title: Enrichment of vitamin D response elements in RA-associated loci supports a role for vitamin D in the pathogenesis of RA.
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.
authors: 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.
authors: A
authors: A
authors: Yarwood
authors: P
authors: P
authors: Martin
authors: J
authors: J
authors: Bowes
authors: M
authors: M
authors: Lunt
authors: J
authors: J
authors: Worthington
authors: A
authors: A
authors: Barton
authors: S
authors: S
authors: Eyre
mesh_terms: D019732:Amide Synthases / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D016017:Odds Ratio; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements / Q000235:genetics*; D012307:Risk Factors; D014807:Vitamin D / Q000097:blood
chemical_list: D014807:Vitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D019732:Amide Synthases; C038479:NAD+ synthase
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