ENVI-RA: Impact of ENVIronmental factors and gene-environment interaction in the development of Rheumatoid Arthritis


Rheumatoid arthritis (RA) is a complex di- sease in which environmental agents are thought to interact with genetic factors to trigger auto-immunity.

The contribution of genetic factors to RA susceptibility is well recognized. The heritability of anticitrullinated protein auto- antibody (ACPA)-positive and ACPA-negative RA implicates different genes [2]. To date, the main known genetic factoris HLA, in particular the HLA-DRB1-shared epitope (SE) alleles, that predispose much more strongly to ACPA. However, the concordance for RA between monozygotic twins is only 15.6%. Thus, environment plays a crucial role in the development of the disease as well.

Facts and Figures

Project Lead
R Seror
Université Paris Sud
FOREUM research grant: € 100.000

Meet the Team

Project Lead

R Seror
Université Paris Sud
D van der Woude
UMC Leiden
C Boutron
Gustave Roussy Institute
D Alpízar-Rodríguez
Hôpitaux Universitaires de Genève
P Preiss
Association France Polyarthrite

Final Results

Achievements in the E3N cohort (including ~100.000 women):

  • A study was performed to validate RA cases:
    This study enabled us to detect a large number of RA cases in a large general population prospective cohort of women: 964 RA cases were validated, including 698 incident cases. This will allow investigating a large number of potential endogenous and exogenous risk factors of RA in women.
  • Chronic diarrhea was identified as associated with an increased risk of developing RA in ever-smokers.
    These data fit with the multistep preclinical scheme of RA where interaction between different events, such as intestinal dysbiosis and smoking, occurs at an early stage to promote emergence of autoimmunity, followed years after by clinical disease.
  • Some hormonal factors are associated with the risk of RA
    Early age at first pregnancy and early menopause were associated with an increased risk of RA, whereas RA was inversely associated with exposure to progestogen in perimenopause.
  • Mediterranean diet was associated with a decreased risk of RA in ever-smoking women
    High adherence to a MD could reduce RA risk in ever-smoking women. Further studies are needed to confirm our findings.  

Lay Summary

Various lifestyle and environmental factors to identify if they might increase the risk of RA.
From a previous work one of the cohort of this project, we identified passive smoking in childhood as being associated with an increased risk of RA, in future active smokers.
Analyses form this project provided interesting results on the following factors:

  1. The findings showed that transit disturbance, such as chronic diarrhoea, might also increase this risk.
  2. Hormonal factors were studied and early menopause was identified as being associated with an increased risk of RA in women, whereas a high lifetime exposure to oestrogen seems to decrease this risk.
  3. Also it was found that dietary factors such as adherence to Mediterranean diet (rich in vegetables, olive oils and omega 3) might protect for developing RA in non-smokers.

This project continues with new research focus.


  • Nguyen Y, Salliot C, Gusto G, Descamps E, Mariette X, Boutron-Ruault MC, Seror R. Improving accuracy of self-reported diagnoses of rheumatoid arthritis in the French prospective E3N-EPIC cohort: a validation study. BMJ Open. 2019 Dec 16;9(12):e033536. doi: 10.1136/bmjopen-2019-033536. PMID: 31848174; PMCID: PMC6937120.
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  • Salliot C, Nguyen Y, Gambaretti J, Gelot A, Mariette X, Boutron-Ruault MC, Seror R. THU0686 Early menopause and/or duration of menopausal hormonal treatment may increase the risk of rheumatoid arthritis in tobacco exposed women: results of the E3N cohort. Annals of the Rheumatic Diseases 2019;78:639-640. Doi: 10.1136/annrheumdis-2019-eular.6599
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  • Nguyen Y, Mariette X, Salliot C, Gusto G, Boutron-Ruault MC, Seror R. Chronic diarrhoea and risk of rheumatoid arthritis: findings from the French E3N-EPIC Cohort Study. Rheumatology (Oxford). 2020 Dec 1;59(12):3767-3775. doi: 10.1093/rheumatology/keaa133. PMID: 32417889.
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  • Nguyen Y, Salliot C, Gelot A, Gambaretti J, Mariette X, Boutron-Ruault MC, Seror R. Mediterranean Diet and Risk of Rheumatoid Arthritis: Findings From the French E3N-EPIC Cohort Study. Arthritis Rheumatol. 2020 Sep 9. doi: 10.1002/art.41487. Epub ahead of print. PMID: 32909390.
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  • Review article:
    Salliot C, Nguyen Y, Boutron-Ruault MC, Seror R. Environment and Lifestyle: Their Influence on the Risk of RA. J Clin Med. 2020 Sep 26;9(10):3109. doi: 10.3390/jcm9103109. PMID: 32993091; PMCID: PMC7601336.
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  • Salliot C, Nguyen Y, Gusto G, Gelot A, Gambaretti J, Mariette X, Boutron-Ruault MC, Seror R. Female hormonal exposures and risk of rheumatoid arthritis in the French E3N-EPIC cohort study. Rheumatology (Oxford). 2021 Feb 6:keab101. doi: 10.1093/rheumatology/keab101. Epub ahead of print. PMID: 33547777.
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