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The role of genetic polymorphisms regulating vitamin D levels in rheumatoid arthritis outcome: a Mendelian randomisation approach
  1. Sebastien Viatte1,
  2. Annie Yarwood1,
  3. Kate McAllister1,
  4. Shibeb Al-Mudhaffer1,
  5. Bo Fu1,2,
  6. Edward Flynn1,
  7. Deborah P M Symmons1,3,
  8. Adam Young4,5,
  9. Anne Barton1,3
  1. 1Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
  2. 2Centre for Biostatistics, Institute of Population Health, The University of Manchester, UK
  3. 3NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK
  4. 4St. Albans City Hospital, St. Albans, UK
  5. 5Health and Human Sciences Research Institute, University of Hertfordshire, UK
  1. Correspondence to Dr Sebastien Viatte, Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK; anne.barton{at}manchester.ac.uk

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Vitamin D has an important immunoregulatory function,1 ,2 and there is suggestive evidence for its role in the aetiology of autoimmune diseases, including rheumatoid arthritis (RA).3 Vitamin D levels are reduced in individuals with severe RA,4 ,5 but it is difficult to determine whether this reduction is cause or effect. The onset of arthritis during winter is associated with greater radiographic progression at 6 months, which would be compatible with a causative role.6 Single nucleotide polymorphisms (SNPs) in four vitamin D metabolism genes (GC, DHCR7/NADSYN1, CYP2R1 and CYP24A1) are associated at genome-wide significance with circulating vitamin D levels.7 ,8 Since vitamin D level is associated with RA severity, an association between those SNPs and RA severity would establish causality. Testing the association of genetic variants in genes that control circulating vitamin D levels provides, therefore, an instrument to obtain an unbiased test of the hypothesis that vitamin D levels are aetiologically linked to RA outcome by controlling unmeasured confounding (Mendelian randomisation9). Hence, we tested SNPs previously associated with vitamin D metabolism,7 ,8 and SNPs in these …

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