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.
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.
Authors: Shan Yu; Constance Chen; Yue Pan; Michael C Kurz; Elizabeth Datner; Phyllis L Hendry; Marc-Anthony Velilla; Christopher Lewandowski; Claire Pearson; Robert Domeier; Samuel A McLean; Sarah D Linnstaedt Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2018-12-11 Impact factor: 3.568
Authors: Sarah M Coffey; Kylee Cook; Nicole Tartaglia; Flora Tassone; Danh V Nguyen; Ruiqin Pan; Hannah E Bronsky; Jennifer Yuhas; Mariya Borodyanskaya; Jim Grigsby; Melanie Doerflinger; Paul J Hagerman; Randi J Hagerman Journal: Am J Med Genet A Date: 2008-04-15 Impact factor: 2.802