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

Introduction: Animal studies suggest that up to 80% of intracellular T-3 in the brain is derived from circulating T-4 by local deiodination. We hypothesized that in patients on T-4 common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T-4/T-3 without necessarily affecting serum thyroid hormone levels. Methods: We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T-4/T-3 in 552 subjects on T-4 from the Weston Area T-4 T-3 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 T-4 (CC vs. TT genotype: 14.1 vs. 12.8, P = 0.03). In addition, this genotype showed greater improvement on T-4/T-3 therapy compared with T-4 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 T-4 and enhanced response to combination T-4/T-3 therapy, but did not affect serum thyroid hormone levels. (J Clin Endocrinol Metab 94: 1623-1629, 2009)