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Submitted on June 17, 2005
Accepted on August 5, 2005
rstavik, Department of Endocrinology, Odense University Hospital, Denmark; University of Oslo, Faculty Division, Rikshospitalet, Department of Medical Genetics, The Danish Twin Registry, University of Southern Denmark; Rikshospitalet University Hospital, Department of Medical Genetics, Oslo, Norway
* To whom correspondence should be addressed. E-mail: thomas.brix{at}ouh.fyns-amt.dk.
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: To examine whether skewed XCI is associated with AITD.
Designs: First, a classical case-control study of twin individuals with and without AITD. Second, a case-control study of twin pairs discordant for AITD.
Participants: Thirty-two 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: 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 prevalences 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, odds ratio 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.
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