Randomized Controlled Trial

. 2018 Aug 14;16(1):142.

doi: 10.1186/s12916-018-1119-2.

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Yazhou He^{1

2

3}, Maria Timofeeva¹, Susan M Farrington¹, Peter Vaughan-Shaw¹, Victoria Svinti¹, Marion Walker¹, Lina Zgaga^{1

4}, Xiangrui Meng³, Xue Li³, Athina Spiliopoulou³, Xia Jiang^{5

6}, Elina Hyppönen^{7

8}, Peter Kraft⁵, Douglas P Kiel^{9

10

11}; SUNLIGHT consortium; Caroline Hayward¹², Archie Campbell¹³, David Porteous¹³, Katarina Vucic¹⁴, Iva Kirac¹⁵, Masa Filipovic¹⁶, Sarah E Harris^{17

18}, Ian J Deary^{17

19}, Richard Houlston²⁰, Ian P Tomlinson²¹, Harry Campbell^{1

3}, Evropi Theodoratou^{22

23}, Malcolm G Dunlop²⁴

Collaborators, Affiliations

Collaborators

SUNLIGHT consortium:
Xia Jiang, Elina Hyppönen, Peter Kraft, Douglas P Kiel

Affiliations

¹ Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK.
² West China School of Medicine/West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
³ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK.
⁴ Department of Public Health and Primary Care, Institute of Population Health, Trinity College Dublin, University of Dublin, Dublin 24, D02 PN40, Ireland.
⁵ Program in Genetic Epidemiology and Statistical Genetics. Department of Epidemiology, Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.
⁶ Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobels vagen 13, Stockholm, 17177, Sweden.
⁷ Australian Centre for Precision Health, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, 5001, Australia.
⁸ Population, Policy and Practice, University College London, Great Ormond Street, Institute of Child Health, WC1E 6BT, London, UK.
⁹ Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA, 02131, USA.
¹⁰ Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA.
¹¹ Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, 02142, USA.
¹² MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
¹³ Generation Scotland, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.
¹⁴ Agency for Medicinal Products and Medical Devices, Department for Quality, Safety and Efficacy Assessment, Zagreb, Croatia.
¹⁵ Department of Surgical Oncology, University Hospital for Tumours, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia.
¹⁶ School of Medicine, University of Zagreb, Zagreb, Croatia.
¹⁷ Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
¹⁸ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
¹⁹ Department of Psychology, The University of Edinburgh, Edinburgh, UK.
²⁰ Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
²¹ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
²² Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK. e.theodoratou@ed.ac.uk.
²³ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK. e.theodoratou@ed.ac.uk.
²⁴ Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK. malcolm.dunlop@ed.ac.uk.

PMID: 30103784
PMCID: PMC6090711
DOI: 10.1186/s12916-018-1119-2

Randomized Controlled Trial

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Yazhou He et al. BMC Med. 2018.

. 2018 Aug 14;16(1):142.

doi: 10.1186/s12916-018-1119-2.

Authors

Collaborators

SUNLIGHT consortium:
Xia Jiang, Elina Hyppönen, Peter Kraft, Douglas P Kiel

Affiliations

¹ Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK.
² West China School of Medicine/West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
³ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK.
⁴ Department of Public Health and Primary Care, Institute of Population Health, Trinity College Dublin, University of Dublin, Dublin 24, D02 PN40, Ireland.
⁵ Program in Genetic Epidemiology and Statistical Genetics. Department of Epidemiology, Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.
⁶ Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobels vagen 13, Stockholm, 17177, Sweden.
⁷ Australian Centre for Precision Health, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, 5001, Australia.
⁸ Population, Policy and Practice, University College London, Great Ormond Street, Institute of Child Health, WC1E 6BT, London, UK.
⁹ Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA, 02131, USA.
¹⁰ Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA.
¹¹ Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, 02142, USA.
¹² MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
¹³ Generation Scotland, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.
¹⁴ Agency for Medicinal Products and Medical Devices, Department for Quality, Safety and Efficacy Assessment, Zagreb, Croatia.
¹⁵ Department of Surgical Oncology, University Hospital for Tumours, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia.
¹⁶ School of Medicine, University of Zagreb, Zagreb, Croatia.
¹⁷ Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
¹⁸ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
¹⁹ Department of Psychology, The University of Edinburgh, Edinburgh, UK.
²⁰ Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
²¹ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
²² Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK. e.theodoratou@ed.ac.uk.
²³ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK. e.theodoratou@ed.ac.uk.
²⁴ Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK. malcolm.dunlop@ed.ac.uk.

