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      • Dept. of Molecular Biology and Genetics - Ph.D. / Sc.D.
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      • Theses - Department of Molecular Biology and Genetics
      • Dept. of Molecular Biology and Genetics - Ph.D. / Sc.D.
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      X chromosome inactivation in female predisposition to autoimmunity

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      Author
      Uz, Elif
      Advisor
      Özçelik, Tayfun
      Date
      2008
      Publisher
      Bilkent University
      Language
      English
      Type
      Thesis
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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.
      Keywords
      autoimmune diseases
      X-chromosome inactivation
      female predisposition
      HUMARA assay
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      http://hdl.handle.net/11693/14728
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