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Testing the role of vitamin D in response to antitumour necrosis factor α therapy in a UK cohort: a Mendelian randomisation approach
  1. Annie Yarwood1,
  2. Sebastien Viatte1,
  3. Darren Plant2,
  4. Ann W Morgan3,4,
  5. John Isaacs5,
  6. Anthony G Wilson6,
  7. Kimme Hyrich1,
  8. Steve Eyre1,
  9. Anne Barton1,2,
  10. Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS)
  1. 1Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK
  2. 2NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester Partnership, Manchester, UK
  3. 3NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, The Leeds Teaching Hospitals NHS Trust, Leeds, UK
  4. 4Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, St. James's University Hospital, Leeds, UK
  5. 5NIHR Newcastle Biomedical Research Centre at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle-upon-Tyne, UK
  6. 6Department of Infection and Immunity, University of Sheffield Medical School, Sheffield, UK
  1. Correspondence to Professor Anne Barton, Arthritis Research UK Epidemiology Unit, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK; anne.barton{at}manchester.ac.uk

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Approximately 30% of rheumatoid arthritis (RA) patients fail to respond to anti-tumour necrosis factor (anti-TNF) treatment;1 hence, the ability to predict which patients will respond to treatment would represent a major clinical advance. Vitamin D has been implicated in many autoimmune diseases including RA; in addition, vitamin D has been shown to induce TNFα production by some immune cells leading to the hypothesis that vitamin D levels may influence anti-TNF treatment response.2 ,3 Several studies have now confirmed the association of genetic variants within four vitamin D metabolism genes (GC, DHCR7/NADSYN1, CYP2R1, CYP24A1) with circulating vitamin D levels in healthy controls.4 ,5 In addition, single nucleotide polymorphisms (SNPs) in these genes have also been associated with autoimmune diseases.6 The association of the same variants in the same genes that control circulating levels of vitamin D with response to anti-TNF treatment provides an unbiased test of the hypothesis that vitamin D levels are important in response to these therapies (Mendelian randomisation).7 We, therefore, investigated the effect of vitamin D on response to anti-TNF therapy, testing six SNPs previously associated with circulating levels of vitamin D4 ,5 for association with response to anti-TNF therapy in RA patients from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort (table 1), which includes patients recruited across the UK.8 SNPs were selected to capture by linkage disequilibrium (LD) (r2>0.8) 94.26% of SNPs previously associated with vitamin D levels in two previous studies.4 ,5 Multivariate linear and logistic regression was used to assess the effects of each SNP on treatment response measured by absolute change in Disease Activity Score in 28 joints (DAS28) over 6 months9 (n=1396) or in poor (n=237) versus good (n=322) responders according to European League …

