Association of DIO2 and MCT10 Polymorphisms With Persistent Symptoms in LT4-Treated Patients in the UK Biobank

• Published in: The journal of clinical endocrinology and metabolism 2024-01, Vol.109 (2), p.e613-e622
• Main Authors: Jensen, Christian Zinck, Isaksen, Jonas Lynggaard, Ahlberg, Gustav, Olesen, Morten Salling, Nygaard, Birte, Ellervik, Christina, Kanters, Jørgen Kim
• Format: Article
• Language: English
• Subjects: Alleles; Biobanks; Biological Specimen Banks; Body mass index; Cardiovascular diseases; Cognitive ability; Cross-Sectional Studies; Humans; Hypothyroidism; Hypothyroidism - drug therapy; Hypothyroidism - genetics; Iodide peroxidase; Iodide Peroxidase - genetics; Iodothyronine Deiodinase Type II; Polymorphism, Single Nucleotide; Population studies; Risk factors; Single-nucleotide polymorphism; Thyroid hormones; Thyroxine; Thyroxine - genetics; Thyroxine - therapeutic use; Triiodothyronine; UK Biobank; Well being
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgad556

Abstract Context Some evidence suggests gene-treatment interactions might cause persistent symptoms in individuals receiving levothyroxine (LT4) treatment. Objective We investigated, as previously hypothesized, if single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms) in rs225014 (Thr92Ala), rs225015, or rs12885300 (ORFa-Gly3Asp) in the deiodinase 2 gene (DIO2), or rs17606253 in the monocarboxylate transporter 10 gene (MCT10) were associated with outcomes indicative of local tissue hypothyroidism in LT4-treated patients and controls. Methods We included 18 761 LT4-treated patients and 360 534 controls in a population-based cross-sectional study in the UK Biobank. LT4 treatment was defined as a diagnosis of hypothyroidism and self-reported use of LT4 without use of 3,5,3′-triiodothyronine. Outcomes were psychological well-being, cognitive function, and cardiovascular risk factors. Associations were evaluated by linear, logistic, or ordinal logistic multiple regression. Adjustments included sex, age, sex-age interaction, and genetic principal components 1 to 10. Results Compared to controls, LT4 treatment was adversely associated with almost all outcomes, most noteworthy: Increased frequency of tiredness (P < .001), decreased well-being factor score (P < .001), increased reaction-time (P < .001), and increased body mass index (P < .001). Except for a significant association between the minor rs225015 A allele and financial dissatisfaction, there was no association of rs225014, rs225015, rs12885300, or rs17606253 with any outcomes in LT4-treated patients. For all outcomes, carrying the risk allele at these 4 SNVs did not amplify symptoms associated with LT4 treatment compared to controls. Conclusion rs225014, rs225015, rs12885300, and rs17606253 could not explain changed psychological well-being, cognitive function, or cardiovascular risk factors in LT4-treated patients. Our findings do not support a gene-treatment interaction between these SNVs and LT4 treatment.