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Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4761 (Published 31 October 2017) Cite this as: BMJ 2017;359:j4761

Circulating Vitamin D Concentration and Risk of Breast Cancer: A Mendelian Randomization Study

Dimitrakopoulou et al. recently published Mendelian randomization analyses which leveraged large genetic epidemiology networks involving a total of 70,563 cancer cases (breast, prostate, lung, ovarian, colorectal, pancreatic, and neuroblastoma) and 84,418 controls to determine if circulating concentrations of vitamin D are causally associated with cancer risk [1]. The authors found little evidence for a linear causal association of serum vitamin D levels with risk of any of the seven cancers or subtypes. In particular, for breast cancer, GWAS summary statistics based on 15,748 cases and 18,084 controls (of which 4,939 were Estrogen Receptor negative (ER-) cases) as collected by DRIVE was used.

We update these analyses using two new GWAS of breast cancer including 122,977 overall cases (105,974 controls) and 21,468 ER cases (100,594 controls) [2,3] and an updated GWAS of circulating vitamin D concentrations, performed in 79,366 individuals, which replicated four and identified two new vitamin D (25(OH)D) genetic loci [4] (Table1). In concordance with previous reported findings [1], and as shown in Table2, the odds ratio per unit increase in the natural log-scale of genetically-predicted 25(OH)D concentration using inverse-variance weighted method was 1.05 (95%CI: 0.92-1.19) for overall breast cancer, 1.00 (0.86-1.16) for the ER+ subset, and 1.05 (0.78-1.40) for the ER- subset.

Causal inference of the inverse-variance weighted Mendelian randomization requires several assumptions being met, we also performed MR-Egger regression which is robust to some violation of these assumptions. We did not find any significant effect (MR-Egger, overall: 1.04 (0.81-1.33); ER+: 1.03 (0.78, 1.35); ER-: 1.15 (0.64-2.08)), with no evidence for directional pleiotropy (P-value for intercept from MR-Egger regression: 0.92, 0.82 and 0.70, respectively). A weighted median Mendelian randomization analysis did not alter the estimates apparently (overall: 1.05 (0.91-1.20); ER+: 1.00 (0.85-1.18); ER-: 1.13 (0.87-1.46)). Our updated results provide no evidence of a putative causal relationship between serum vitamin D levels and risk of breast cancer.

A link to Table1 and Table2 https://drive.google.com/open?id=1ksH5-hhEqz-JPXMlppZZouXBnJG3b5qf

Xia Jiang, Postdoctoral Fellow1, Shaneda Warren Andersen, Assistant Professor2, Niki L Dimou, Post-doctoral Fellow3, Deborah Thompson, Professor4, Konstantinos K Tsilidis, Assistant Professor3,5, Wei Zheng, Professor2, Peter Kraft, Professor1

1. Department of Epidemiology and Biostatistics, Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston 02115, MA, USA.
2. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville 37232, TN, USA.
3. Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece.
4. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK.
5. Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.

References:
1 Dimitrakopoulou VI, Tsilidis KK, Haycock PC, et al. Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study. BMJ 2017;359:j4761.
2 Milne RL, Kuchenbaecker KB, Michailidou K, et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet Published Online First: 23 October 2017. doi:10.1038/ng.3785
3 Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature Published Online First: 23 October 2017. doi:10.1038/nature24284
4 Jiang X, O’Reilly PF, Aschard H, et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun 2018;9:260. doi:10.1038/s41467-017-02662-2

Acknowledgements
The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders for the breast cancer genome-wide association analyses are listed in Michailidou et al. (2017) and Milne et al. (2017). All studies and funders for the vitamin D genome-wide association analyses are listed in Jiang et al. (2018). The authors would like to thank the Breast Cancer Association Consortium (BCAC) for providing GWAS summary estimates of breast cancer, and the SUNLIGHT consortium for providing GWAS summary estimates of circulating vitamin D concentrations.

Competing interests: No competing interests

19 January 2018
Xia Jiang
Postdoctoral research fellow
Shaneda Warren Andersen, Assistant Professor, Niki L Dimou, Post-doctoral Fellow, Deborah Thompson, Professor, Konstantinos K Tsilidis, Assistant Professor, Wei Zheng, Professor, Peter Kraft, Professor
Harvard T.H.Chan School of Public Health
Department of Epidemiology and Biostatistics, Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston 02115, MA, USA.