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

Jue Sheng Ong, QIMR Berghofer Medical Research Institute
Gabriel Cuellar-Partida, QIMR Berghofer Medical Research Institute
Yi Lu, QIMR Berghofer Medical Research Institute
Peter A. Fasching, David Geffen School of Medicine at UCLA
Alexander Hein, Universitätsklinikum Erlangen
Stefanie Burghaus, Universitätsklinikum Erlangen
Matthias W. Beckmann, Universitätsklinikum Erlangen
Diether Lambrechts, Departement Menselijke Erfelijkheid
Els Van Nieuwenhuysen, KU Leuven– University Hospital Leuven
Ignace Vergote, KU Leuven– University Hospital Leuven
Adriaan Vanderstichele, KU Leuven– University Hospital Leuven
Jennifer Anne Doherty, Geisel School of Medicine at Dartmouth
Mary Anne Rossing, University of Washington
Jenny Chang-Claude, German Cancer Research Center
Ursula Eilber, German Cancer Research Center
Anja Rudolph, German Cancer Research Center
Shan Wang-Gohrke, Universität Ulm
Marc T. Goodman, Cedars-Sinai Medical Center
Natalia Bogdanova, Medizinische Hochschule Hannover (MHH)
Thilo Dörk, Medizinische Hochschule Hannover (MHH)
Matthias Dürst, Friedrich-Schiller-Universität Jena


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.