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Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.
Int J Epidemiol. 2016 10; 45(5):1619-1630.IJ

Abstract

BACKGROUND

In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.

METHODS

We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).

RESULTS

The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).

CONCLUSIONS

Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Authors+Show Affiliations

Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia. School of Medicine, University of Queensland, St Lucia, QLD 4072, Australia.Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia. School of Medicine, University of Queensland, St Lucia, QLD 4072, Australia.Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.No affiliation info availableDivision of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles. University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium. Vesalius Research Center, VIB, Leuven, Belgium.Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia. School of Medicine, University of Queensland, St Lucia, QLD 4072, Australia.Department of Epidemiology, University of Washington, Seattle, WA, USA. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, Germany.Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, Germany.N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.No affiliation info availableDepartment of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.The University of Texas School of Public Health, Houston, TX, USA.Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.No affiliation info availableCancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.No affiliation info availableDepartment of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, Netherlands. Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, Netherlands.Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Obstetrics and Gynaecology, Nijmegen, The Netherlands.Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY, USA.Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.Pathology and Laboratory Medicine, University of British Columbia, Vancouver BC, Canada.International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.Institute of Midwifery and Emergency Medicine, Clinic of Obstetrics and Gynecology, Frederick Chopin Clinical Provincial Hospital No 1, Faculty of Medicine, University of Rzeszów, Poland.The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.Department of Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.Public Health Ontario, Toronto, ON, Canada.Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.Department of Epidemiology, University of California Irvine, Irvine, CA, USA. Center for Cancer Genetics Research & Prevention, School of Medicine, University of California Irvine, Irvine, CA, USA.Department of Epidemiology, University of California Irvine, Irvine, CA, USA.Faculty of Medicine, University of Southampton, Southampton, UK.Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.Department of Biostatistics, University of Kansas, Kansas City, KS, USA.Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.Departments of Pathology and Obstetrics & Gynaecology, OHSU, Portland, OR, USA.Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA. Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA and.The Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Cancer Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.Gynaecological Cancers laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia. Cancer Aetiology and Prevention laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.Gynaecological Cancers laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia, stuart.macgregor@qimrberghofer.edu.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27594614

