Chabchoub Ghazi, Uz Elif, Maalej Abdellatif, Mustafa Chigdem A, Rebai Ahmed, Mnif Mouna, Bahloul Zouheir, Farid Nadir R, Ozcelik Tayfun, Ayadi Hammadi
Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, Sfax, Tunisia.
Arthritis Res Ther. 2009;11(4):R106. doi: 10.1186/ar2759. Epub 2009 Jul 9.
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.
大多数自身免疫性疾病，如类风湿性关节炎（RA）和自身免疫性甲状腺疾病（AITD），其特征是在易感基因背景上女性明显占主导。在几种自身免疫性疾病的发病机制中，X染色体极度偏斜失活（XCI）的作用一直存在争议。
我们检测了患有RA（n = 106）、AITD（n = 145）的女性以及年龄匹配的健康女性（n = 257）的XCI谱。通过用甲基化敏感酶（HpaII）对DNA进行酶切，然后对雄激素受体（AR）基因中的多态性CAG重复序列进行PCR来进行XCI分析。当80%或更多细胞优先使同一条X染色体失活时，XCI模式被分类为偏斜。
在76例信息充分的RA患者中有26例（34.2%）观察到偏斜XCI，100例信息充分的AITD患者中有26例（26%），170例信息充分的对照中有19例（11.2%）（P < 0.0001；P = 0.0015）。更重要的是，定义为一个等位基因失活> 90%的极度偏斜XCI在17例RA患者（22.4%）、14例AITD患者（14.0%）中存在，而在仅7例对照中存在（4.1%，P < 0.0001；P = 0.0034）。根据实验室指标（类风湿因子和抗瓜氨酸化蛋白抗体）、临床表现（侵蚀性疾病和结节）以及其他自身免疫性疾病的存在对RA患者进行分层，未发现任何统计学意义（P > 0.05）。
这些结果表明XCI嵌合体在RA和AITD的发病机制中可能起作用，并且可能部分解释了这些疾病中女性占优势的现象。
