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High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case–control study
  1. Paola de Pablo1,
  2. Dora Romaguera2,3,
  3. Helena L Fisk4,5,
  4. Philip C Calder4,5,
  5. Anne-Marie Quirke6,
  6. Alison J Cartwright6,
  7. Salvatore Panico7,
  8. Amalia Mattiello7,
  9. Diana Gavrila8,9,
  10. Carman Navarro8,9,10,
  11. Carlotta Sacerdote11,
  12. Paolo Vineis12,13,
  13. Rosario Tumino14,
  14. William E Ollier15,
  15. Dominique S Michaud2,16,
  16. Elio Riboli2,
  17. Patrick J Venables6,
  18. Benjamin A Fisher1
  1. 1 Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
  2. 2 School of Public Health, Imperial College London, London, UK
  3. 3 CIBER-OBN (Fisiopatología de la Obesidad y Nutrición) and IdISBa, University Hospital Son Espases, Palma, Spain
  4. 4 Faculty of Medicine, University of Southampton, Southampton, UK
  5. 5 NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
  6. 6 Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
  7. 7 Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy
  8. 8 Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
  9. 9 CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  10. 10 Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain
  11. 11 Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy
  12. 12 Unit of Genetic and Molecular Epidemiology, Italian Institute for Genomic Medicine, Turin, Italy
  13. 13 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
  14. 14 Cancer Registry and Histopathology Unit, ‘Civic - M.P.Arezzo’ Hospital, Ragusa, Italy
  15. 15 Division of Population Health, Faculty of Biology, Medicine and Health, Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK
  16. 16 Department of Public Health and Community Medicine, Tufts University Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Benjamin A Fisher, Centre for Translational Inflammation Research, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK; b.fisher{at}


Objectives Findings relating to dietary intake of n-3 polyunsaturated fatty acids (PUFA) and risk of rheumatoid arthritis (RA) are mixed. Erythrocyte membrane PUFA is an accurate objective biomarker of PUFA status; however, there are little data on erythrocyte membrane PUFA and risk of RA. The objective was therefore to compare erythrocyte membrane PUFA between pre-RA individuals and matched controls from a population-based sample, and specifically to test the hypothesis that higher levels of longer chain n-3 PUFA are associated with lower risk of RA.

Methods The European Prospective Investigation into Cancer and Nutrition (EPIC) is a large European prospective cohort study of apparently healthy populations. We undertook a nested case–control study by identifying RA cases with onset after enrolment (pre-RA) in four EPIC cohorts in Italy and Spain. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. Conditional logistic regression analysis was used to estimate associations of PUFA with the development of RA, adjusting for potential confounders including body mass index, waist circumference, education level, physical activity, smoking status and alcohol intake.

Results The study analysed samples from 96 pre-RA subjects and 258 matched controls. In this analysis, the median time to diagnosis (defined as time between date of blood sample and date of diagnosis) was 6.71 years (range 0.8–15). A significant inverse association was observed with n-6 PUFA linoleic acid (LA) levels and pre-RA in the fully adjusted model (highest tertile: OR 0.29; 95% CI 0.12 to 0.75; P for trend 0.01). No association was observed with any individual n-3 PUFA, total n-3 PUFA or total n-3:n-6 ratio.

Conclusions Erythrocyte levels of the n-6 PUFA LA were inversely associated with risk of RA, whereas no associations were observed for other n-6 or n-3 PUFA. Further work is warranted to replicate these findings and to investigate if lower LA levels are a bystander or contributor to the process of RA development.

  • rheumatoid arthritis
  • early rheumatoid arthritis
  • epidemiology
  • lipids

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  • Handling editor Tore K Kvien

  • Contributors BAF, DR, DSM, ER and PV conceived the study. PdP performed statistical analysis. All other authors contributed to the generation of data. BAF drafted the manuscript, which was reviewed and revised by all authors.

  • Funding Funding was received from the Imperial College London National Institute of Health Research (NIHR) Biomedical Research Centre. We would like to acknowledge Arthritis Research UK funding for the Rheumatoid Arthritis Pathogenesis Centre of Excellence. PdP was supported by an NIHR Fellowship. PCC is supported by the NIHR Southampton Biomedical Research Centre.

  • Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

  • Competing interests None declared.

  • Ethics approval The study was approved by the International Agency for Research on Cancer (IARC) review board as well as by the local committees of participating EPIC centres.

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

  • Presented at An abstract of this work was previously presented at the 2017 American College of Rheumatology Annual Congress.56