1. bookVolume 27 (2019): Issue 2 (April 2019)
Journal Details
License
Format
Journal
eISSN
2284-5623
First Published
08 Aug 2013
Publication timeframe
4 times per year
Languages
English
access type Open Access

Prevalence of a Iodothyronine Deiodinase 2 gene single nucleotide polymorphism in children with congenital hypothyroidism from Western Romania and impact on TSH levels

Published Online: 02 May 2019
Page range: 169 - 178
Received: 06 Nov 2018
Accepted: 07 Jan 2019
Journal Details
License
Format
Journal
eISSN
2284-5623
First Published
08 Aug 2013
Publication timeframe
4 times per year
Languages
English
Abstract

The aim of this study was to evaluate the prevalence of the Iodothyronine Deiodinase 2 gene Thr92Ala polymorphism in children from West of Romania with congenital hypothyroidism (CH) and association with TSH levels in response to levothyroxine monotherapy.

Genotyping in 50 children with CH and 52 healthy controls was done using real time PCR.

The results showed that there was no statistical difference between the frequencies of genotypes in patients vs. controls. Patients were treated with L-thyroxine and most had normal values for fT3 and fT4. However, high TSH values were found in 21 patients (42%) after treatment. Among patients with high TSH values, AA genotypes were significantly more prevalent (p = 0.044) than TT and AT genotypes. Our results suggest that for the D2 gene Ala92Thr polymorphism, the AA genotype may be detrimental for achieving euthyroidism in patients with CH and levothyroxine monotherapy, therefore polytherapy could be considered as a better approach in these patients.

Keywords

1. Büyükgebiz A. Newborn screening for congenital hypothyroidism. J Clin Res Pediatr Endocrinol. 2013;5 Suppl 1:8-12Search in Google Scholar

2. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010;5:17. DOI: 10.1186/1750-1172-5-1710.1186/1750-1172-5-17290352420537182Open DOISearch in Google Scholar

3. Gaudino R, Garel C, Czernichow P, Léger J. Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clin Endocrinol (Oxf). 2005;62(4):444-8. DOI: 10.1111/j.1365-2265.2005.02239.x10.1111/j.1365-2265.2005.02239.x15807875Search in Google Scholar

4. Anastasovska V, Koviloska R, Kocova M. High incidence of congenital hypothyroidism in one region of the Republic of Macedonia. Balkan J Med Genet. 2014;17(1):31-6. DOI: 10.2478/bjmg-2014-002410.2478/bjmg-2014-0024434747425741212Open DOISearch in Google Scholar

5. Kara C, Günindi F, Can Yılmaz G, Aydın M. Transient congenital hypothyroidism in Turkey: an analysis on frequency and natural course. J Clin Res Pediatr Endocrinol. 2016;8(2):170-9. DOI: 10.4274/jcrpe.234510.4274/jcrpe.2345509647227086592Open DOISearch in Google Scholar

6. Grasberger H, Refetoff S. Genetic causes of congenital hypothyroidism due to dyshormonogenesis. Curr Opin Pediatr. 2011;23(4):421-8. DOI: 10.1097/MOP.0b013e32834726a410.1097/MOP.0b013e32834726a4326331921543982Search in Google Scholar

7. Senese R, Cioffi F, de Lange P, Goglia F, Lanni A. Thyroid: biological actions of ‘nonclassical’ thyroid hormones. J Endocrinol. 2014;221(2):R1-12. DOI: 10.1530/JOE-13-057310.1530/JOE-13-057324464019Open DOISearch in Google Scholar

8. Gnidehou S, Caillou B, Talbot M, Ohayon R, Kaniewski J, Noël-Hudson MS, et al. Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site. FASEB J. 2004;18(13):1574-6. DOI: 10.1096/fj.04-2023fje10.1096/fj.04-2023fje15289438Search in Google Scholar

9. Maia AL, Goemann IM, Meyer EL, Wajner SM. Deiodinases: the balance of thyroid hormone: type 1 iodothyronine deiodinase in human physiology and disease. J Endocrinol. 2011;209(3):283-97. DOI: 10.1530/JOE-10-048110.1530/JOE-10-048121415143Open DOISearch in Google Scholar

10. Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 2006;116(10):2571-9. DOI: 10.1172/JCI2981210.1172/JCI29812157859917016550Search in Google Scholar