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  • Collaborators Members of BRAGGSS: Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Professor H Gaston. Mid Staffordshire NHS Foundation Trust, Cannock Chase Hospital, Dr D Mulherin, Dr T Price, Dr T Sheeran, Dr V Chalam, Dr S Baskar. The Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Professor P Emery, Professor A W Morgan, Dr M Buch, Dr S Bingham. Derby Hospitals NHS Foundation Trust, Derbyshire Royal Infirmary, Dr S O’Reilly, Dr L Badcock, Dr M Regan, Dr T Ding, Dr C Deighton, Dr G Summers, Dr N Raj. Doncaster and Bassetlaw Hospitals NHS Foundation Trust, Doncaster Royal Infirmary, Dr R Stevens. Peterborough and Stamford Hospitals NHS Foundation Trust, Edith Cavell Hospital, Dr N Williams. The Newcastle upon Tyne Hospitals NHS Trust, Freeman Hospital, Professor J Isaacs, Dr P Platt, Dr D Walker, Dr L Kay, Dr B Griffiths, Dr W-F Ng, Dr P Peterson, Dr A Lorenzi, Professor H Foster, Dr M Friswell, Dr B Thompson, Dr M Lee, Dr I Griffiths. University Hospital of North Staffordshire NHS Trust, Haywood Hospital (Stoke-on-Trent), Dr A Hassell, Dr P Dawes, Dr C Dowson, Dr S Kamath, Dr J Packham, Dr M Shadforth, Ann Brownfield. Hereford Hospitals NHS Trust, Hereford County Hospital, Dr R Williams. Norfolk & Norwich University Hospital NHS Trust, Norfolk & Norwich University Hospital, Dr C Mukhtyar. Pennine Acute Hospitals NHS Trust, North Manchester General Hospital, Dr B Harrison, Dr N Snowden, Dr S Naz. Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Dr J Ledingham, Dr R Hull, Dr F McCrae, Dr A Thomas, Dr S Young Min, Dr R Shaban, Dr E Wong. Gateshead Health NHS Trust, Queen Elizabeth Hospital, Dr C Kelly, Dr C Heycock, Dr J Hamilton, Dr V Saravanan. Sheffield Teaching Hospitals NHS Trust, Royal Hallamshire Hospital, Professor G Wilson, Professor D Bax, Dr L Dunkley, Dr M Akil, Dr R Tattersall, Dr R Kilding, Dr S Till, Dr J Boulton, Dr T Tait. University Hospital of Morcambe Bay NHS Trust, Royal Lancaster Infirmary, Dr M Bukhari, Dr J Halsey, Dr L Ottewell. Sandwell and West Birmingham Hospitals NHS Trust, Sandwell General/City Hospital, Professor C Buckley, Dr D Situnayake, Dr D Carruthers, Dr K Grindulis, Dr F Khatack, Dr S Elamanchi, Dr K Raza. University Hospital Birmingham NHS Foundation Trust, Selly Oak Hospital, Dr A Filer, Dr R Jubb. St Helens and Knowsley Hospitals NHS Trust, St Helens Hospital, Dr R Abernathy. South Tees Hospitals NHS Trust, The James Cook University Hospital, Middlesbrough, Dr M Plant, Dr S Pathare, Dr F Clarke, Dr S Tuck, Dr J Fordham, Dr A Paul. County Durham and Darlington Acute Hospitals NHS Trust, University Hospital of North Durham, Dr M Bridges. Whipps Cross University Hospital NHS Trust, Whipps Cross University Hospital, Dr A Hakim. The West Suffolk Hospital NHS Trust, West Suffolk Hospital, Dr D O’Reilly, Dr V Rajagopal, Dr S Bhagat. Southampton University Hospital NHS Trust, Southampton General Hospital, Dr C Edwards. Basingstoke & North Hampshire NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Dr P Prouse, Dr R Moitra, Dr D Shawe. Queen Mary’s Sidcup NHS Trust, Queen Mary’s Sidcup (QMS) Hospital, Dr A Bamji. Pennine Acute Hospitals NHS Trust, Royal Oldham Hospital, Dr P Klimiuk. Pennine Acute Hospitals NHS Trust, Rochdale Infirmary, Dr A Bowden. University Hospitals of Morecambe Bay NHS Trust, Furness Hospital, Dr W Mitchell. Central Manchester University Hospital NHS Foundation Trust, Manchester Royal Infirmary, Professor I Bruce, Professor A Barton, Dr R Gorodkin, Dr P Ho, Dr K Hyrich, Dr W Dixon. Worcestershire Acute Hospitals NHS Trust, Worcestershire Royal Hospital, Dr A Rai. The Dudley Group of Hospitals NHS Foundation Trust, Russells Hall Hospital, Professor G Kitas, Dr N Erb, Dr R Klocke, Dr K Douglas, Dr