Sami Engin MUZ, Sibel ÖZDAŞ, Talih ÖZDAŞ, Mahmut Huntürk ATİLLA, Sibel BAŞTİMUR, Işılay ÖZ, İpek CANATAR

Protective Effect of 5-HTTLPR (S) and VNTR (10) Allele Combinationsof 5-HTT Gene Against Adenotonsillary Hypertrophy

INTRODUCTION: Serotonin transporter protein which is coded by 5HTT gene is responsible for presynaptic reuptake of serotonin. In this study, we investigated the relationship between polymorphisms in the promoter region (5-HTTLPR) and in the second intron (VNTR) in the 5-HTTgene and adenotonsillar hypertrophy (ATH) in pediatric cases. METHODS: Genotyped of the 5-HTT gene promotor 5-HTTLPR and intronic VNTR of in 197 children were analyzed using Snap Shot, Multifactor Dimensionality Reduction (MDR) software and carried out to assess the interactions among two polymorphisms and phenotype. RESULTS: A total of 119 children with ATH (48 girls, 71 boys age range: 3-10 years; mean age: 5.38 years) and 78 healthy children (27 girls, 51 boys, age range: 4-13 years; mean age: 6.76 years) were included in this study. The frequencies of the genotype in all of inheritance models of the 5-HTTLPR and the VNTR (10) allele showed no significant differences between ATH patient and healthy controls (for all P> 0.05). However, frequency of the 5-HTTLPR (S) allele and VNTR_5-HTTLPR (10/S) haplotype and (10/10+S/S) diplotype were significantly higher in the control group compared to ATH cases (P= 0.048, P= 0.041, P= 0.13). DISCUSSION AND CONCLUSION: In this study, we observed that S/S genotype, 10/S haplotype and 10/10 + S/S diplotype of 5-HTT gene could have protective effect against ATH.

5-HTT Geninin 5-HTTLPR (S) ve VNTR (10) Alel Kombinasyonlarının Adenotonsiller Hipertrofiye Karşı Koruyucu Etkisi

GİRİŞ ve AMAÇ: 5HTT geni tarafından kodlanan serotonin taşıyıcı protein, serotoninin presinaptik geri alımından sorumludur. Bu çalışmada pediatrik olgularda 5-HTT genindeki promotör (5-HTTLPR) ve ikinci intron (VNTR) bölgedeki polimorfizmler ile adenotonsiller hipertrofi (ATH) arasındaki ilişkiyi araştırdık. YÖNTEM ve GEREÇLER: 197 çocuğun 5-HTT gen promotor 5-HTTLPR ve intronic VNTR’si Snap Shot ile genotiplendirilerek, polimorfizmlerin birbiri ve fenotip arasındaki etkileşimler Çok Faktörlü Boyut Azaltma (Multifactor Dimensionality Reduction; MDR) programı ile analiz edildi. BULGULAR: Çalışmaya ATH tanısı almış 119 hasta (48 kız, 71 erkek yaş aralığı: 3-10 yıl; ortalama yaş: 5.38 yıl) ve 78 sağlıklı çocuk (27 kız, 51 erkek, yaş aralığı: 4-13 yıl; ortalama yaş: 6.76 yıl) dahil edildi. 5-HTTLPR (S) ve VNTR (10) allelinin tüm kalıtım modellerinde genotipik frekanslar açısından, ATH’li ile kontrol grubu arasında anlamlı bir fark gözlenmedi (tümü için P> 0.05). Bununla birlikte, 5-HTTLPR (S) allel ve VNTR_5-HTTLPR (10 / S) haplotip ve (10/10 + S / S) diplotipinin sıklığı ATH olgularına göre kontrol grubunda anlamlı olarak daha yüksekti (sırasıyla, P= 0.048, P = 0.041, P = 0.13). TARTIŞMA ve SONUÇ: 5-HTT geninin S / S genotipi, 10 / S haplotipi ve 10/10 + S / S diplotipinin ATH’ye karşı koruyucu etkisi olabilir.

