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Evidence of epistasis between Interleukin-1 and Selenoprotein-S with susceptibility to RA.
  1. Ioanna Marinou (mdp04im{at}shef.ac.uk)
  1. University of Sheffield, United Kingdom
    1. Kevin Walters (k.walters{at}shef.ac.uk)
    1. University of Sheffield, United Kingdom
      1. Marion C Dickson (marion.c.dickson{at}gsk.com)
      1. GlaxoSmithKline R&D, United Kingdom
        1. Michael H Binks (michael.h.binks{at}gsk.com)
        1. GlaxoSmithKline R&D, United Kingdom
          1. Deborah E Bax (d.e.bax{at}shef.ac.uk)
          1. University of Sheffield, United Kingdom
            1. Anthony G Wilson (a.g.wilson{at}sheffield.ac.uk)
            1. University of Sheffield, United Kingdom

              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 IL-6, IL-1β and TNF. We hypothesized that these variants could influence RA susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL-1, IL-6 and TNF.

              Methods: Genotyping was performed in 988 unrelated healthy controls and 965 RA patients. Stratified analysis was used to test for interactions. We examined both single gene effects and for evidence of epistasis using both 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 IL-1 -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 IL-1B -511 locus was significantly lower than that in individuals having the AA genotype at the IL-1β-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=2x10-4). No interaction was observed between SELS -105 and IL-6 or TNF variants.

              Conclusion: Our results reveal evidence of strong epistasis in two genes in the IL-1 production pathway and highlight the potential importance of gene-gene interactions in the pathogenesis of RA.

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