Introduction: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. Methods: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T4replacement. Suggestive findingsweretakenforwardinto three additional studies in people not on T4(total n = 2513) and metaanalyzed for confirmation. Results: A SNP in the DIO1 gene, rs2235544, was associated with the free T3to free T4ratio with genome-wide levels of significance (P = 3.6 × 10-13). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T3/T4ratio and free T3and decrease in free T4and rT3. There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. Conclusions: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T3to free T4. This should prove a valuable tool to assess the relative effects of circulating free T3vs. free T4on a wide range of biological parameters. Copyright

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Journal Journal of Clinical Endocrinology and Metabolism
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Panicker, V, Cluett, C, Shields, B.M, Murray, J.C, Parnell, K.S, Perry, J.R.B, … Frayling, T.M. (2008). A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. Journal of Clinical Endocrinology and Metabolism, 93(8), 3075–3081. doi:10.1210/jc.2008-0397