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      Evaluation of X chromosome inactivation with respect to HLA genetic susceptibility in rheumatoid arthritis and systemic sclerosis

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      Author(s)
      Kanaan, S. B.
      Onat, O. E.
      Balandraud, N.
      Martin, G. V.
      Nelson, J. L.
      Azzouz, D. F.
      Auger, I.
      Arnoux, F.
      Martin, M.
      Roudier, J.
      Ozcelik, T.
      Lambert, N. C.
      Date
      2016
      Source Title
      PLoS ONE
      Print ISSN
      1932-6203
      Publisher
      Public Library of Science
      Volume
      11
      Issue
      6
      Pages
      1 - 12
      Language
      English
      Type
      Article
      Item Usage Stats
      233
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      174
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      Abstract
      Background: Autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc) are characterized by a strong genetic susceptibility from the Human Leucocyte Antigen (HLA) locus. Additionally, disorders of epigenetic processes, in particular non-random X chromosome inactivation (XCI), have been reported in many female-predominant autoimmune diseases. Here we test the hypothesis that women with RA or SSc who are strongly genetically predisposed are less susceptible to XCI bias. Methods: Using methylation sensitive genotyping of the androgen receptor (AR) gene, XCI profiles were performed in peripheral blood mononuclear cells from 161 women with RA, 96 women with SSc and 100 healthy women. HLA-DRB1 and DQB1 were genotyped. Presence of specific autoantibodies was documented for patients. XCI skewing was defined as having a ratio ≥ 80:20 of cells inactivating the same X chromosome. Results: 110 women with RA, 68 women with SSc, and 69 controls were informative for the AR polymorphism. Among them 40.9% of RA patients and 36.8% of SSc patients had skewed XCI compared to 17.4% of healthy women (P = 0.002 and 0.018, respectively). Presence of RA-susceptibility alleles coding for the "shared epitope" correlated with higher skewing among RA patients (P = 0.002) and such correlation was not observed in other women, healthy or with SSc. Presence of SSc-susceptibility alleles did not correlate with XCI patterns among SSc patients. Conclusion: Data demonstrate XCI skewing in both RA and SSc compared to healthy women. Unexpectedly, skewed XCI occurs more often in women with RA carrying the shared epitope, which usually reflects severe disease. This reinforces the view that loss of mosaicism in peripheral blood may be a consequence of chronic autoimmunity. © 2016 Kanaan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
      Keywords
      HLA DQB1 antigen
      HLA DRB1 antigen
      Androgen receptor
      Autoantibody
      HLA antigen
      HLA DQ antigen
      Autoimmunity
      Chromosome mosaicism
      Controlled study
      Gene locus
      Genetic susceptibility
      DNA methylation
      Genetic epigenesis
      Genetic predisposition
      Mononuclear cell
      Rheumatoid arthritis
      Systemic sclerosis
      Autoantibodies
      Case-Control Studies
      DNA Methylation
      Genotype
      HLA Antigens
      HLA-DQ beta-Chains
      HLA-DRB1 Chains
      Humans
      X Chromosome Inactivation
      Permalink
      http://hdl.handle.net/11693/36786
      Published Version (Please cite this version)
      http://dx.doi.org/10.1371/journal.pone.0158550
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