Variation in levels of skewed X chromosome inactivation represents a shared pathogenic pathway for the common autoimmune thyroid diseases
Matthew Simmonds1, Oliver Brand1, Paul Newby2, Laura Jackson2, Chantal Hargreaves2, Jackie Carr-Smith2, Jayne Franklyn2 & Stephen Gough1
Graves disease (GD) and Hashimotos thyroiditis (HT), two of the most common autoimmune thyroid diseases (AITD), are caused by both shared and disease specific genetic determinants. In females one copy of the X chromosome is randomly inactivated, and although inactivation should occur with a parent of origin ratio of 50:50, skewed X chromosome inactivation (XCI) can occur, whereby >80% of a specific copy of the X chromosome is inactivated. Increased skewed XCI in GD is believed to explain the strong female preponderance seen. Using data taken from all known GD XCI studies (5 studies totalling 454 GD and 610 controls), we performed meta-analysis which supported a role for skewed XCI in GD P=1.61×10−8, OR=2.56 (95% CI=1.833.57). Some evidence for a role of skewed XCI in HT has previously been reported, but from relatively small datasets. We aimed to confirm these findings using microsatellite marker genotyping within the androgen receptor to determine XCI levels in a large UK Caucasian HT cohort consisting of 490 informative female HT patients and 325 female controls. All subjects gave informed written consent and the project was approved by the local ethics committee. Even using the largest HT dataset investigated to date only a trend towards increased skewed XCI (P=0.079) was found in our HT patients. Clinical correlations revealed that skewed XCI was more frequent in thyroid autoantibody negative HT patients than autoantibody positive patients (27.6 vs 13.6%), suggesting XCI skewing does not contribute to thyroid autoantibody production. However, meta-analysis of the current data and others (five studies totalling 671 HT cases and 592 controls) produced an overall significant pooled P=2.39×10−5 OR=1.93 (95% CI=1.412.64), confirming a role for XCI in HT. These and other ongoing studies determining how skewed XCI contributes to GD and HT will increase our understanding of this important shared AITD pathogenic pathway.