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Int J Epidemiol. 2016 Oct;45(5):1619-1630. Epub 2016 Sep 4.

Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Ong JS1,2, Cuellar-Partida G1,2, Lu Y1; Australian Ovarian Cancer Study, Fasching PA3,4, Hein A4, Burghaus S4, Beckmann MW4, Lambrechts D5,6, Van Nieuwenhuysen E7, Vergote I7, Vanderstichele A7, Anne Doherty J1,2, Anne Rossing M8,9, Chang-Claude J10, Eilber U10, Rudolph A10, Wang-Gohrke S11, Goodman MT12,13, Bogdanova N14, Dörk T15, Dürst M16, Hillemanns P17, Runnebaum IB16, Antonenkova N18, Butzow R19, Leminen A20, Nevanlinna H20, Pelttari LM20, Edwards RP21,22, Kelley JL21, Modugno F, Moysich KB23, Ness RB24, Cannioto R23, Høgdall E25,26, Høgdall CK27, Jensen A25, Giles GG, Bruinsma F28, Kjaer SK25,27, Hildebrandt MA29, Liang D30, Lu KH31, Wu X29, Bisogna M32, Dao F32, Levine DA32, Cramer DW33, Terry KL33, Tworoger SS34,35, Stampfer M34,35, Missmer S, Bjorge L36,37, Salvesen HB36,37, Kopperud RK36,37, Bischof K36,37, Aben KK38,39, Kiemeney LA38, Massuger LF40, Brooks-Wilson A41,42, Olson SH43, McGuire V44, Rothstein JH44, Sieh W44, Whittemore AS44, Cook LS45, Le ND46, Gilks CB47, Gronwald J48, Jakubowska A48, Lubiński J48, Kluz T49, Song H50, Tyrer JP50, Wentzensen N51, Brinton L51, Trabert B51, Lissowska J52, McLaughlin JR53, Narod SA54, Phelan C55, Anton-Culver H56,57, Ziogas A56, Eccles D58, Campbell I59, Gayther SA60, Gentry-Maharaj A61, Menon U61, Ramus SJ60, Wu AH60, Dansonka-Mieszkowska A62, Kupryjanczyk J63, Timorek A63, Szafron L62, Cunningham JM64, Fridley BL65, Winham SJ66, Bandera EV67, Poole EM34,35, Morgan TK68, Risch HA69, Goode EL70, Schildkraut JM71,72, Pearce CL60,73, Berchuck A74, Pharoah PD75,50, Chenevix-Trench G76, Gharahkhani P1, Neale RE77,78, Webb PM77, MacGregor S79.

Author information

1
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
2
School of Medicine, University of Queensland, St Lucia, QLD 4072, Australia.
3
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles.
4
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
5
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium.
6
Vesalius Research Center, VIB, Leuven, Belgium.
7
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
8
Department of Epidemiology, University of Washington, Seattle, WA, USA.
9
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
10
German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
11
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
12
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
13
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
14
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
15
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
16
Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, Germany.
17
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
18
N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.
19
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
20
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
21
Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
22
Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
23
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
24
The University of Texas School of Public Health, Houston, TX, USA.
25
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
26
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
27
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
28
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
29
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
30
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
31
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
32
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
33
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
34
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
35
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
36
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
37
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
38
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, Netherlands.
39
Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
40
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Obstetrics and Gynaecology, Nijmegen, The Netherlands.
41
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
42
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
43
Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY, USA.
44
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.
45
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
46
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
47
Pathology and Laboratory Medicine, University of British Columbia, Vancouver BC, Canada.
48
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
49
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.
50
The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
51
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
52
Department of Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.
53
Public Health Ontario, Toronto, ON, Canada.
54
Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.
55
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
56
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
57
Center for Cancer Genetics Research & Prevention, School of Medicine, University of California Irvine, Irvine, CA, USA.
58
Faculty of Medicine, University of Southampton, Southampton, UK.
59
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
60
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
61
Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
62
Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
63
Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
64
Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
65
Department of Biostatistics, University of Kansas, Kansas City, KS, USA.
66
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
67
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
68
Departments of Pathology and Obstetrics & Gynaecology, OHSU, Portland, OR, USA.
69
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
70
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
71
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
72
Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
73
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
74
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA and.
75
The Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
76
Cancer Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
77
Gynaecological Cancers laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
78
Cancer Aetiology and Prevention laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
79
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia, stuart.macgregor@qimrberghofer.edu.au.

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.

PMID:
27594614
PMCID:
PMC5100621
DOI:
10.1093/ije/dyw207
[Indexed for MEDLINE]
Free PMC Article

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