PDF

___

1. Wysocka J, Hassmann E, Lipska A, Musiatowicz M. Naive and memory T cells in hypertrophied adenoids in children according to age. Int J Pediatr Otorhinolaryngol. 2003;67:237-241. https://doi.org/10.1016/S0165-5876(02)00374-9

2. Messner AH. Evaluation of obstructive sleep apnea by polysomnography prior to pediatric adenotonsillectomy. Arch Otolaryngol Head Neck Surg. 1999;125:353-6. https://doi.org/10.1001/archotol.125.3.353

3. Modrzynski M, Zawisza E. An analysis of the incidence of adenoid hypertrophy in allergic children. Int J Pediatr Otorhinolaryngol. 2007; 1:713-9. https://doi.org/10.1016/j.ijporl.2006.12.018

4. Brodsky L. Adenotonsillar disease in children. Pract Paediatr Otolaryngol. 1999;2:15-39.

5. Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I Affective Disorders Molecular Psychiatry. 2003;8:574-91. https://doi.org/10.1038/sj.mp.4001328

6. Shabaldina EV, Shabaldin AV,Riazantsev SV, Simbirtsev SV. The role of cytokine gene polymorphisms in the development of hypertrophy of the tonsils of the lymphoid pharyngeal ring and atopic march in the children.Vestn Otorinolaringol. 2013;6:18-23.

7. Ozdas S, Ozdas T, Acar M, Erbek SS, Koseoglu S, Gokturk G, Izbirak A. Association of Interleukin-10 gene promoter polymorphisms with obstructive sleep apnea. Sleep Breath. 2016;20:855-66. https://doi.org/10.1007/s11325-015-1216-9

8. Xu H, Guan J, Yi H, Yin S. A systematic review and metaanalysis of the association between serotonergic gene polymorphisms and obstructive sleep apnea syndrome. PloS ONE. 2014;9: e86460. https://doi.org/10.1371/journal.pone.0086460

9. Schroder CM, Primeau MM, Hallmayer JF, Lazzeroni LC, Hubbard JT, O’Hara R. Serotonin transporter polymorphism is associated with increased apnea-hypopnea index in older adults. International Journal of Geriatric Psychiatry. 2014;29:227-35. https://doi.org/10.1002/gps.3994

10. Lechin F, van der Dijs B, Orozco B, Lechin M, Lechin AE. Increased levels of free serotonin in plasma of symptomatic asthmatic patients. Ann Allergy Asthma Immunol. 1996;77:245-53. https://doi.org/10.1016/S1081-1206(10)63263-2

11. Veasey SC. Serotonin agonists and antagonists in obstructive sleep apnea: therapeutic potential. Am J Respir Med. 2003;2:21-9. https://doi.org/10.1007/BF03256636

12. Baugh RF, Archer SM, Mitchell RB, Rosenfeld RM, Amin R, Burns JJ, Darrow DH, Giordano T, Litman RS, Li KK et al. Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg. 2011;144:1e30. https://doi.org/10.1177/0194599810389949

13. AmeliF,BrocchettiF,SeminoL,FibbiA.Adenotonsillectomy in obstructive sleepapnea syndrome, Proposal of a surgical decision taking algorithm. Int J Pediatr Otorhinolaryngol. 2007;71:729-34. https://doi.org/10.1016/j.ijporl.2007.01.007

14. Busse WW. Asthma diagnosis and treatment: filling in the information gaps. J Allergy Clin Immunol. 2011;28:740-50. https://doi.org/10.1016/j.jaci.2011.08.014

15. SoleX,GuinoE,VallsJ,IniestaR,MorenoV.SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22:1928-9. https://doi.org/10.1093/bioinformatics/btl268

16. Aydin S, Sanli A, Celebi O, Tasdemir O, Paksoy M, Eken M, Hardal U, Ayduran E. Prevalence of adenoid hypertrophy and nocturnal enuresisin primary school children in Istanbul, Turkey. Int J Pediatr Otorhinolaryngol. 2008;72:665-8. https://doi.org/10.1016/j.ijporl.2008.01.028

17. Pang H, Jung SH. Sample size considerations of predictionvalidation methods in high-dimensional data for survival outcomes. Genet Epidemiol. 2013;37:276-82. https://doi.org/10.1002/gepi.21721

18. Hranilović D, Bujas-Petković Z, Tomicić M, BordukaloNiksić T, Blazević S, Cicin-Sain L. Hyperserotonemia in autism: activity of 5HT-associated platelet proteins. J Neurol Transm (Vienna). 2009;116:493-501. https://doi.org/10.1007/s00702-009-0192-2

