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Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases

Ghazi Chabchoub1*, Elif Uz2, Abdellatif Maalej1, Chigdem A Mustafa2, Ahmed Rebai3, Mouna Mnif4, Zouheir Bahloul5, Nadir R Farid6, Tayfun Ozcelik27 and Hammadi Ayadi1

Author Affiliations

1 Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, Sfax, 3029, Tunisie

2 Department of Molecular Biology and Genetics, Faculty of Science. Bilkent University, Ankara, 06800, Turkey

3 Unité de Bioinformatique, Centre de Biotechnologie de Sfax, Sfax, BP 3018, Tunisie

4 Service d'Endocrinologie, Centre Hospitalo-universitaire Hédi Chaker de Sfax. Rue El-Ferdaous, Sfax, 3029, Tunisie

5 Service de Médecine Interne, Centre Hospitalo-universitaire Hédi Chaker de Sfax. Rue El-Ferdaous, Sfax, 3029, Tunisie

6 Osancor Biotech Inc, 31 Woodland Drive, Watford, Herts, WD17 3BY, UK

7 Institute for Materials Science and Nanotechnology (UNAM), Bilkent University, Ankara, 06800, Turkey

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Arthritis Research & Therapy 2009, 11:R106  doi:10.1186/ar2759

Published: 9 July 2009



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.


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.


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).


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.