The Relationship Between Skewed X Chromosome Inactivation and the Prognosis of Graves' and Hashimoto's Diseases

Background: Autoimmune thyroid diseases (AITDs) predominantly develop in females. One of two X chromosomes is randomly inactivated by methylation in each female cell, but it has been reported that skewed X chromosome inactivation (XCI) may be associated with the development of autoimmune diseases. To clarify the significance of skewed XCI in the prognosis and development of AITD, we investigated the proportion of skewed XCI in female patients with AITD. Methods: We analyzed the degree of XCI skewing in 120 female patients with AITD (77 patients with Graves' disease [GD] and 43 patients with Hashimoto's disease [HD]) and 49 female controls in DNA from peripheral blood mononuclear cells (PBMC). We performed XCI analysis by digesting inactive DNA with a methylation-sensitive restriction enzyme (HpaII) followed by a polymerase chain reaction (PCR) assay for the polymorphic CAG repeat of the androgen receptor gene and electrophoresis of the PCR products. Results: The proportion of skewed XCI (>= 65% skewing) was not significantly different between AITD patients and control subjects but was higher in patients with intractable GD (66.7%) than those with GD in remission (25.0%, p=0.0033) and control subjects (32.6%, p=0.0038). When the cutoff value for XCI skewing was relaxed, the proportion of skewed XCI (>= 60% skewing) was higher in patients with severe HD (76.5%) than in those with mild HD (41.2%, p=0.0342). Conclusions: Skewed XCI is related to the prognosis of AITD, particularly the intractability of GD.