Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases.
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.
Chabchoub
Ghazi
G
Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, Sfax, Tunisia. ghazi.chabchoub@laposte.net
Uz
Elif
E
Maalej
Abdellatif
A
Mustafa
Chigdem A
CA
Rebai
Ahmed
A
Mnif
Mouna
M
Bahloul
Zouheir
Z
Farid
Nadir R
NR
Ozcelik
Tayfun
T
Ayadi
Hammadi
H
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*
D001323:Autoantibodies