Context: Autoimmune thyroid diseases (AITD) comprise Graves' disease (GD) and Hashimoto's thyroiditis (HT). They are characterized by loss of immunological self-tolerance and female preponderance. Theoretically, X chromosome inactivation (XCI) and resultant tissue chimerism could offer an explanation for the female predisposition to AITD.
Aim: Our aim was to examine whether skewed XCI is associated with AITD.
Designs: We first conducted a classical case-control study of twin individuals with and without AITD, and then a case-control study of twin pairs discordant for AITD.
Participants: Participants included 32 female twins with AITD and a control group of 96 healthy female twin individuals.
Methods: XCI analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X chromosome.
Main outcome measures: We assessed the prevalence of skewed XCI.
Results: The frequency of skewed XCI in female twins with AITD, GD, and HT was 34, 37, and 31%, respectively, which was higher than the prevalence in the corresponding control populations, 11% (P = 0.003), 14% (P = 0.045), and 8% (P = 0.057), respectively. Similar results were found in twin pairs discordant for AITD. Overall, skewed XCI was associated with an increased risk of developing AITD, with an odds ratio of 9.0 (95% confidence interval, 1.64-49.4) (P = 0.022).
Conclusion: These observations suggest a possible role of XCI in the etiology of AITD and may in part explain the female preponderance of AITD.