Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone

二氧化二钠 脱碘酶 内科学 内分泌学 左旋甲状腺素 医学 激素 甲状腺 多态性(计算机科学) 甲状腺切除术 碘甲状腺原氨酸脱碘酶 置信区间 SNP公司 前瞻性队列研究 基因型 单核苷酸多态性 生物 甲状腺激素 基因 遗传学
作者
Cristina Luongo,Maria Angela De Stefano,Raffaele Ambrosio,Fabio Volpe,Tommaso Porcelli,Valeria Golia,Claudio Bellevicine,Giancarlo Troncone,Stefania Masone,Vincenzo Damiano,Elide Matano,Michele Klain,Martin Schlumberger,Domenico Salvatore
出处
期刊:Thyroid [Mary Ann Liebert, Inc.]
卷期号:33 (3): 294-300 被引量:4
标识
DOI:10.1089/thy.2022.0472
摘要

Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15–30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r = −0.45, p = 0.0002, 95% confidence interval [CI] −0.63 to −0.23; Ala/Thr r = −0.39, p = 0.0012, CI −0.60 to −0.67; and Ala/Ala r = −0.30, p = 0.2347; CI −0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients (p = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21).
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