title: Evaluation of X Chromosome Inactivation with Respect to HLA Genetic Susceptibility in Rheumatoid Arthritis and Systemic Sclerosis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.
authors.forename: Sami B
authors.initials: SB
authors.lastname: Kanaan
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Onur E
authors.initials: OE
authors.lastname: Onat
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Service de Rhumatologie, Hôpital Sainte Marguerite, AP-HM, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Balandraud
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.
authors.forename: Gabriel V
authors.initials: GV
authors.lastname: Martin
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Division of Rheumatology, University of Washington, Seattle, Washington, United States of America.
authors.forename: J Lee
authors.initials: JL
authors.lastname: Nelson
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.
authors.forename: Doua F
authors.initials: DF
authors.lastname: Azzouz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Auger
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Arnoux
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Martin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.|Service de Rhumatologie, Hôpital Sainte Marguerite, AP-HM, Marseille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Roudier
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Tayfun
authors.initials: T
authors.lastname: Ozcelik
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRs1097, Scientific Park of Luminy, Marseille, France.|Aix-Marseille University, Marseille, France.
authors.forename: Nathalie C
authors.initials: NC
authors.lastname: Lambert
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008875:Middle Aged; D011944:Receptors, Androgen / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: C410798:AR protein, human; D001323:Autoantibodies; D006680:HLA Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D011944:Receptors, Androgen