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Ann Rheum Dis 2009;68:1494-1497 doi:10.1136/ard.2008.090001
  • Clinical and epidemiological research
  • Extended report

Evidence of epistasis between interleukin 1 and selenoprotein-S with susceptibility to rheumatoid arthritis

  1. I Marinou1,
  2. K Walters1,
  3. M C Dickson2,
  4. M H Binks2,
  5. D E Bax1,
  6. A G Wilson1
  1. 1
    School of Medicine & Biomedical Sciences, The University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK
  2. 2
    GlaxoSmithKline R&D, Stevenage, UK
  1. Correspondence to A G Wilson, Section of Musculoskeletal Sciences, School of Medicine & Biomedical Sciences, The University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK; a.g.wilson{at}shef.ac.uk
  • Accepted 26 July 2008
  • Published Online First 26 August 2008

Abstract

Objective: Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1β and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF.

Methods: Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel–Haenszel (M–H) test and the linkage disequilibrium (LD)-based statistic.

Results: No association of SELS −105 genotype and RA susceptibility was detected. Stratification of SELS −105 genotypes by IL1 −511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS −105 locus) in individuals with the GG/AG genotype at the IL1β −511 locus was significantly lower than that in individuals having the AA genotype at the IL1β −511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M–H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS −105 and IL6 or TNF variants.

Conclusion: Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene–gene interactions in the pathogenesis of RA.

Footnotes

  • IM and KW contributed equally to this study.

  • Funding This work was funded by a research grant from GlaxoSmithKline R&D, UK (Genetics of Rheumatoid Arthritis, GORA).

  • Competing interests None.

  • Ethics approval The South Sheffield Research Ethics Committee approved this study and informed consent was obtained from all participants.

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