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

Some evidence suggests gene-treatment interactions might cause persistent symptoms in individuals receiving levothyroxine (LT4) treatment. We investigated, as previously hypothesized, if single nucleotide polymorphisms (SNPs) 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.We included 18,761 LT4-treated patients and 360,534 controls in a population-based cross-sectional study in UK Biobank. LT4 treatment was defined as a diagnosis of hypothyroidism and self-reported use of LT4 without use of T3. 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 1-10.Compared to controls, LT4 treatment was adversely associated with almost all outcomes, most noteworthy: Increased frequency of tiredness (p < 0.001), decreased well-being factor score (p < 0.001), increased reaction-time (p < 0.001), and increased BMI (p < 0.001). 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 four SNPs did not amplify symptoms associated with LT4 treatment compared to controls.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 SNPs and LT4 treatment.