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A Common Variation in Deiodinase 1 Gene DIO1 Is Associated with the Relative Levels of Free Thyroxine and Triiodothyronine

Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology (V.P., P.S., C.M.D.) and Academic Unit of Psychiatry (J.E., C.D.), University of Bristol, Bristol BS1 3NY, United Kingdom; Faculty of Medicine, Dentistry, and Health Sciences (V.P.), University of Western Australia, Perth 6009, Australia; Genetics of Complex Traits (V.P., C.C., B.S., A.M., K.S.P., J.R.B.P., M.N.W., D.M., A.T.H., T.M.F.), Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter EX1 2LU, United Kingdom; Molecular Genetics Unit (A.S., D.H.) and Longitudinal Studies Section (L.F.), Clinical Research Branch, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892; Clinical Sciences Research Unit (P.S.), University of Warwick, Warwick CV2 2DX United Kingdom; Department of Internal Medicine (T.J.V.), Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands; Department of Internal Medicine and Biomedical Sciences (G.C.), Section of Geriatrics, University of Parma, 43100 Parma, Italy; and Department of Endocrinology (B.V.), Royal Devon and Exeter Hospital, Exeter EX2 5DW, United Kingdom

Address all correspondence and requests for reprints to: Dr. C. M. Dayan, Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, United Kingdom. E-mail: Colin.Dayan{at}bristol.ac.uk.

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 T₄ replacement. Suggestive findings were taken forward into 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 T₃ to free T₄ ratio with genome-wide levels of significance (P = 3.6 x 10^–13). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T₃/T₄ ratio and free T₃ and decrease in free T₄ and 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 T₃ to free T₄. This should prove a valuable tool to assess the relative effects of circulating free T₃ vs. free T₄ on a wide range of biological parameters.