jakubowska, A, Jasmine, F, John, EM, Johnson, N, Kabisch, M, Khan, S, Kibriya, M, Knight, JA, Kosma, VM, Kriege, M, Kristensen, V, Le Marchand, L, Lee, E, Li, J, Lindblom, A, Lophatananon, A, Luben, R, Lubinski, J, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, McLean, C, Meijers-Heijboer, H, Meindl, A, Miao, H, Muir, K, Neuhausen, SL, Nevanlinna, H, Neven, P, Olson, JE, Perkins, B, Peterlongo, P, Phillips, KA, Pylkäs, K, Rudolph, A, Santella, R, Sawyer, EJ, Schmutzler, RK, Schoemaker, M, Shah, M, Shrubsole, M, Southey, MC, Swerdlow, AJ, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Ursin, G, Van Der Luijt, RB, Verhoef, S, Wang-Gohrke, S, Whittemore, AS, Winqvist, R, Pilar Zamora, M, Zhao, H, Dunning, AM, Simard, J, Hall, P, Kraft, P, Pharoah, P, Hunter, D, Easton, DF & Zheng, W 2016, 'Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry', Cancer Causes and Control, vol. 27, no. 5, pp. 679-693. https://doi.org/10.1007/s10552-016-0741-6

@article{211a970e21e8487f910e11a4a38d5d6d,

title = "Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry",

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",

author = "Zhiguo Zhao and Wanqing Wen and Kyriaki Michailidou and Bolla, {Manjeet K.} and Qin Wang and Ben Zhang and Jirong Long and Shu, {Xiao Ou} and Schmidt, {Marjanka K.} and Milne, {Roger L.} and Montserrat Garc{\'i}a-Closas and Jenny Chang-Claude and Sara Lindstrom and Bojesen, {Stig E.} and Habibul Ahsan and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Hoda Anton-Culver and Volker Arndt and Beckmann, {Matthias W.} and Alicia Beeghly-Fadiel and Javier Benitez and Carl Blomqvist and Bogdanova, {Natalia V.} and B{\o}rresen-Dale, {Anne Lise} and Judith Brand and Hiltrud Brauch and Hermann Brenner and Barbara Burwinkel and Qiuyin Cai and Graham Casey and Georgia Chenevix-Trench and Couch, {Fergus J.} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Thilo D{\"o}rk and Martine Dumont and Fasching, {Peter A.} and Jonine Figueroa and Dieter Flesch-Janys and Olivia Fletcher and Henrik Flyger and Florentia Fostira and Marilie Gammon and Giles, {Graham G.} and Pascal Gu{\'e}nel and Haiman, {Christopher A.} and Ute Hamann and Patricia Harrington and Mikael Hartman and Hooning, {Maartje J.} and Hopper, {John L.} and Anna Jakubowska and Farzana Jasmine and John, {Esther M.} and Nichola Johnson and Maria Kabisch and Sofia Khan and Muhammad Kibriya and Knight, {Julia A.} and Kosma, {Veli Matti} and Mieke Kriege and Vessela Kristensen and {Le Marchand}, Loic and Eunjung Lee and Jingmei Li and Annika Lindblom and Artitaya Lophatananon and Robert Luben and Jan Lubinski and Malone, {Kathleen E.} and Arto Mannermaa and Siranoush Manoukian and Sara Margolin and Frederik Marme and Catriona McLean and Hanne Meijers-Heijboer and Alfons Meindl and Hui Miao and Kenneth Muir and Neuhausen, {Susan L.} and Heli Nevanlinna and Patrick Neven and Olson, {Janet E.} and Barbara Perkins and Paolo Peterlongo and Phillips, {Kelly Anne} and Katri Pylk{\"a}s and Anja Rudolph and Regina Santella and Sawyer, {Elinor J.} and Schmutzler, {Rita K.} and Minouk Schoemaker and Mitul Shah and Martha Shrubsole and Southey, {Melissa C.} and Swerdlow, {Anthony J.} and Toland, {Amanda E.} and Ian Tomlinson and Diana Torres and Th{\'e}r{\`e}se Truong and Giske Ursin and {Van Der Luijt}, {Rob B.} and Senno Verhoef and Shan Wang-Gohrke and Whittemore, {Alice S.} and Robert Winqvist and {Pilar Zamora}, M. and Hui Zhao and Dunning, {Alison M.} and Jacques Simard and Per Hall and Peter Kraft and Paul Pharoah and David Hunter and Easton, {Douglas F.} and Wei Zheng",

note = "Funding Information: 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{\^a}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{\^a}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 S{\~A}{\textcopyright}curit{\~A}{\textcopyright} 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 Tem{\~A}¡tica de Investigaci{\~A}³n Cooperativa en C{\~A}¡ncer, and grants from the Asociaci{\~A}³n Espa{\~A}±ola Contra el C{\~A}¡ncer and the Fondo de Investigaci{\~A}³n 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{\^A} 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden W{\~A}¼rttemberg 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{\^A} 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{\^A} {\~A}{\^A} 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{\^a}Grant No CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade{\^a}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 M{\~A}¤rit 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{\^a}ESF), and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF){\^a}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. Publisher Copyright: {\textcopyright} 2016, Springer International Publishing Switzerland.",

year = "2016",

month = may,

day = "1",

doi = "10.1007/s10552-016-0741-6",

language = "English (US)",

volume = "27",

pages = "679--693",

journal = "Cancer Causes and Control",

issn = "0957-5243",

publisher = "Springer Netherlands",

number = "5",

}

TY - JOUR

T1 - Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

AU - Zhao, Zhiguo

AU - Wen, Wanqing

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Zhang, Ben

AU - Long, Jirong

AU - Shu, Xiao Ou

AU - Schmidt, Marjanka K.

