Endocrine Abstracts

In healthy subjects, there is a substantial variability in circulating concentrations of thyroid hormone (TH) between individuals, whereas the variability within an individual over time is usually within a narrow range. It is estimated that about 65% of this variation is genetically determined, resulting in a thyroid function set-point that is different for each individual. The major causative genes are, however, not well established.

The biological activity of TH is not only determined by serum concentrations of TH, but also by the expression and activity of iodothyronine deiodinases, TH transporters and TH receptors. It has been shown that polymorphisms in the deiodinases, TSH receptor, and TH transporters are associated with serum TH levels, but their contribution to the overall variance is modest. However, because DNA variations are stable throughout life, they are likely to have an influence during the lifetime of an individual and polymorphisms in these genes have been associated with diabetes mellitus, hypertension, neurocognitive functioning, bone mineral density and osteoarthritis.

The availability of high-throughput genotyping techniques has made it possible to switch from hypothesis-driven candidate gene studies to hypothesis-free genome wide association (GWA) studies, in which multiple tagging SNPs are used to cover the genome. Recently, Arnaud Lopez et al. demonstrated using GWA studies that a polymorphism in the phosphodiesterase 8B gene, which catalyzes the inactivation of cAMP in the thyroid, is associated with serum TSH and Panicker et al. identified several loci associated with serum FT4 and TSH by a genome-wide linkage scan with 737 microsatellite markers. It is likely that future GWA studies will provide more candidate genes involved in thyroid function.

During this symposium, the interpretation of the above mentioned studies will be discussed, as well as the potential consequences of the increasing knowledge of these genetic determinants for clinical practice.