Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study

Xia Jiang; Niki L Dimou; Kawthar Al-Dabhani; Sarah J Lewis; Richard M Martin; Philip C Haycock; Marc J Gunter; Timothy J Key; Rosalind A Eeles; Kenneth Muir; David Neal; Graham G Giles; Edward L Giovannucci; Meir Stampfer; Brandon L Pierce; Joellen M Schildkraut; Shaneda Warren Andersen; Deborah Thompson; Wei Zheng; Peter Kraft; Konstantinos K Tsilidis; PRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia

doi:10.1093/ije/dyy284

Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study

Int J Epidemiol. 2019 Oct 1;48(5):1416-1424. doi: 10.1093/ije/dyy284.

Authors

Xia Jiang^{1

2}, Niki L Dimou³, Kawthar Al-Dabhani⁴, Sarah J Lewis^{5

6}, Richard M Martin^{5

6

7}, Philip C Haycock^{5

6}, Marc J Gunter⁸, Timothy J Key⁹, Rosalind A Eeles^{10

11}, Kenneth Muir¹², David Neal^{13

14}, Graham G Giles^{15

16

17}, Edward L Giovannucci^{18

19

20}, Meir Stampfer^{18

19

20}, Brandon L Pierce^{21

22

23}, Joellen M Schildkraut²⁴, Shaneda Warren Andersen²⁵, Deborah Thompson²⁶, Wei Zheng²⁷, Peter Kraft¹, Konstantinos K Tsilidis^{3

4}; PRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia

Affiliations

¹ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² Cardiovascular Epidemiology Unit, Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³ Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece.
⁴ Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.
⁵ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁶ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁷ National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.
⁸ Nutritional Epidemiology Group, Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France.
⁹ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁰ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹¹ Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, UK.
¹² Institute of Population Health, University of Manchester, Manchester, UK.
¹³ Nuffield Department of Surgery, University of Oxford, Oxford, UK.
¹⁴ Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁵ Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁷ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
¹⁸ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁰ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
²² Department of Human Genetics, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA.
²³ Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
²⁴ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
²⁵ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
²⁷ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Abstract

Background: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power.

Methods: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods.

Results: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy.

Conclusions: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.

Keywords: Mendelian randomization; breast; malignancy; prostate; serum vitamin D concentrations.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Breast Neoplasms / epidemiology*
Breast Neoplasms / genetics
Causality
Female
Genome-Wide Association Study
Humans
Male
Mendelian Randomization Analysis
Middle Aged
Polymorphism, Single Nucleotide
Prostatic Neoplasms / epidemiology*
Prostatic Neoplasms / genetics
Receptors, Estrogen / biosynthesis
Risk Factors
Vitamin D / blood*

Substances

Receptors, Estrogen
Vitamin D

Abstract

Publication types

MeSH terms

Substances

Grants and funding