X chromosome inactivation in female predisposition to autoimmunity
Author
Uz, Elif
Advisor
Özçelik, Tayfun
Date
2008Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
The high female preponderance is thought to be important in identifying the
etiological factors. Sex hormones, pregnancy related microchimerism, and
environmental factors are investigated as likely candidates. Disturbed Xchromosome
inactivation (XCI) is another candidate, which may contribute to the
break-down of self-tolerance. In this study, we tested the hypothesis that “loss of
mosaicism” for X-linked gene expression may contribute to autoimmune disease
etiology. Therefore, XCI status of healthy individuals and patients diagnosed with
scleroderma (SSc), autoimmune thyroiditis (AITDs), Sjogren’s syndrome
(SICCA), and juvenile idiopathic arthritis (JIA) in the Turkish population were
analyzed by genotyping the methylation status of a CAG polymorphism in the
androgen receptor (AR) gene. Extremely skewed XCI was observed in a significant
proportion of SSc (OR: 38.9; P<0.0001), AITDs (OR: 9.6; P<0.0001), and JIA
(OR: 4.4; P=0.0022). Further genotyping of AITDs in Tunisian and SSc in the US
population supported the initial observations (OR: 3.8; P=0.0046; OR: 3.8;
P<0.0001) respectively. Analysis of rheumatoid arthritis (RA) in the Tunisian
population suggests that extremely skewed XCI (OR: 6.7; P<0.0001) could be
involved in disease pathogenesis. Moreover, pre-eclampsia, a disease in which
autoimmunity may be important, skewed XCI was observed (OR; 11.7; P=0.0005).
However, in SICCA random patterns of XCI was observed suggesting that extreme
skewing is not a common feature of all female prevalent autoimmune disorders. In
conclusion, our results suggest that extremely skewed XCI may be important
factor in autoimmune disease pathogenesis.