A Pace, Dr R Sandhu, Dr A Whallett. Northumbria Healthcare NHS Foundation Trust, Wansbeck Hospital, Dr F Birrell. University Hospitals of Coventry and Warwickshire NHS Trust, University Hospital (earlier Walsgrave Hospital), Dr M Allen, Dr K Chaudhuri. Wrightington, Wigan and Leigh Hospitals NHS Foundation Trust, Wrightington Hospital, Dr C Chattopadhyay. Nottingham University Hospitals NHS Trust, Nottingham Hospital, Dr J McHale, Dr A Jones, Dr A Gupta, Dr I Pande, Dr I Gaywood, Dr P Lanyon, Dr P Courtney, Dr M Doherty. Salford Royal NHS Foundation Trust, Hope Hospital, Dr H Chinoy, Professor T O’Neill, Professor A Herrick, Professor A Jones, Dr R Cooper, Dr R Bucknall. South Warwickshire General Hospital NHS Trust, Warwick Hospital, Dr C Marguerie, Dr S Rigby, Dr N Dunn. Weston Area Health NHS Trust, Weston General Hospital, Dr S Green, Dr A Al-Ansari, Dr S Webber. The Royal Bournemouth & Christchurch Hospitals NHS Foundation Trust, Christchurch Hospital, Dr N Hopkinson, Dr C Dunne, Dr B Quilty. Northern Lincolnshire and Goole Hospitals NHS Foundation Trust, Diana, Princess of Wales Hospital, Dr B Szebenyi. York Hospitals NHS Foundation Trust, York District Hospital, Dr M Green, Dr M Quinn, Dr A Isdale, Dr A Brown, Dr B Saleem. University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Dr A Samanta, Dr P Sheldon, Dr W Hassan, Dr J Francis, Dr A Kinder, Dr R Neame, Dr A Moorthy. The Royal Wolverhampton Hospitals NHS Trust, New Cross Hospital, Dr W Al-Allaf. Greenpark Healthcare NHS Trust, Musgrave Park Hospital, Dr A Taggart. Chesterfield Royal Hospital NHS Foundation Trust, Chesterfield Royal Hospital, Dr K Fairburn. Trafford Healthcare NHS Trust, Trafford General Hospital, Dr F McKenna. Harrogate and District NHS Foundation Trust, Harrogate District Hospital, Dr M Green, Dr A Gough, Dr C Lawson. Royal National Hospital for Rheumatic Diseases NHS Foundation Trust, Bath Hospital, Dr M Piper, Dr E Korendowych, Dr T Jenkinson, Dr R Sengupta, Dr A Bhalla, Professor N McHugh, Debbie Bond. Oxford Radcliffe Hospitals NHS Trust, John Radcliffe Hospital, Nuffield, Professor R Luqmani, Professor B Bowness, Professor P Wordsworth, Dr J David. Milton Keynes Hospital NHS Foundation Trust, Milton Keynes Hospital, Dr W Smith. Royal Liverpool and Broadgreen University Hospitals NHS Trust, Royal Liverpool Hospital, Dr D Mewar, Dr E Tunn, Dr K Nelson, Dr T Kennedy. Countess of Chester Hospital NHS Foundation Trust, Countess of Chester Hospital, Dr J Nixon. Royal Cornwall Hospitals NHS Trust, Royal Cornwall Hospital, Professor A Woolf, Dr M Davis, Dr D Hutchinson, Dr A Endean. City Hospitals Sunderland NHS Foundation Trust, Royal Sunderland Hospital, Dr D Coady, Dr D Wright, Dr C Morley, Dr G Raftery, Dr C Bracewell, Dr L Kidd. Stockport NHS Foundation Trust, Stepping Hill Hospital, Dr I Abbas, Dr C Filer. Kettering General Hospital NHS Foundation Trust, Kettering General Hospital, Dr G Kallarackal.

  • Contributors Conception and design of study: AY, AB and SE; Acquisition and analysis of data: AY, SV, DP, AWM, JI, AGW, KH, SE and AB; Interpretation of data: AY, SV, DP, AB and SE; Manuscript preparation: AY, SV, DP, AWM, JI, AGW, KH, SE and AB.

  • Funding Arthritis Research UK.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval North West Greater Manchester Central ethics committee (COREC 04/Q1403/37).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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