Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
Center for Endocrinology and Metabolism, Copenhagen University Hospital-Herlev and Gentofte, Herlev DK-2730, Denmark.
J Clin Endocrinol Metab. 2024 Jan 18;109(2):e613-e622. doi: 10.1210/clinem/dgad556.
Some evidence suggests gene-treatment interactions might cause persistent symptoms in individuals receiving levothyroxine (LT4) treatment.
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.
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.
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.
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.
一些证据表明，基因-治疗相互作用可能导致接受左甲状腺素（LT4）治疗的个体持续出现症状。
我们之前假设，如果甲状腺激素脱碘酶 2 基因（DIO2）中的 rs225014（Thr92Ala）、rs225015 或 rs12885300（ORFa-Gly3Asp）或单羧酸转运蛋白 10 基因（MCT10）中的 rs17606253 中的单核苷酸变异（SNVs；以前称为单核苷酸多态性）与 LT4 治疗患者和对照组中局部组织甲状腺功能减退的结果指标相关，我们对此进行了调查。
我们在英国生物库的一项基于人群的横断面研究中纳入了 18761 名 LT4 治疗患者和 360534 名对照。LT4 治疗的定义为甲状腺功能减退症的诊断和自述使用 LT4 而不使用 3,5,3'-三碘甲状腺原氨酸。结果是心理健康、认知功能和心血管危险因素。通过线性、逻辑或有序逻辑多回归评估关联。调整包括性别、年龄、性别-年龄相互作用以及遗传主成分 1 至 10。
与对照组相比，LT4 治疗与几乎所有结果均呈负相关，最显著的是：疲劳频率增加（P <.001）、幸福感因子评分降低（P <.001）、反应时间延长（P <.001）和体重指数增加（P <.001）。除了 rs225015 较小的 A 等位基因与经济不满之间存在显著关联外，rs225014、rs225015、rs12885300 或 rs17606253 与 LT4 治疗患者的任何结果均无关联。对于所有结果，与对照组相比，这些 4 个 SNV 的风险等位基因携带并不能放大与 LT4 治疗相关的症状。
rs225014、rs225015、rs12885300 和 rs17606253 不能解释 LT4 治疗患者心理幸福感、认知功能或心血管危险因素的变化。我们的研究结果不支持这些 SNV 与 LT4 治疗之间的基因-治疗相互作用。
