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Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid Patients

Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology (V.P., P.S., C.M.D.), University of Bristol BS1 3NY, Bristol, United Kingdom; Faculty of Medicine, Dentistry and Health Sciences (V.P.), University of Western Australia, Crawley, Western Australia 6009, Australia; Clinical Sciences Research Institute (P.S.), University of Warwick, Coventry CV4 7AL, United Kingdom; Department of Endocrinology (B.V.), Royal Devon and Exeter Hospital, Exeter EX2 5DW, United Kingdom; Academic Unit of Psychiatry (J.E.), University of Bristol, Bristol BS6 6JL, United Kingdom; and Genetics of Complex Traits (A.T.H., T.M.F.), Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter EX1 2LU, 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: Animal studies suggest that up to 80% of intracellular T₃ in the brain is derived from circulating T₄ by local deiodination. We hypothesized that in patients on T₄ common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T₄/T₃ without necessarily affecting serum thyroid hormone levels.

Methods: We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T₄/T₃ in 552 subjects on T₄ from the Weston Area T₄ T₃ Study (WATTS). Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12).

Results: The rarer CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2) was present in 16% of the study population and was associated with worse baseline GHQ scores in patients on T₄ (CC vs. TT genotype: 14.1 vs. 12.8, P = 0.03). In addition, this genotype showed greater improvement on T₄/T₃ therapy compared with T₄ only by 2.3 GHQ points at 3 months and 1.4 at 12 months (P = 0.03 for repeated measures ANOVA). This polymorphism had no impact on circulating thyroid hormone levels.

Conclusions: Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T₄ and enhanced response to combination T₄/T₃ therapy, but did not affect serum thyroid hormone levels.

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