Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 1, Pages 285-298Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu431
Keywords
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Funding
- European Community [223175, HEALTH-F2-2009-223175]
- Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/ A11174, C1281/Al2014, C5047/A8384, C5047/A15007, C5047/A10692]
- National Institutes of Health [CA128978, RO1 CA77398]
- Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- Department of Defence [W81XWH-10-1 -0341]
- Canadian Institutes of Health Research (CIHR)
- Komen Foundation for the Cure
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund
- United States National Cancer Institute
- National Institutes of Health (NIH) [RFA-CA-06-503, U01 CA69467, U01 CA69417, U01 CA69638]
- National Health and Medical Research Council of Australia
- New South Wales Cancer Council
- Victorian Health Promotion Foundation (Australia)
- Victorian Breast Cancer Research Consortium
- Dutch Cancer Society [NKI 2007-3839, 2009 4363, RUL 1997-1505]
- Dutch government [NWO 184.021.007]
- Dutch National Genomics Initiative
- Breast Cancer Research Trust, UK
- ELAN-Fond of the University Hospital of Erlangen
- UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
- Breakthrough Breast Cancer
- NHS
- National Cancer Research Network (NCRN)
- Institut National de Cancer
- NIHR Comprehensive Biomedical Research Centre
- Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK
- Oxford Biomedical Research Centre
- Dietmar-Hopp Foundation
- Helmholtz Society
- German Cancer Research Center (DKFZ)
- Fondation de France
- Institut National du Cancer (INCa)
- Ligue Nationale contre le Cancer
- Ligue contre le Cancer Grand Ouest
- Agence Nationale de Securite Sanitaire (ANSES)
- Agence Nationale de la Recherche (ANR)
- Chief Physician Johan Boserup
- Lise Boserup Fund
- Danish Medical Research Council
- Herlev Hospital
- Genome Spain Foundation
- Red Tematica de Investigacion Cooperativa en Cancer
- Asociacion Espaliola Contra el Cancer
- Fondo de Investigacion Sanitario [PI11/00923, PI081120]
- Instituto de Salud Carlos III
- California Breast Cancer Act
- Lon V Smith Foundation [LV539420]
- California Breast Cancer Research Fund [97-10500]
- California Department of Public Health [103885]
- Baden Wurttemberg Ministry of Science, Research and Arts
- German Cancer Aid (Deutsche Krebshilfe)
- German Cancer Aid [109076]
- Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]
- 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), Bochum, Germany
- Department of Internal Medicine
- Evangelische Kliniken Bonn gGmbH
- Johanniter Krankenhaus, Bonn, Germany
- Helsinki University Central Hospital Research Fund
- Academy of Finland [266528]
- Finnish Cancer Society
- Nordic Cancer Union
- Sigrid Juselius Foundation
- Nordic Center of Excellence in Disease Genetics based on samples regionally selected from Finland
- Ministry of Education, Science, Sports, Culture and Technology of Japan
- Ministry Health, Labour and Welfare of Japan
- Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan
- National Cancer Center Research and Development Fund
- Friends of Hannover Medical School
- Rudolf Baffling Foundation
- Stockholm County Council
- Karolinska Institutet
- Swedish Cancer Society
- Gustav V Jubilee foundation
- special Government Funding (EVO) of Kuopio University Hospital grants
- Cancer Fund of North Savo
- Finnish Cancer Organizations
- Academy of Finland
- strategic funding of the University of Eastern Finland
- National Breast Cancer Foundation
- NHMRC
- Queensland Cancer Fund
- Cancer Councils of New South Wales
- Victoria, Tasmania and South Australia
- Cancer Foundation of Western Australia
- NHMRC [145684, 288704, 454508, 199600]
- United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council of Tasmania and Human Molecular Genetics [I 295]
- California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]
- California Department of Health
- National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]
- Stichting tegen Kanker' [232-2008, 196-2010]
- FWO
- Deutsche Krebshilfe e.V. [70-2892-BR I]
- Hamburg Cancer Society
- German Cancer Research Center
- Federal Ministry of Education and Research (BMBF) German [01KH0402, 01KH0408, 01KH0409]
