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Gene switch in premature births may link to thyroid disease
06 May 2012
European Society of Endocrinology
New research may explain why premature babies are more likely to have biochemical findings consistent with the diagnosis of an underactive thyroid gland. Previous studies show that premature babies are 3-5 times more likely to be diagnosed with hypothyroidism at birth (congenital hypothyroidism, CH). The findings presented at the joint International Congress of Endocrinology/European Congress of Endocrinology in Florence, Italy, suggest that premature birth is associated with a general misregulation of gene expression that may affect genes involved in fetal growth and thyroid function.
CH is an inborn lack of the thyroid hormone, thyroxine. Thyroxine is essential for general health but in children it is particularly important for brain development, and a lack of thyroxine during early years can result in brain damage or reduced IQ. Early diagnosis and replacement of thyroxine, a relatively simple process, is key to prevent these complications, and as a result newborns in many countries are screened for thyroid function at birth. CH is a relatively common condition, affecting roughly 1 in 2-3,000 births worldwide.
The research team, led by Professor Luca Persani, at the University of Milan, Italy investigated patterns of blood DNA methylation in 31 babies with congenital hypothyroidism (CH) who were born prematurely, compared to 31 controls without CH who were born premature or at term. The babies were categorized according to their gestational age (weeks in the womb), growth percentile (relative size at birth) and levels of thyroid stimulating hormone, a hormone used to diagnose CH. Three independent runs of methylation analyses were performed. The technique used measures the total methylation patterns in each group and identifies those genes that are differentially methylated.
Methylation is used by all cells in the body to regulate gene expression, whereby methyl molecules are attached to DNA to switch genes off, or removed to switch genes on. DNA is methylated in response to the environment, but methylated DNA can also be inherited via sperm or eggs. The findings revealed significantly impaired DNA methylation in CH-cases with low gestational age when compared to control babies born either prematurely or at term. This hypomethylation mainly affects premature CH-children born small for gestational age.
When the team assessed the roles of the genes potentially affected, they identified genes involved in fetal growth and thyroid hormone metabolism.
Professor Persani suggests that the widespread deregulation of genes that his team observed may be related to premature birth and growth restriction in the womb. Furthermore the team may have identified a number of genes involved in hormone metabolism which could contribute to the link between premature birth and CH. He and his team now intend to explore these genes in greater detail.
Professor Luca Persani, Associate Professor of Endocrinology at the University of Milan, said:
“It is encouraging that the number of children born prematurely and small for gestational age that survive and reach adulthood is growing in economically-advanced countries. Interestingly, children born prematurely are more likely to experience congenital hypothyroidism, and our aim was to look into why this might be. Several studies have suggested that children born prematurely may exhibit different patterns of regulation in their genome, so we decided to look into whether this may explain the link between premature birth and congenital hypothyroidism.
“We found that far less of the DNA of premature babies with congenital hypothyroidism is methylated, that is, far less is found in the ‘off position’. The analysis was performed on blood cell DNA and therefore caution should be given in the interpretation of such results. However, a number of the potentially affected genes we found are involved in fetal growth and thyroid hormone metabolism, which gives us a preliminary indication that this could be related to premature birth and could predispose children to congenital hypothyroidism. Whether this deregulation is a cause or an effect of premature birth is an area for further investigation.
“This is a complicated field of study and at present we are just scratching the surface. Our research has potentially identified a novel mechanism which may also help us to understand how the expression of genetic defects associated with congenital hypothyroidism may be modified.”