Citation

Ong, Jue-Sheng, et al. "Association of Vitamin D Levels and Risk of Ovarian Cancer: a Mendelian Randomization Study." International Journal of Epidemiology, vol. 45, no. 5, 2016, pp. 1619-1630.
Ong JS, Cuellar-Partida G, Lu Y, et al. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. Int J Epidemiol. 2016;45(5):1619-1630.
Ong, J. S., Cuellar-Partida, G., Lu, Y., Fasching, P. A., Hein, A., Burghaus, S., Beckmann, M. W., Lambrechts, D., Van Nieuwenhuysen, E., Vergote, I., Vanderstichele, A., Anne Doherty, J., Anne Rossing, M., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M. T., Bogdanova, N., ... MacGregor, S. (2016). Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. International Journal of Epidemiology, 45(5), 1619-1630.
Ong JS, et al. Association of Vitamin D Levels and Risk of Ovarian Cancer: a Mendelian Randomization Study. Int J Epidemiol. 2016;45(5):1619-1630. PubMed PMID: 27594614.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. AU - Ong,Jue-Sheng, AU - Cuellar-Partida,Gabriel, AU - Lu,Yi, AU - ,, AU - Fasching,Peter A, AU - Hein,Alexander, AU - Burghaus,Stefanie, AU - Beckmann,Matthias W, AU - Lambrechts,Diether, AU - Van Nieuwenhuysen,Els, AU - Vergote,Ignace, AU - Vanderstichele,Adriaan, AU - Anne Doherty,Jennifer, AU - Anne Rossing,Mary, AU - Chang-Claude,Jenny, AU - Eilber,Ursula, AU - Rudolph,Anja, AU - Wang-Gohrke,Shan, AU - Goodman,Marc T, AU - Bogdanova,Natalia, AU - Dörk,Thilo, AU - Dürst,Matthias, AU - Hillemanns,Peter, AU - Runnebaum,Ingo B, AU - Antonenkova,Natalia, AU - Butzow,Ralf, AU - Leminen,Arto, AU - Nevanlinna,Heli, AU - Pelttari,Liisa M, AU - Edwards,Robert P, AU - Kelley,Joseph L, AU - Modugno,Francesmary, AU - Moysich,Kirsten B, AU - Ness,Roberta B, AU - Cannioto,Rikki, AU - Høgdall,Estrid, AU - Høgdall,Claus K, AU - Jensen,Allan, AU - Giles,Graham G, AU - Bruinsma,Fiona, AU - Kjaer,Susanne K, AU - Hildebrandt,Michelle At, AU - Liang,Dong, AU - Lu,Karen H, AU - Wu,Xifeng, AU - Bisogna,Maria, AU - Dao,Fanny, AU - Levine,Douglas A, AU - Cramer,Daniel W, AU - Terry,Kathryn L, AU - Tworoger,Shelley S, AU - Stampfer,Meir, AU - Missmer,Stacey, AU - Bjorge,Line, AU - Salvesen,Helga B, AU - Kopperud,Reidun K, AU - Bischof,Katharina, AU - Aben,Katja Kh, AU - Kiemeney,Lambertus A, AU - Massuger,Leon Fag, AU - Brooks-Wilson,Angela, AU - Olson,Sara H, AU - McGuire,Valerie, AU - Rothstein,Joseph H, AU - Sieh,Weiva, AU - Whittemore,Alice S, AU - Cook,Linda S, AU - Le,Nhu D, AU - Gilks,C Blake, AU - Gronwald,Jacek, AU - Jakubowska,Anna, AU - Lubiński,Jan, AU - Kluz,Tomasz, AU - Song,Honglin, AU - Tyrer,Jonathan P, AU - Wentzensen,Nicolas, AU - Brinton,Louise, AU - Trabert,Britton, AU - Lissowska,Jolanta, AU - McLaughlin,John R, AU - Narod,Steven A, AU - Phelan,Catherine, AU - Anton-Culver,Hoda, AU - Ziogas,Argyrios, AU - Eccles,Diana, AU - Campbell,Ian, AU - Gayther,Simon A, AU - Gentry-Maharaj,Aleksandra, AU - Menon,Usha, AU - Ramus,Susan J, AU - Wu,Anna H, AU - Dansonka-Mieszkowska,Agnieszka, AU - Kupryjanczyk,Jolanta, AU - Timorek,Agnieszka, AU - Szafron,Lukasz, AU - Cunningham,Julie M, AU - Fridley,Brooke L, AU - Winham,Stacey J, AU - Bandera,Elisa V, AU - Poole,Elizabeth M, AU - Morgan,Terry K, AU - Risch,Harvey A, AU - Goode,Ellen L, AU - Schildkraut,Joellen M, AU - Pearce,Celeste L, AU - Berchuck,Andrew, AU - Pharoah,Paul Dp, AU - Chenevix-Trench,Georgia, AU - Gharahkhani,Puya, AU - Neale,Rachel E, AU - Webb,Penelope M, AU - MacGregor,Stuart, Y1 - 2016/09/04/ PY - 2016/06/24/accepted PY - 2016/9/7/pubmed PY - 2018/2/6/medline PY - 2016/9/6/entrez SP - 1619 EP - 1630 JF - International journal of epidemiology JO - Int J Epidemiol VL - 45 IS - 5 N2 - BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer. SN - 1464-3685 UR - https://www.unboundmedicine.com/medline/citation/27594614/Association_of_vitamin_D_levels_and_risk_of_ovarian_cancer:_a_Mendelian_randomization_study_ L2 - https://academic.oup.com/ije/article-lookup/doi/10.1093/ije/dyw207 DB - PRIME DP - Unbound Medicine ER -