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Enrichment of vitamin D response elements in RA-associated loci supports a role for vitamin D in the pathogenesis of RA

Genes & Immunity volume 14, pages 325–329 (2013)Cite this article

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Abstract

The aim of this study was to explore the role of vitamin D in rheumatoid arthritis (RA) pathogenesis by investigating the enrichment of vitamin D response elements (VDREs) in confirmed RA susceptibility loci and testing variants associated with vitamin D levels for association with RA. Bioinformatically, VDRE genomic positions were overlaid with non-HLA (human leukocyte antigen)-confirmed RA susceptibility regions. The number of VDREs at RA loci was compared to a randomly selected set of genomic loci to calculate an average relative risk (RR). Single-nucleotide polymorphisms (SNPs) in the DHCR7/NADSYN1 (nicotinamide adenine dinucleotide synthase 1) and CYP2R1 loci, previously associated with circulating vitamin D levels, were tested in UK RA cases (n=3870) and controls (n=8430). Significant enrichment of VDREs was seen at RA loci (P=9.23 × 10−8) when regions were defined either by gene (RR 5.50) or position (RR 5.86). SNPs in the DHCR7/NADSYN1 locus showed evidence of positive association with RA, rs4944076 (P=0.008, odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03–1.24). The significant enrichment of VDREs at RA-associated loci and the modest association of variants in loci-controlling levels of circulating vitamin D supports the hypothesis that vitamin D has a role in the development of RA.

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Acknowledgements

We thank Arthritis Research UK for their support (grant ref 17552). This work was supported by the innovative medicines initiative joint undertaking (IMI JU) funded project BeTheCure, (contract number 115142-2).

Author contributions

Conception and design of study: AY, SE, AB; acquisition and analysis of data: AY, PM, ML, JB; interpretation of data: AY, PM; manuscript preparation: AY, PM, SE, AB, JW.

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  1. A Yarwood and P Martin: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

    A Yarwood, P Martin, J Bowes, M Lunt, J Worthington, A Barton & S Eyre

  2. NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Central Manchester Foundation Trust, Manchester, UK

    J Worthington & A Barton

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  1. A Yarwood
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  2. P Martin
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Correspondence to S Eyre.

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Yarwood, A., Martin, P., Bowes, J. et al. Enrichment of vitamin D response elements in RA-associated loci supports a role for vitamin D in the pathogenesis of RA. Genes Immun 14, 325–329 (2013). https://doi.org/10.1038/gene.2013.23

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