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Effect of vitamin D supplementation on biomarkers of inflammation and immune function: functional genomics analysis of the BEST-D trial

Antonio J. Berlanga-Taylor, Katherine Plant, Andrew Dahl, Evelyn Lau, Michael Hill, David Sims, Andreas Heger, Jonathan Emberson, Jane Armitage, Robert Clarke, Julian C. Knight
doi: https://doi.org/10.1101/217612
Antonio J. Berlanga-Taylor
1Computational Genomics Analysis and Training (CGAT), Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK
2Wellcome Centre for Human Genetics (WHG), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
3MRC-PHE Centre for Environment and Health, Department of Epidemiology & Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK
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Katherine Plant
2Wellcome Centre for Human Genetics (WHG), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Andrew Dahl
2Wellcome Centre for Human Genetics (WHG), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Evelyn Lau
2Wellcome Centre for Human Genetics (WHG), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Michael Hill
4Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK
5MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK
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David Sims
1Computational Genomics Analysis and Training (CGAT), Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK
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Andreas Heger
1Computational Genomics Analysis and Training (CGAT), Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK
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Jonathan Emberson
4Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK
5MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK
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Jane Armitage
4Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK
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Robert Clarke
4Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK
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Julian C. Knight
2Wellcome Centre for Human Genetics (WHG), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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  • For correspondence: julian@well.ox.ac.uk
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Abstract

Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomised trials may afford an opportunity to systematically assess molecular responses to treatments. In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D34000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) at baseline and after 12 months, were measured. The trial had >90% power to detect a 2-fold change in gene expression. Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D), but had no significant effect on whole-blood gene expression (FDR <5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose but not on the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose), but had no significant effect on cis-eQTLs specific to vitamin D supplementation. The trial demonstrates the feasibility of application of functional genomics approaches in randomised trials to assess the effects of vitamin D on immune function.

One sentence summary Supplementation with high-dose vitamin D in older people for 12 months in a randomised, placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of cytokines.

Trial registration SRCTN registry (Number 07034656) and the European Clinical Trials Database (EudraCT Number 2011-005763-24).

Funding Medical Research Council, British Heart Foundation, Wellcome Trust, European Research Council and Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom

Copyright Open access article under the terms of CC BY.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 21, 2017.
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Effect of vitamin D supplementation on biomarkers of inflammation and immune function: functional genomics analysis of the BEST-D trial
Antonio J. Berlanga-Taylor, Katherine Plant, Andrew Dahl, Evelyn Lau, Michael Hill, David Sims, Andreas Heger, Jonathan Emberson, Jane Armitage, Robert Clarke, Julian C. Knight
bioRxiv 217612; doi: https://doi.org/10.1101/217612
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Effect of vitamin D supplementation on biomarkers of inflammation and immune function: functional genomics analysis of the BEST-D trial
Antonio J. Berlanga-Taylor, Katherine Plant, Andrew Dahl, Evelyn Lau, Michael Hill, David Sims, Andreas Heger, Jonathan Emberson, Jane Armitage, Robert Clarke, Julian C. Knight
bioRxiv 217612; doi: https://doi.org/10.1101/217612

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