Research progress in association of the DIO2 and UGT1A1 gene polymorphisms with Levothyroxine dose

Abstract

Abstract: Hypothyroidism occurs as a result of underproduction or underutilization of thyroid hormone due to various causes. It is one of the most common endocrine disorders. Oral levothyroxine (L-T₄) is the drug of choice for the management of hypothyroidism. But approximately 10% of hypothyroid patients are dissatisfied with the outcome of L-T₄ replacement. Several factors can affect achieving the goals with L-T₄ therapy; in addition to age, concurrent medications, patient compliance and so on, genetic factors are also important, such as the type 2 deiodinase gene (DIO2) and the uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene polymorphisms. To understand the association between gene polymorphisms and L-T₄ dose in patients with primary hypothyroidism will be further improved patient outcomes and provide reference for clinical use.

Key words: levothyroxine, dosing regimen, gene polymorphism, DIO2, UGT1A1

CLC Number:

R968
R977.1

XU Jiao, CHEN Bin, JI Cheng. Research progress in association of the DIO2 and UGT1A1 gene polymorphisms with Levothyroxine dose[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(4): 476-480.

References

[1] 中华医学会内分泌学分会. 甲状腺疾病诊治指南-甲状腺功能减退症[J]. 中华内科杂志,2007,46(11):967-971.
[2] 初蕾. 甲状腺功能减退患者甲状腺素替代治疗临床分析[J]. 中国临床药理学与治疗学,2013,18(4):420-423.
[3] Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association[J]. Endocr Pract, 2012, 18(6):988-1028.
[4] Wiersinga WM. Do we need still more trials on T4 and T3 combination therapy in hypothyroidism[J] ? Eur J Endocrinol, 2009, 161(6):955-959.
[5] Williams GR, Bassett JH. Deiodinases: the balance of thyroid hormone: local control of thyroid hormone action: role of type 2 deiodinase[J]. J Endocrinol, 2011, 209(3):261-272.
[6] Arrojo E Drigo R, Fonseca TL, Werneck-de-Castro JP, et al. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling[J]. Biochim Biophys Acta, 2013, 1830(7):3956-3964.
[7] Celi FS, Canettieri G, Mentuccia D, et al. Structural organization and chromosomal localization of the human type II deiodinase gene[J]. Eur J Endocrinol, 2000, 143(2):267-271.
[8] Hoftijzer HC, Heemstra KA, Visser TJ, et al. The type 2 deiodinase ORFa-Gly3Asp polymorphism (rs12885300) influences the set point of the hypothalamus-pituitary-thyroid axis in patients treated for differentiated thyroid carcinoma[J]. J Clin Endocrinol Metab, 2011, 96(9):E1527-E1533.
[9] Al-azzam SI, Alkhateeb AM, Al-Azzeh O, et al. The role of type II deiodinase polymorphisms in clinical management of hypothyroid patients treated with levothyroxine[J]. Exp Clin Endocrinol Diabetes, 2013, 121(5):300-305.
[10]Bianco AC, Casula S. Thyroid hormone replacement therapy: three 'simple' questions, complex answers[J]. Eur Thyroid J, 2012, 1(2):88-98.
[11]Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer[J]. Thyroid, 2009, 19(11):1167-1214.
[12]Torlontano M, Durante C, Torrente L, et al. Type 2 deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin levels in thyroidectomized patients[J]. J Clin Endocrinol Metab, 2008, 93(3):910-913.
[13]Heemstra KA, Hoftijzer HC, van der Deure WM, et al. Thr92Ala polymorphism in the type 2 deiodinase is not associated with T₄ dose in athyroid patients or patients with Hashimoto thyroiditis[J]. Clin Endocrinol, 2009, 71(2):279-283.
[14]Richardson VM, Ferguson SS, Sey YM, et al. In vitro metabolism of thyroxine by rat and human hepatocytes[J]. Xenobiotica, 2014, 44(5):391-403.
[15]Stingl JC, Bartels H, Viviani R, et al. Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review[J]. Pharmacol Ther, 2014, 141(1):92-116.
[16]Kato Y, Ikushiro S, Emi Y, et al. Hepatic UDP-glucuronosyltransferases responsible for glucuronidation of thyroxine in humans[J]. Drug Metab Dispos, 2008, 36(1):51-55.
[17]Sugatani J. Function, genetic polymorphism, and transcriptional regulation of human UDP-glucuronosyltransferase (UGT) 1A1[J]. Drug Metab Pharmacokinet, 2013, 28(2):83-92.
[18]Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism[J]? Proc Natl Acad Sci USA, 1998, 95(14):8170-8174.
[19]Yoder Graber AL, Ramírez J, Innocenti F, et al. UGT1A1^*28 genotype affects the in-vitro glucuronidation of thyroxine in human livers[J]. Pharmacogenet Genomics, 2007, 17(8):619-627.
[20]Vargens DD, Neves RR, Bulzico DA, et al. Association of the UGT1A1-53(TA)_n polymorphism with L-thyroxine doses required for thyrotropin suppression in patients with differentiated thyroid cancer[J]. Pharmacogenet Genomics, 2011, 21(6):341-343.
[21]Santoro AB, Vargens DD, Barros Filho Mde C, et al. Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer[J]. Br J Clin Pharmacol, 2014, 78(5):1067-1075.
[22]Al-Azzam SI, Alzoubi KH, Khabour O, et al. The associations of polymorphisms of TSH receptor and thyroid hormone receptor genes with L-thyroxine treatment in hypothyroid patients[J]. Hormones (Athens), 2014, 13(3):389-397.