Browsing by Subject "X chromosome."

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Open Access
Analysis of X chromosome inactivation in primary and secondary Sjogren syndrome
(2008) Kantar, Melda
Sjogren Syndrome is an autoimmune disease with one of the highest prevalences and unknown etiology. The majority of the patients (~90%) are female similar to several other autoimmune diseases. Based on this observation, a hypothesis was proposed stating that X chromosome inactivation (XCI) could be involved in female predisposition to autoimmunity. XCI is a physiological mechanism which takes place early in development resulting in the transcriptional silencing of one of the pair of X chromosomes at random in each cell. A significant deviation from a random distribution of two cell populations with paternal and maternal X chromosome inactive is called skewed XCI. Skewing in the dendritic cell population involved in tolerance induction in the thymus was proposed to cause escape of autoreactive lymphocytes and result in autoimmunity (Immunol Today, 19, 352-7, 1998). Skewed XCI was observed in scleroderma (Arth Rheum 52, 1564-70, 2005) and autoimmune thyroiditis (Eur J Hum Genet 14, 791-7, 2006). But this observation is not true for all autoimmune diseases. For example, the XCI profiles of primary biliary cirrhosis patients are similar to normal controls (Hepatol Res 37, Suppl 3, 384-8, 2007). The aim of this study is to determine the XCI profiles of patients diagnosed with primary Sjogren Syndrome, manifesting exocrinopathy or secondary Sjogren Syndrome displaying additional systemic features. DNA was isolated from the peripheric blood samples of 78 Sjogren syndrome patients and 160 controls. XCI profile was determined by the genotyping of a polymorphism in the androgen receptor (AR) gene. For this analysis, restriction enzyme HpaII was used which does not cut methylated regions. Analysis was done with Genescan Abi Prism 310 or 8% polyacrylamide gel electrophoresis and densitometric analysis. Extreme skewing (>90%) of XCI was observed in 3 (5.9%) patients and 3 controls (2.4%) samples (P = 0.3651). Our findings do not support a role for skewed XCI in Sjogren Syndrome.
Open Access
Extremely skewed x-chromosome inactivation in juvenile idiopathic arthritis
(2007) Mustafa, Chigdem Aydın
Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with female predominance and an incidence between 7-21/100,000. There are several explanations for the reason of disease development, such as environmental factors that trigger autoimmunity and genetic basis. The genetic basis of JIA is not well defined. It rarely manifests familial recurrence. But the monozygotic twin data suggest that there is a considerable genetic basis, which is likely to involve multiple epigenetic events. It was proposed that a disturbance in mosaicism of females may cause autoimmune disease development. Recently, in our lab, an association between extremely skewed X-chromosome inactivation (XCI) patterns and female predisposition to autoimmunity was identified. Since JIA is thought to have an autoimmune etiology, we hypothesized that skewed XCI might play a role in the disease development. To determine XCI status, androgen receptor locus was analyzed by methylation sensitive Hpa II digestion followed by PCR by using of 72 female patients diagnosed with JIA and 183 female controls, which comprised of newborns (n=91) and children with no history of an autoimmune condition (n=92). A male control (46, XY) was used for complete digestion in the analysis of XCI pattern. We expect to see an association between extremely skewed XCI and female predisposition to JIA.
Open Access
Skewed x-chromosome inactivation in juvenile idiopathic arthritis and rheumatoid arthritis
(2012) Mustafa, Chigdem Aydın
There is a female predominance in most of the autoimmune diseases, and it is thought to play an important role in identifying the etiological factors. Sex hormones, microchimerism and environmental factors are thought to be responsible. Nowadays, it is proposed that a disturbance in mosaicism of females may cause autoimmune disease development. Recently, in our lab, an association between extremely skewed X-chromosome inactivation (XCI) patterns and female predisposition to autoimmunity was identified in Turkish population. In this study, we hypothesized that skewed XCI might play a role in the disease development of Juvenile idiopathic arthritis (JIA) in Turkish, and Rheumatoid Arthritis (RA) in French population. Therefore, XCI status of healthy individuals and patients diagnosed with JIA and RA were genotyped by analyzing androgen receptor (AR) locus by methylation sensitive HpaII digestion followed by PCR. Extremely skewed XCI was observed in a significant proportion of JIA (OR: 11.33; P=0.0008) in Turkish population, and RA (OR: 7.6; P=0.005) in French population. In conclusion, our results suggest that extremely skewed XCI may play an important role in autoimmune disease pathogenesis.
Open Access
X chromosome inactivation in female predisposition to autoimmunity
(2008) Uz, Elif
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.