11. Dentice M, Salvatore D. Deiodinases: the balance of thyroid hormone: local impact of thyroid hormone inactivation. J Endocrinol. 2011;209(3):273-82. DOI: 10.1530/JOE-11-000210.1530/JOE-11-000221398344Open DOISearch in Google Scholar

12. Arrojo E Drigo R, Bianco AC. Type 2 deiodinase at the crossroads of thyroid hormone action. Int J Biochem Cell Biol. 2011;43(10):1432-4. DOI: 10.1016/j.biocel.2011.05.01610.1016/j.biocel.2011.05.016316377921679772Search in Google Scholar

13. Arrojo E Drigo R, Fonseca TL, Werneck-de-Castro JP, Bianco AC. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signalling. Biochim Biophys Acta. 2013;1830(7):3956-64. DOI: 10.1016/j.bbagen.2012.08.01910.1016/j.bbagen.2012.08.019497922622967761Open DOISearch in Google Scholar

14. Dentice M, Marsili A, Zavacki A, Larsen PR, Salvatore D. The deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation. Biochim Biophys Acta. 2013;1830(7):3937-45. DOI: 10.1016/j.bbagen.2012.05.00710.1016/j.bbagen.2012.05.007367067222634734Open DOISearch in Google Scholar

15. Alina B, Daria P, Olga F, Vladislav S, Anna K, Elena G. Thr92Ala polymorphism of human type 2 deiodinase gene (hD2) affects the development of Graves’ disease, treatment efficiency, and rate of remission. Clin Dev Immunol. 2012;2012:340542. DOI: 10.1155/2012/34054210.1155/2012/340542350284023193417Open DOISearch in Google Scholar

16. Verloop H, Dekkers OM, Peeters RP1, Schoones JW, Smit JW. Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans, Eur J Endocrinol. 2014;171(3):R123-35. DOI: 10.1530/EJE-14-030210.1530/EJE-14-030224878678Open DOISearch in Google Scholar

17. McAninch EA, Jo S, Preite NZ, Farkas E, Mohácsik P, Fekete C, et al. Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. J Clin Endocrinol Metab. 2015;100(3):920-33. DOI: 10.1210/jc.2014-409210.1210/jc.2014-4092433304825569702Open DOISearch in Google Scholar

18. Dilli D, Çzbaş S, Acıcan D, Yamak N, Ertek M, Dilmen U. Establishment and development of a national newborn screening programme for congenital hypothyroidism in Turkey. J Clin Res Pediatr Endocrinol. 2013;5(2):73-9. DOI: 10.4274/Jcrpe.92910.4274/Jcrpe.929370192523748057Open DOISearch in Google Scholar

19. Carlé A, Faber J, Steffensen R, Laurberg P, Nygaard B. Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment Data Using a Blind, Randomized, Clinical Study. Eur Thyroid J. 2017;6(3):143-151. DOI: 10.1159/00046970910.1159/000469709552722428785541Search in Google Scholar

20. Oto Y, Muroya K, Hanakawa J, Asakura Y, Adachi M. The ratio of serum free triiodothyronine to free thyroxine in children: a retrospective database survey of healthy short individuals and patients with severe thyroid hypoplasia or central hypothyroidism. Thyroid Res. 2015;8:10. DOI: 10.1186/s13044-015-0023-510.1186/s13044-015-0023-5449564426157488Open DOISearch in Google Scholar

21. Butler PW, Smith SM, Linderman JD, Brychta RJ, Alberobello AT, Dubaz OM, et al. The Thr92Ala 5’ type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomic study. Thyroid. 2010;20(12):1407-12. DOI: 10.1089/thy.2010.024410.1089/thy.2010.0244299028021054208Open DOISearch in Google Scholar

22. Wartofsky L. Combination L-T3 and L-T4 therapy for hypothyroidism., Curr Opin Endocrinol Diabetes Obes. 2013;20(5):460-6. DOI: 10.1097/01.med.0000432611.03732.4910.1097/01.med.0000432611.03732.4923974776Open DOISearch in Google Scholar

23. Simionescu R, Cherecheanu A, Voinea L, Sfrenț-Cornățeanu R. TNF-α Gene Polymorphisms and Primary Open Angle Glaucoma in Romanian Population. Rev Romana Med Lab. 2015; 23(1): 47-58. DOI: 10.1515/rrlm-2015-000410.1515/rrlm-2015-0004Open DOISearch in Google Scholar