- Italian Association for Cancer Research (AIRC)
- NTH [CA128978]
- NTH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- David F. and Margaret T. Grohne Family Foundation
- Ting Tsung and Wei Fong Chao Foundation
- VicHealth and Cancer Council Victoria
- Australian NHMRC [209057, 251553, 504711]
- NIH [CA63464, CA54281, CA098758, CA132839, R01CA100374]
- Quebec Breast Cancer Foundation
- Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program [CRN-87521]
- Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]
- Malaysian Ministry of Science, Technology and Innovation (MOSTI)
- Malaysian Ministry of Higher Education [UM.C/H1R/MOHE/06]
- Cancer Research Initiatives Foundation (CARIF)
- Biomedical Research Council, Singapore [BMRC08/1/35/19/550]
- National medical Research Council, Singapore [NMRC/CG/SERI/2010]
- Norwegian Research council [155218/V40, 175240/S10, FUGE-NFR 181600N11, 155218/ V40]
- Swizz Bridge Award
- Finnish Cancer Foundation
- Academy of Finland Centre [251314]
- University of Oulu
- Oulu University Hospital special Govermental EVO Research Funds
- National Cancer Institute [UM1 CA164920]
- Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]
- Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA
- Writ and Hans Rausings Initiative Against Breast Cancer
- Agency for Science, Technology and Research of Singapore (A* STAR)
- US National Institute of Health (NIH)
- Susan G. Komen Breast Cancer Foundation
- NIH grants [RO1CA64277, RO1CA148667, R37CA70867, CA 65725, CA87969, CA49449, CA67262, CA50385, 5U01CA098233]
- Yorkshire Cancer Research awards [S295, S299, 5305PA]
- Sheffield Experimental Cancer Medicine Centre Network
- NCI [RO1 CA163353]
- Avon Foundation [02-2009-080]
- National Institute of Health [R01 CA092447]
- National Program of Cancer Registries
- Centers for Disease Control and Prevention (CDC)
- Korea Health 21 RD Project [A030001]
- Ministry of Health and Welfare, Republic of Korea
- National Medical Research Council
- Biomedical Research Council [05/1/21/19/ 425]
- DKFZ
- National Cancer Institute Thailand
- MCBCS (National Institutes of Health) [CA116167, CA176785]
- Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- European Union (European Social Fund ESF)
- Greek national funds through the Operational Program Education and Lifelong Learning of the National Strategic Reference Framework (NSRF) Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA
- Taiwan Biobank project of the Institute of Biomedical Sciences
- Academia Sinica, Taiwan
- Institute of Cancer Research (ICR)
- Wellcome Trust
- Cancer Research [C8620/A8372]
- Netherlands Organisation for Scientific Research (NWO) as part of a ZonMwNIDI grant [91756341]
- NWO Groot Investments [175.010.2005.011]
- [KULPFV/10/016-SymBioSysII]
- [P30 CA68485]
- [DDHK 2004-3124]
- [DDHK 2009-4318]
- [NMRC/CG/NCIS /2010]
- [PBZ_KBN_122/P05/2004]
- Cancer Research UK [16561, 11022, 16563, 10118, 15106] Funding Source: researchfish
- National Institute for Health Research [03/DHCS/03/G121/51] Funding Source: researchfish
- Cancer Foundation Finland sr [140141, 130168] Funding Source: researchfish
- National Breast Cancer Foundation [PF-11-20, IF-12-06] Funding Source: researchfish
- The Francis Crick Institute [10124] Funding Source: researchfish
- NATIONAL CANCER INSTITUTE [R01CA100374, R01CA148667, R01CA092447, P50CA116201, U01CA063464, U01CA069467, R01CA116167, R01CA067262, U19CA148112, R01CA054281, R01CA176785, R01CA132839, R01CA049449, U19CA148065, U01CA067262, R01CA077398, U01CA098758, R01CA128978, P30CA068485, P01CA087969, R01CA064277, U01CA069638, U19CA148537, R01CA163353, R37CA070867, P30CA015083, U01CA116167, U01CA049449, ZIACP010126, R01CA050385, R01CA063464, UM1CA164920, U01CA069417, R37CA054281, U01CA098233, R01CA065725] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH090941, R01MH090948, R01MH090951, R01MH090937, R01MH090936] Funding Source: NIH RePORTER
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Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, Cl)] for the minor allele of 1.05(1.03-1.07), P = 1 x 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 x 10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
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