DNA methylation at a nutritionally sensitive region of the <i>PAX8</i> gene is associated with thyroid volume and function in Gambian children

Abstract

PAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, and <i>PAX8</i> gene methylation is reported to be sensitive to the periconceptional environment. Using a novel recall-by-epigenotype study in Gambian children, we found that <i>PAX8</i> hypomethylation at age 2 years is associated with a 21% increase in thyroid volume and an increase in free thyroxine (T4) at 5 to 8 years, the latter equivalent to 8.4% of the normal range. Free T4 was associated with a decrease in DXA-derived body fat and bone mineral density. Furthermore, offspring <i>PAX8</i> methylation was associated with periconceptional maternal nutrition, and methylation variability was influenced by genotype, suggesting that sensitivity to environmental exposures may be under partial genetic control. Together, our results demonstrate a possible link between early environment, <i>PAX8</i> gene methylation and thyroid gland development and function, with potential implications for early embryonic programming of thyroid-related health and disease.