PMID: 30103784
PMCID: PMC6090711
DOI: 10.1186/s12916-018-1119-2

Abstract

Background: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD.

Methods: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach.

Results: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10^{- 11}), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48).

Conclusions: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.

Keywords: Colorectal cancer; Mendelian randomisation; Vitamin D.

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Conflict of interest statement

SOCCS received ethical and management approvals from the MultiCentre Research Ethics committee for Scotland (approval number MREC/ 01/0/5), 18 Local Research Ethics committees, 18 Caldicott guardians and 16 NHS Trust management committees.

GS:SFHS: 05/S1401/89 Tayside Committee on Medical Research Ethics A, Generic Research Tissue Bank approval: GS:SFHS: 10/S1402/20 Tayside Committee on Medical Research Ethics B.

Ethics permission for the Lothian Birth Cohort 1921 (LBC1921) was obtained from the Lothian Research Ethics Committee (LREC/1998/4/183).

Ethics permission for the Lothian Birth Cohort 1936 (LBC1936) was obtained from the Multi-Centre Research Ethics Committee for Scotland (MREC/01/0/56) and the Lothian Research Ethics Committee (LREC/2003/2/29).

The research activities of UK Biobank were approved by the North West Multi-centre Research Ethics Committee (11/NW/0382) in relation to the process of participant invitation, assessment and follow-up procedures. Additionally, ethics approvals from the National Information Governance Board for Health & Social Care in England and Wales and approval from the Community Health Index Advisory Group in Scotland were also obtained to gain access to the information that would allow the invitation of participants. This study did not need to recontact the participants, and no separate ethics approval was required according to the Ethics and Governance Framework (EGF) of UK Biobank. The approved data request application ID for this analysis is 7441.

No consent for publication was required.

The authors declare that they have no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
a Conceptional framework of Mendelian randomisation (MR). The instrumental variable is based on genome-wide significant single nucleotide polymorphisms from independent studies of the association between the exposure of interest (serum 25-hydroxyvitamin D (25-OHD) concentrations) and the outcome (colorectal cancer (CRC)). The effect of an instrumental variable should be independent from the confounding factors and should affect CRC risk only through exposure. In the presence of a causal relationship, the association between instrumental variable and CRC would be expected to be proportionate to its association with the serum 25-OHD concentrations, given the relationship between the serum 25-OHD concentrations and CRC risk. Figure adapted from Timpson et al. [65]. b Basic design of our MR on the causal effect of 25-OHD on CRC risk. The blue text of outer contour showed individual level MR analysis. β1 is the regression coefficient of instrumental variable (IV) on exposure (25-OHD level) using controls from the Scotland Colorectal Cancer Study (SOCCS); β2 is the regression coefficient of IV on outcome (CRC) using SOCCS series, Croatia and UK biobank case control studies. Causal effect is estimated by the ratio of β2 and β1. The red text of inner contour showed summary statistics MR analysis. Effect sizes of IVs on 25-OHD and CRC are extracted from two GWAS meta-analyses and causal estimate is derived from an inverse variance-weighted MR analysis

**Fig. 2**
Association of 25-hydroxyvitamin D (25-OHD) affecting genetic variants with log transformed 25-OHD concentration and colorectal cancer risk. The slope of the red line is the causal estimate derived from inverse variance-weighted (IVW) Mendelian randomisation and slope of the blue dash line represents the 95% confidence interval of IVW estimate

See this image and copyright information in PMC

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Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Collaborators

Affiliations

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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