ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Commun. 2018;9:4455.

Here, the largest genome-wide association study (GWAS) to date on thyroid function and dysfunction, in 72,167 individuals testing 8 million genetic variants, substantially increased the number of loci that are involved in the regulation of thyroid function. It provides functional evidence that two newly identified genes are involved in thyroid hormone transport and metabolism.

This extensive study adds to the understanding of our current knowledge in three ways: first, previous GWAS identified about 30 loci for thyroid function, explaining <9% of heritability in TSH and FT4 variation. The current study increased this number to 109 loci associated with thyroid function, replicating all known loci from earlier studies. Second, the authors calculated a genetic risk score based on combined effects of variants for TSH and FT4 levels, and showed significant associations with risk for overt hyperthyroidism and subclinical hypothyroidism. Finally, based on newly identified loci, the authors identified two new interesting genes for thyroid hormone action in target tissues: 1) SLC17A4, encoding a transport protein of the solute carrier family, and 2) AADAT, encoding a mitochondrial aminotransferase with broad substrate specificity. By in vitro studies, they provide functional evidence that SLC17A4 is a yet unknown high-affinity transmembrane transporter of T3 and T4, and that AADAT effectively converts T3 and T4 to their pyruvic acid metabolites TK3 and TK4 by oxidative deamination of the alanine side-chain of thyroid hormones. This pathway was described in 1957 by Wilkinson, but the responsible enzyme was not known until now [1, 2]. T3 and T4 conversion to TK3 and TK4 represents an alternative synthetic route of triiodothyroacetic acid (Triac) and tetraiodothyroacetic acid (Tetrac) [2].

Finally, as an outlook, the authors suggest future studies to investigate the use of the known markers to predict individual hypothalamo-pituitary-thyroid axis set points for more accurate individualized treatment of patients with thyroid diseases. In summary, these results clearly confirm the value of GWAS in the general population to identify new genes of interest, extend current knowledge of thyroid hormone physiology and open avenues for personalized thyroid disease treatment.

References: 1. Wilkinson JH. Recent work on thyroid hormones. Postgrad Med J 1957;33:333–7.

2. Groeneweg S, Peeters RP, Visser TJ, Visser WE. Triiodothyroacetic acid in health and disease. J Endocrinol 2017;234:R99–121.