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CONTEXT: A number of small data sets have suggested a potential role for skewed X chromosome activation (XCI), away from the expected 50:50 parent of origin ratio, as an explanation for the strong female preponderance seen in the common autoimmune thyroid diseases (AITD), Graves' disease (GD), and Hashimoto's thyroiditis (HT). OBJECTIVE: The objective of the study was to confirm a role for XCI skewing as a potential explanation for the strong female preponderance seen in AITD. DESIGN: The design of the study was to screen XCI in the largest GD, HT, and control case-control cohort and family cohort to date and undertake a meta-analysis of previous AITD XCI reports. SETTING: The study was conducted at a research laboratory. PATIENTS: Three hundred and nine GD, 490 HT, and 325 female UK Caucasians controls, 273 UK Caucasian GD families, and a meta-analysis of 454 GD, 673 HT, and 643 female Caucasian controls were included in the study. MAIN OUTCOME MEASURES: Case-control and family-based association studies and meta-analysis were measured. RESULTS: Skewed XCI was observed with GD [odds ratio (OR) 2.17 [95% confidence interval (CI) 1.43-3.30], P=2.1×10(-4)] and a trend toward skewing with HT (P=.08) compared with the control cohort. A meta-analysis of our UK data and that of four previous non-UK Caucasian studies confirmed significant skewing of XCI with GD [OR 2.54 (95% CI 1.58-4.10), P=1.0×10(-4), I2=30.2%] and HT [OR 2.40 (95% CI 1.10-5.26), P=.03, I2=74.3%]. CONCLUSIONS: Convincing evidence exists to support a role for skewed XCI in female subjects with AITD, which may, in part, explain the strong female preponderance observed in this disease.

Original publication




Journal article


J Clin Endocrinol Metab

Publication Date





E127 - E131


Adult, Case-Control Studies, European Continental Ancestry Group, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Pedigree, Sex Factors, Thyroiditis, Autoimmune, United Kingdom, X Chromosome Inactivation, Young Adult