High Frequency of Skewed X-Chromosome Inactivation in Females with Autoimmune Thyroid Disease: A Possible Explanation for the Female Predisposition to Thyroid Autoimmunity

• Published in: The journal of clinical endocrinology and metabolism 2005-11, Vol.90 (11), p.5949-5953
• Main Authors: Brix, Thomas Heiberg, Knudsen, Gun Peggy S., Kristiansen, Marianne, Kyvik, Kirsten Ohm, Ørstavik, Karen Helene, Hegedüs, Laszlo
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Case-Control Studies; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Genetic Predisposition to Disease; Graves Disease - etiology; Graves Disease - genetics; Humans; Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Thyroid. Thyroid axis (diseases); Thyroiditis, Autoimmune - etiology; Thyroiditis, Autoimmune - genetics; Vertebrates: endocrinology; X Chromosome Inactivation - genetics
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2005-1366

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.