Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis

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).

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.

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.

The study was conducted at a research laboratory.

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.

Case-control and family-based association studies and meta-analysis were measured.

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%].

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.