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



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).



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).



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.
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.|School of Medicine, University of Queensland, St Lucia, QLD 4072, Australia.
Jue-Sheng
JS
Ong
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.|School of Medicine, University of Queensland, St Lucia, QLD 4072, Australia.
Gabriel
G
Cuellar-Partida
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Yi
Y
Lu
Division 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.
Peter A
PA
Fasching
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
Alexander
A
Hein
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
Stefanie
S
Burghaus
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
Matthias W
MW
Beckmann
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium.|Vesalius Research Center, VIB, Leuven, Belgium.
Diether
D
Lambrechts
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
Els
E
Van Nieuwenhuysen
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
Ignace
I
Vergote
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
Adriaan
A
Vanderstichele
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.|School of Medicine, University of Queensland, St Lucia, QLD 4072, Australia.
Jennifer
J
Anne Doherty
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.
Mary
M
Anne Rossing
German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
Jenny
J
Chang-Claude
German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
Ursula
U
Eilber
German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
Anja
A
Rudolph
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
Shan
S
Wang-Gohrke
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.
Marc T
MT
Goodman
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
Natalia
N
Bogdanova
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Thilo
T
Dörk
Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, Germany.
Matthias
M
Dürst
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
Peter
P
Hillemanns
Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, Germany.
Ingo B
IB
Runnebaum
N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.
Natalia
N
Antonenkova
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Ralf
R
Butzow
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Arto
A
Leminen
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Heli
H
Nevanlinna
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Liisa M
LM
Pelttari
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.
Robert P
RP
Edwards
Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Joseph L
JL
Kelley
Francesmary
F
Modugno
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
Kirsten B
KB
Moysich
The University of Texas School of Public Health, Houston, TX, USA.
Roberta B
RB
Ness
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
Rikki
R
Cannioto
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.
Estrid
E
Høgdall
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Claus K
CK
Høgdall
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
Allan
A
Jensen
Graham G
GG
Giles
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
Fiona
F
Bruinsma
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Susanne K
SK
Kjaer
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michelle At
MA
Hildebrandt
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
Dong
D
Liang
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Karen H
KH
Lu
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Xifeng
X
Wu
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Maria
M
Bisogna
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Fanny
F
Dao
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Douglas A
DA
Levine
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
Daniel W
DW
Cramer
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
Kathryn L
KL
Terry
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.
Shelley S
SS
Tworoger
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.
Meir
M
Stampfer
Stacey
S
Missmer
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
Line
L
Bjorge
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
Helga B
HB
Salvesen
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
Reidun K
RK
Kopperud
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
Katharina
K
Bischof
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, Netherlands.|Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
Katja Kh
KK
Aben
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, Netherlands.
Lambertus A
LA
Kiemeney
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Obstetrics and Gynaecology, Nijmegen, The Netherlands.
Leon Fag
LF
Massuger
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.
Angela
A
Brooks-Wilson
Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY, USA.
Sara H
SH
Olson
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.
Valerie
V
McGuire
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.
Joseph H
JH
Rothstein
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.
Weiva
W
Sieh
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford CA, USA.
Alice S
AS
Whittemore
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
Linda S
LS
Cook
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
Nhu D
ND
Le
Pathology and Laboratory Medicine, University of British Columbia, Vancouver BC, Canada.
C Blake
CB
Gilks
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Jacek
J
Gronwald
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Anna
A
Jakubowska
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Jan
J
Lubiński
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.
Tomasz
T
Kluz
The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Honglin
H
Song
The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Jonathan P
JP
Tyrer
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Nicolas
N
Wentzensen
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Louise
L
Brinton
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Britton
B
Trabert
Department of Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.
Jolanta
J
Lissowska
Public Health Ontario, Toronto, ON, Canada.
John R
JR
McLaughlin
Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.
Steven A
SA
Narod
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
Catherine
C
Phelan
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.
Hoda
H
Anton-Culver
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
Argyrios
A
Ziogas
Faculty of Medicine, University of Southampton, Southampton, UK.
Diana
D
Eccles
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Ian
I
Campbell
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
Simon A
SA
Gayther
Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
Aleksandra
A
Gentry-Maharaj
Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
Usha
U
Menon
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
Susan J
SJ
Ramus
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
Anna H
AH
Wu
Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
Agnieszka
A
Dansonka-Mieszkowska
Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
Jolanta
J
Kupryjanczyk
Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
Agnieszka
A
Timorek
Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
Lukasz
L
Szafron
Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
Julie M
JM
Cunningham
Department of Biostatistics, University of Kansas, Kansas City, KS, USA.
Brooke L
BL
Fridley
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
Stacey J
SJ
Winham
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Elisa V
EV
Bandera
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.
Elizabeth M
EM
Poole
Departments of Pathology and Obstetrics & Gynaecology, OHSU, Portland, OR, USA.
Terry K
TK
Morgan
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
Harvey A
HA
Risch
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
Ellen L
EL
Goode
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.|Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
Joellen M
JM
Schildkraut
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.
Celeste L
CL
Pearce
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA and.
Andrew
A
Berchuck
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.
Paul Dp
PD
Pharoah
Cancer Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Georgia
G
Chenevix-Trench
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Puya
P
Gharahkhani
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.
Rachel E
RE
Neale
Gynaecological Cancers laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Penelope M
PM
Webb
Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia, stuart.macgregor@qimrberghofer.edu.au.
Stuart
S
MacGregor
D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D057182:Mendelian Randomization Analysis; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
D014807:Vitamin D; C104450:25-hydroxyvitamin D