Endocrine Abstracts

Graves’ disease (GD) affects >2% of the population and occurs more frequently in females than males. Several hypotheses have been put forward to explain the female preponderance including increased immune responsiveness, gonadal steriods, sex chromosome susceptibility loci and, more recently, skewed X inactivation (XCI). XCI occurs in females causing one of their X chromosomes to be randomly inactivated enabling dosage compensation with males who only have one copy of the X chromosome. Although each X chromosome should be inactivated with a parent of origin ratio of 50:50, skewed XCI can occur whereby >80% of a specific copy of the female X chromosome is inactivated (or extreme skewing with >90% inactivation). Several smaller GD datasets have detected association of skewed XCI, suggesting a possible role for skewed XCI in GD onset in females. The aim of this study using microsatellite marker genotyping within the androgen receptor was to determine levels of XCI in a large UK Caucasian GD cohort consisting of 417 female GD patients and 385 female controls. All subjects gave informed written consent and the project was approved by the local ethic committee. Skewed XCI was found to be strongly associated with GD (P=2.14×10⁻⁴, OR=2.17 (95% CI=1.43–3.30)), although no evidence of extreme skewing was detected (P=0.236). When we investigated parent of origin effects of the skewed chromosome we found that in 60% of skewed GD cases the father’s X chromosome was preferentially skewed. This suggests that products from the skewed father’s X chromosome are less likely to be seen and tolerated by the immune system of these GD subjects. Components from the skewed X chromosome when encountered later in life could not be recognized as self and an autoimmune response could occur. Further work is currently establishing to what extent XCI skewing explains the increased female preponderance in GD.