title: Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases.
abstract: BACKGROUND
  The majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.
  
  
  METHODS
  We examined XCI profiles of females affected with RA (n = 106), AITDs (n = 145) and age-matched healthy women (n = 257). XCI analysis was performed by enzymatic digestion of DNA with a methylation sensitive enzyme (HpaII) followed by PCR of a polymorphic CAG repeat in the androgen receptor (AR) gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X-chromosome.
  
  
  RESULTS
  Skewed XCI was observed in 26 of the 76 informative RA patients (34.2%), 26 of the 100 informative AITDs patients (26%), and 19 of the 170 informative controls (11.2%) (P < 0.0001; P = 0.0015, respectively). More importantly, extremely skewed XCI, defined as > 90% inactivation of one allele, was present in 17 RA patients (22.4%), 14 AITDs patients (14.0%), and in only seven controls (4.1%, P < 0.0001; P = 0.0034, respectively). Stratifying RA patients according to laboratory profiles (rheumatoid factor and anti-citrullinated protein antibodies), clinical manifestations (erosive disease and nodules) and the presence of others autoimmune diseases did not reveal any statistical significance (P > 0.05).
  
  
  CONCLUSIONS
  These results suggest a possible role for XCI mosaicism in the pathogenesis of RA and AITDs and may in part explain the female preponderance of these diseases.
authors: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, Sfax, Tunisia. ghazi.chabchoub@laposte.net
authors: Ghazi
authors: G
authors: Chabchoub
authors: Elif
authors: E
authors: Uz
authors: Abdellatif
authors: A
authors: Maalej
authors: Chigdem A
authors: CA
authors: Mustafa
authors: Ahmed
authors: A
authors: Rebai
authors: Mouna
authors: M
authors: Mnif
authors: Zouheir
authors: Z
authors: Bahloul
authors: Nadir R
authors: NR
authors: Farid
authors: Tayfun
authors: T
authors: Ozcelik
authors: Hammadi
authors: H
authors: Ayadi
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics*; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D013959:Thyroid Diseases / Q000097:blood / Q000235:genetics*; D014416:Tunisia; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: D001323:Autoantibodies