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

Genes Immun. 2013 Jul-Aug;14(5):325-9. doi: 10.1038/gene.2013.23. Epub 2013 May 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amide Synthases / genetics*
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / genetics*
  • Cholestanetriol 26-Monooxygenase / genetics*
  • Cytochrome P450 Family 2
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Logistic Models
  • Odds Ratio
  • Oxidoreductases Acting on CH-CH Group Donors / genetics*
  • Polymorphism, Single Nucleotide*
  • Response Elements / genetics*
  • Risk Factors
  • Vitamin D / blood


  • Vitamin D
  • Cytochrome P450 Family 2
  • CYP2R1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • Oxidoreductases Acting on CH-CH Group Donors
  • 7-dehydrocholesterol reductase
  • Amide Synthases
  • NAD+ synthase