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.