19. Kim TH, An SH, Cha JY, Shin EK, Lee JY, Yoon SH, Lee YM, Uh ST, Park SW, Park JS, et al. Association of 5- hydroxytryptamine (serotonin) receptor 4 (5-HTR4) gene polymorphisms with asthma. Respirology. 2011;16:630-8. https://doi.org/10.1111/j.1440-1843.2011.01963.x

20. Lau WK, Chan-Yeung MM, Yip BH, Cheung AH, Ip MS, Mak JC. COPD Study Group of the Hong Kong Thoracic Society. The role of circulating serotonin in the development of chronic obstructive pulmonary disease. PLoS ONE. 2012;7:e31617. https://doi.org/10.1371/journal.pone.0031617

21. Kang BN, Ha SG, Bahaie NS, Hosseinkhani MR, Ge XN, Blumenthal MN, Rao SP, Sriramarao P. Regulation of serotonin-induced trafficking and migration of eosinophils. PLoS ONE. 2013;8:e54840. https://doi.org/10.1371/journal.pone.0054840

22. Barnes KC. Evidence for common genetic elements in allergic disease. J Allergy Clin Immunol. 2000; 06:192-200. https://doi.org/10.1067/mai.2000.110150

23. Olusesi AD, Undie NB, Amodu JE. Allergy history as a predictor of early onset adenoids/adenotonsillarhypertrophy among Nigerian children. Int J Pediatr Otorhinolaryngol. 2013;77:1032-5. https://doi.org/10.1016/j.ijporl.2013.04.004

24. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316:1341-5. https://doi.org/10.1126/science.1142382

25. Moore JH.Aglobal view of epistasis. Nat Genet. 2005;37:13- 4. https://doi.org/10.1038/ng0105-13

26. Babademez MA, Ozdas T, Ozdas S. The common genetic variants of toll-like receptor and susceptibility to adenoid hypertrophy: a hospital-based cohort study. Turk J Med Sci. 2016;13:46-56. https://doi.org/10.3906/sag-1511-16

27. Jacobs N, Kenis G, Peeters F, Derom C, Vlietinck R, van Os J. Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. Arch Gen Psychiatry. 2006;63:989-96. https://doi.org/10.1001/archpsyc.63.9.989

28. Hu XZ, Lipsky RH, Zhu G, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet. 2008;78:815-26. https://doi.org/10.1086/503850

29. Shen Y, Li H, Gu N, Tan Z, Tang J, Fan J, Li X, Sun W, He L et al. Relationship between suicidal behavior of psychotic inpatients and serotonin transporter gene in Han Chinese. Neurosci Lett. 2004;372:94-8. https://doi.org/10.1016/j.neulet.2004.09.018

30. Narita N, Narita M, Takashima S, Nakayama M, Nagai T, Okado N. Serotonin transporter gene variation is a risk factor forsudden infant death syndrome in the Japanese population. Pediatrics. 2001;107:690-2. https://doi.org/10.1542/peds.107.4.690

31. Yilmaz M, Erdal ME, Herken H, Cataloluk O, Barlas O, Bayazit YA. Significance of serotonin transporter gene polymorphism in migraine. J Neurol Sci. 2001;186:27-30. https://doi.org/10.1016/S0022-510X(01)00491-9

32. Akar T, Sayin A, Bakkaloglu Z, Cabuk DK, Kucukyildirim S, Demirel B, Candansayar S, Ozsoy ED, Mergen H. Investigation of serotonin transporter gene promoter (5- HTTLPR) and intron 2 (variable number of tandem repeats) polymorphisms with suicidal behavior in a Turkish population. DNA Cell Biol. 2010;29:429-34. https://doi.org/10.1089/dna.2010.1031

33. Klauck SM, Pautska F, Benzer A. Serotonin transporter (5- HTT) gene variants associated with autism. Hum Mol Genet. 1997;6:2233-5. https://doi.org/10.1093/hmg/6.13.2233

34. Gelertner J, Kranzler H, Coccaro E. Serotonin transporter protein gene polimorphism and personlality measures in African American and Europen American Subjects. Am J Psychiatry. 1998;155:1332-8. https://doi.org/10.1176/ajp.155.10.1332

35. Fareed M, Afzal M. Single nucleotide polymorphism in genome-wide association of human population: A tool for broad spectrum service. Egypt J Med Hum Genet. 2013;14:123-3 https://doi.org/10.1016/j.ejmhg.2012.08.001