24. Anghel A, Enache A, Seclaman E, Gruin G, Ursoniu S, Alexa A, et al. Genetic polymorphism data on 15 autosomal STR markers in a Western Romanian population sample. Leg Med (Tokyo). 2014;16(4):238-40. DOI: 10.1016/j.legalmed.2014.04.00110.1016/j.legalmed.2014.04.00124767967Open DOISearch in Google Scholar

25. Appelhof BC, Peeters RP, Wiersinga WM, Visser TJ, Wekking EM, Huyser J, et al. Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3’-triiodothyronine therapy. J Clin Endocrinol Metab. 2005;90(11):6296-9. DOI: 10.1210/jc.2005-045110.1210/jc.2005-045116144953Open DOISearch in Google Scholar

26. Peeters RP, van Toor H, Klootwijk W, de Rijke YB, Kuiper GG, Uitterlinden AG, et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab. 2003;88(6):2880-8. DOI: 10.1210/jc.2002-02159210.1210/jc.2002-02159212788902Search in Google Scholar

27. Torlontano M, Durante C, Torrente I, Crocetti U, Augello G, Ronga G, et al. Type 2 deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin levels in thyroidectomized patients. J Clin Endocrinol Metab. 2008;93(3):910-3. DOI: 10.1210/jc.2007-106710.1210/jc.2007-106718073314Open DOISearch in Google Scholar

28. Peeters RP, van den Beld AW, Attalki H, Toor Hv, de Rijke YB, Kuiper GG, et al. A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. Am J Physiol Endocrinol Metab. 2005;289:E75–E81 DOI: 10.1152/ajpendo.00571.200410.1152/ajpendo.00571.200415727947Open DOISearch in Google Scholar

29. Bernal J. Thyroid Hormones in Brain Development and Function. De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext (Internet). South Dartmouth (MA): MDText.com, Inc.; 2000. https://www.ncbi.nlm.nih.gov/books/NBK285549/ (Updated 2015 Sep 2).Search in Google Scholar

30. Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, et al. Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab. 2009;94(5):1623-9. DOI: 10.1210/jc.2008-130110.1210/jc.2008-130119190113Open DOISearch in Google Scholar

31. McDermott MT. Does combination T4 and T3 therapy make sense?, Endocr Pract. 2012;18(5):750-7. DOI: 10.4158/EP12076.RA10.4158/EP12076.RA22548953Open DOISearch in Google Scholar

32. Korkmaz L, Akın MA, Güneş T, Daar G, Baştuğ O, Yıkılmaz A, et al. Unusual course of congenital hypothyroidism and route of the L-thyroxine treatment in a preterm newborn. J Clin Res Pediatr Endocrinol. 2014;6(3):177-9. DOI: 10.4274/jcrpe.138310.4274/jcrpe.1383429364825241613Open DOISearch in Google Scholar

33. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism, Eur Thyroid J. 2012;1(2):55-71. DOI: 10.1159/00033944410.1159/000339444382146724782999Open DOISearch in Google Scholar

34. Fisher DA, Schoen EJ, La Franchi S, Mandel SH, Nelson JC, Carlton EI, et al. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab. 2000;85(8):2722-7. DOI: 10.1210/jcem.85.8.671810.1210/jcem.85.8.671810946871Search in Google Scholar

35. Kempers MJ, van Trotsenburg AS, van Tijn DA, Bakker E, Wiedijk BM, Endert E, et al. Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism. J Clin Endocrinol Metab. 2005;90(7):4094100. DOI: 10.1210/jc.2005-019710.1210/jc.2005-019715827096Open DOISearch in Google Scholar

36. van Mullem AA, Visser TJ, Peeters RP. Clinical Consequences of Mutations in Thyroid Hormone Receptor-α1. Eur Thyroid J. 2014; 3(1): 17–24. DOI: 10.1159/00036063710.1159/000360637400526424847461Open DOISearch in Google Scholar

37. Wiersinga WM. Therapy of endocrine disease: T4+T3 combination therapy: is there a true effect?. Eur J Endocrinol. 2017;177(6):R287-R296. DOI: 10.1530/EJE-17-064510.1530/EJE-17-064528855267Open DOISearch in Google Scholar

38. Biondi B, Wartofsky L. Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism?. J Clin Endocrinol Metab. 2012;97(7):2256-71. DOI: 10.1210/jc.2011-339910.1210/jc.2011-339922593590Open DOISearch in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo