DNA Methylation at a Nutritionally Sensitive Region of the PAX8 Gene Is Associated With Thyroid Volume and Function in Gambian Children

Authors

Toby Candler
Noah J Kessler
Chathura J Gunasekara
Kate A Ward
Philip James
Eleonora Laritsky
Maria S Baker
Roger Dyer
Rajavel Elango
David Jeffries
Robert A Waterland
Sophie E Moore
Marian Ludgate
Andrew M Prentice
Matt J Silver

Publication Date

11-5-2021

Journal

Science Advances

DOI

10.1126/sciadv.abj1561

PMID

34739318

PMCID

PMC8570597

PubMedCentral® Posted Date

11-5-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Abstract

PAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, and PAX8 gene methylation is reported to be sensitive to the periconceptional environment. Using a novel recall-by-epigenotype study in Gambian children, we found that PAX8 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 PAX8 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, PAX8 gene methylation and thyroid gland development and function, with potential implications for early embryonic programming of thyroid-related health and disease.