Skewed X chromosome inactivation may contribute to paediatric thyroid disease

By Eleanor McDermid
Clin Endocrinol 2018; doi:10.1111/cen.13857
30 September 2018

medwireNews: Skewed inactivation of the X chromosome may underlie a proportion of cases of autoimmune thyroid disease (ATD) in girls, research suggests.

The study by Preamrudee Poomthavorn (Mahidol University, Bangkok, Thailand) and team included 83 patients (57 with Graves’ disease and 26 with Hashimoto thyroiditis), who were diagnosed at a median age of 10.3 years, and 52 age-matched healthy controls.

X chromosome inactivation is the process whereby one X chromosome is inactivated in female mammals, so they do not receive a double dose of X chromosome gene products. In humans, either the maternal or paternal X chromosome in each cell is randomly inactivated, but the process can be skewed, leading to an increased proportion of cells with inactivation of one or the other.

This skewing, defined here as having at least 80% of cells inactivated on the same chromosome, was found in 8% of the control study participants, but in a significantly greater 23% of the ATD patients. The rate was higher for patients with Hashimoto thyroiditis than with Graves’ disease, at a respective 38% and 16%.

The researchers explain that this skewing could hypothetically lead to “breakdown of self-tolerance in the thymus”; if only a small proportion of antigens from one X chromosome are expressed in the thymus, then these may not become recognised as self by the immune system, triggering autoimmune disease.

However, skewing was also present in controls, the median degree of skewing was not significantly different between the ATD patients and controls and neither was the frequency of extreme skewing (>90% inactivation of same chromosome; 10 vs 2%).

“These findings suggest that [X chromosome inactivation] skewing, if any, might explain the pathogenesis of childhood ATD only in some cases”, write the researchers in Clinical Endocrinology.

There were no significant age differences between study participants with and without skewing, and no differences in clinical variables including measures of disease severity (TRAb levels for Graves’ disease and anti-thyroglobulin or anti-thyroperoxidase levels for Hashimoto thyroiditis).

The research team therefore suggests that skewed X chromosome inactivation “may be associated with the predisposition to development of ATD, but […] not associated with the severity or activity of the disease.”

Of the seven patients with skewed inactivation for whom parental samples were available, six had preferential inactivation of the paternal X chromosome.

“However, due to small number of available parental samples, this study could not find a relationship with family history of thyroid disorders which might suggest the imprinting effect of the as-yet-unknown disease-associated gene”, Poomthavorn and team conclude.

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