NEW YORK – Lower-than-usual methylation in the PAX8 gene in toddlers appears to be tied to larger thyroid glands and enhanced thyroxine hormone levels later in childhood, new research has found. Methylation of the gene, which encodes a thyroid transcription factor, seems to be influenced by both genotype and maternal nutrition, according to the study.
"Our work has potential implications for understanding the fetal origins of health and disease and may contribute to our understanding of the epigenetic drivers of thyroid development and function," senior author Matt Silver, a researcher at the MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, and his co-authors wrote.
As they reported in Science Advances on Friday, the researchers, which also hailed from the University of Cambridge and other centers in the UK, US, and Canada, performed targeted PAX8 DNA methylation profiling on peripheral blood samples collected from nearly 700 2-year-old children born to mothers in Gambia who were participating in the Early Nutrition and Immune Development trial.
The team was able to follow up with 118 of the children several years later, when they were about 5 to 9 years old, including 60 children who had had low PAX8 methylation as toddlers and 58 children with high PAX8 methylation as 2-year-olds.
The investigators also considered relationships between methylation, thyroid features, and gene expression using available data from the Cancer Genome Atlas and the Genotype-Tissue Expression Project, and followed features such as maternal nutrition and PAX8 methylation stability over time with other samples collected for the study in Gambia.
Based on ultrasound measurements for all but a few of the children, the team found that thyroid gland volume was roughly 21 percent greater, on average, in children with low PAX8 methylation at the two-year mark.
Low methylation at PAX8 early in childhood not only corresponded to larger thyroid glands, but also to thyroids that pumped out more thyroxine. High levels of that hormone have been implicated in reduced body fat and diminished bone mineral density, consistent with the patterns identified by body composition and bone mineral density measurements for children participating in the study.
The 71 male children the researchers studied appeared more likely to have low PAX8 methylation than their 47 female counterparts, but maternal or child body mass index, the season when a child was conceived, and other factors were not significantly linked to low or high methylation in the analyses.
The researchers saw a role for genotype in the methylation patterns observed, as well: the wild-type version of a SNP near PAX8 associated with a wider range of methylation options, while the presence of two copies of an alternative allele coincided with a higher but more limited PAX8 methylation range.
"[T]he effect of the PAX8 methylation group on thyroid volume and free [thyroxine] did not appear to be purely driven by genotype, as [heterozygous and homozygous wild type] individuals were well represented in both the high and low PAX8 methylation groups," the authors explained.
Based on these and other results, the investigators suggested that the prenatal environment may influence molecular features and physiology of children as they age by moderating genotype through epigenetic marks in the PAX8 region.
"Together, our results demonstrate a possible link between early environment, PAX8 gene methylation, and thyroid gland development and function," they wrote, "with potential implications for early embryonic programming of thyroid-related health and disease."