Journal
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Volume 49, Issue 4, Pages 1117-1131Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ije/dyz242
Keywords
Breast cancer; lipids; cholesterol; genetics; Mendelian randomization; instrumental variable; epidemiology
Categories
Funding
- National Cancer Institute at the National Institutes of Health [R37CA070867]
- National Institutes of Health [R25CA160056, CA128978, R01 CA77398, CA116167, CA176785, CA192393, CA63464, CA54281, CA098758, CA132839, R01CA100374, P30 CA68485, UM1 CA164920]
- Cancer Research UK [C1287/A16563, C1287/A12014, C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C490/A10124, C490/A16561]
- European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]
- Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- Department of Defense [W81XWH-10-1-0341]
- Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer
- Komen Foundation for the Cure
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund
- NIH [U19 CA148065]
- Cancer UK Grant [C1287/A16563]
- Government of Canada through Genome Canada
- Canadian Institutes of Health Research [GPH-129344]
- Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec
- Quebec Breast Cancer Foundation
- National Institutes of Health (USA) [UM1 CA164920]
- 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, DDHK 2004-3124, DDHK 2009-4318]
- BBMRI-NL
- Dutch government [NWO 184.021.007]
- ELAN-Fond of the University Hospital of Erlangen
- Cancer Research UK
- Breakthrough Breast Cancer
- NHS
- National Cancer Research Network (NCRN)
- NIHR Comprehensive Biomedical Research Centre
- Guy's & St Thomas' NHS Foundation Trust
- King's College London, UK
- Oxford Biomedical Research Centre
- Dietmar-Hopp Foundation
- Fondation de France
- Institut National du Cancer (INCa)
- Ligue Nationale contre le Cancer
- Agence Nationale de Securite Sanitaire (ANSES)
- Agence Nationale de la Recherche (ANR)
- Chief Physician Johan Boserup and Lise Boserup Fund
- Danish Medical Research Council
- Herlev Hospital
- Spanish Network on Rare Diseases (CIBERER)
- Asociacion Espanola Contra el Cancer
- Fondo de Investigacion Sanitario [PI11/00923, PI12/00070]
- Instituto de Salud Carlos III
- California Breast Cancer Act of 1993
- California Breast Cancer Research Fund [97-10500]
- California Department of Public Health as part of the statewide cancer reporting programme [103885]
- Lon V Smith Foundation [LVS39420]
- Baden Wurttemberg Ministry of Science, Research and Arts
- German Cancer Aid (Deutsche Krebshilfe)
- Deutsche Krebshilfe [107 352]
- Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]
- Robert Bosch Foundation, Stuttgart
- Deutsches Krebsforschungszentrum (DKFZ), Heidelberg
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance
- Institute of the RuhrUniversity Bochum (IPA)
- Department of Internal Medicine
- Evangelische Kliniken Bonn gGmbH
- Johanniter Krankenhaus Bonn, Germany
- Finnish Cancer Society
- Sigrid Juselius Foundation
- Rudolf Bartling Foundation
- Stockholm County Council
- Karolinska Institutet
- Swedish Cancer Society
- Gustav V Jubilee foundation
- Bert von Kantzows Foundation
- special Government Funding (EVO) of Kuopio University Hospital grants
- Cancer Fund of North Savo
- Academy of Finland
- University of Eastern Finland
- National Breast Cancer Foundation
- National Health and Medical Research Council (NHMRC)
- Queensland Cancer Fund
- Cancer Council of New South Wales
- Cancer Council of Victoria
- Cancer Council of Tasmania
- Cancer Council of South Australia
- Cancer Foundation of Western Australia
- Stichting tegen Kanker [232-2008, 196-2010]
- FWO
- ERC consolidator grant
- Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]
- Hamburg Cancer Society
- German Cancer Research Center (DKFZ)
- Italian Association for Cancer Research (AIRC)
- Fondazione IRCCS Istituto Nazionale Tumori
- National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- VicHealth
- Australian NHMRC [209057, 251553, 504711]
- 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]
- Norwegian Research council [155218/V40, 175240/S10, FUGE-NFR 181600/V11]
- Finnish Cancer Foundation
- Academy of Finland [250083, 122715, 266528]
- Academy of Finland (Center of Excellence) [251314]
- University of Oulu
- University of Oulu Support Foundation
- special Governmental EVO funds for Oulu University Hospital-based research activities
- Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]
- National Cancer Institute, Department of Health and Human Services, USA
- Marit and Hans Rausings Initiative Against Breast Cancer
- Agency for Science, Technology and Research of Singapore (A*STAR)
- US National Institute of Health
- Susan G Komen Breast Cancer Foundation
- Sheffield Experimental Cancer Medicine Centre
- Breast Cancer Now Tissue Bank
- UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
- DKFZ
- Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- Hellenic Cooperative Oncology Group research grant [HR R_BG/04]
- Greek General Secretary for Research and Technology (GSRT) Program
- European Union (European Social Fund -ESF)
- Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) -ARISTEIA
- Breast Cancer Now
- Institute of Cancer Research (ICR), London
- Helmholtz Society
- Helsinki University Central Hospital Research Fund
- Cancer Council Victoria
- [PSRSIIRI-701]
- [KULPFV/10/016-SymBioSysII]
- [PBZ_KBN_122/P05/2004]
Ask authors/readers for more resources
Background: Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. Methods: Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. Results: Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08-1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. Conclusions: This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.
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