AU - Milne, Roger L.

AU - García-Closas, Montserrat

AU - Chang-Claude, Jenny

AU - Lindstrom, Sara

AU - Bojesen, Stig E.

AU - Ahsan, Habibul

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Beckmann, Matthias W.

AU - Beeghly-Fadiel, Alicia

AU - Benitez, Javier

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Børresen-Dale, Anne Lise

AU - Brand, Judith

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Burwinkel, Barbara

AU - Cai, Qiuyin

AU - Casey, Graham

AU - Chenevix-Trench, Georgia

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Dörk, Thilo

AU - Dumont, Martine

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Flesch-Janys, Dieter

AU - Fletcher, Olivia

AU - Flyger, Henrik

AU - Fostira, Florentia

AU - Gammon, Marilie

AU - Giles, Graham G.

AU - Guénel, Pascal

AU - Haiman, Christopher A.

AU - Hamann, Ute

AU - Harrington, Patricia

AU - Hartman, Mikael

AU - Hooning, Maartje J.

AU - Hopper, John L.

AU - Jakubowska, Anna

AU - Jasmine, Farzana

AU - John, Esther M.

AU - Johnson, Nichola

AU - Kabisch, Maria

AU - Khan, Sofia

AU - Kibriya, Muhammad

AU - Knight, Julia A.

AU - Kosma, Veli Matti

AU - Kriege, Mieke

AU - Kristensen, Vessela

AU - Le Marchand, Loic

AU - Lee, Eunjung

AU - Li, Jingmei

AU - Lindblom, Annika

AU - Lophatananon, Artitaya

AU - Luben, Robert

AU - Lubinski, Jan

AU - Malone, Kathleen E.

AU - Mannermaa, Arto

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Marme, Frederik

AU - McLean, Catriona

AU - Meijers-Heijboer, Hanne

AU - Meindl, Alfons

AU - Miao, Hui

AU - Muir, Kenneth

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Neven, Patrick

AU - Olson, Janet E.

AU - Perkins, Barbara

AU - Peterlongo, Paolo

AU - Phillips, Kelly Anne

AU - Pylkäs, Katri

AU - Rudolph, Anja

AU - Santella, Regina

AU - Sawyer, Elinor J.

AU - Schmutzler, Rita K.

AU - Schoemaker, Minouk

AU - Shah, Mitul

AU - Shrubsole, Martha

AU - Southey, Melissa C.

AU - Swerdlow, Anthony J.

AU - Toland, Amanda E.

AU - Tomlinson, Ian

AU - Torres, Diana

AU - Truong, Thérèse

AU - Ursin, Giske

AU - Van Der Luijt, Rob B.

AU - Verhoef, Senno

AU - Wang-Gohrke, Shan

AU - Whittemore, Alice S.

AU - Winqvist, Robert

AU - Pilar Zamora, M.

AU - Zhao, Hui

AU - Dunning, Alison M.

AU - Simard, Jacques

AU - Hall, Per

AU - Kraft, Peter

AU - Pharoah, Paul

AU - Hunter, David

AU - Easton, Douglas F.

AU - Zheng, Wei

N1 - Funding Information: 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-F2â2009-223175) (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 CA148112âthe 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 SÃ©curitÃ© 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 TemÃ¡tica de InvestigaciÃ³n Cooperativa en CÃ¡ncer, and grants from the AsociaciÃ³n EspaÃ±ola Contra el CÃ¡ncer and the Fondo de InvestigaciÃ³n 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 SectionÂ 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden WÃ¼rttemberg 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 byÂ 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 '5Â ÃÂ 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' programâGrant No CRN-87521 and the Ministry of Economic Development, Innovation and Export TradeâGrant 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 MÃ¤rit 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 FundâESF), and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)âARISTEIA. 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. Publisher Copyright: © 2016, Springer International Publishing Switzerland.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Epidemiology

KW - GWAS

KW - Genetic susceptibility

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=84962776158&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962776158&partnerID=8YFLogxK

U2 - 10.1007/s10552-016-0741-6

DO - 10.1007/s10552-016-0741-6

M3 - Article

C2 - 27053251

AN - SCOPUS:84962776158

SN - 0957-5243

VL - 27

SP - 679

EP - 693

JO - Cancer Causes and Control

JF - Cancer Causes and Control

IS - 5

ER -

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

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