Işılay ÖZ, Mehmet Ali BABADEMEZ, Sibel ÖZDAŞ, Sami Engin MUZ, Kenan KURT, M. Huntürk ATİLLA, Talih ÖZDAŞ, Sibel BAŞTİMUR, Afife İZBIRAK

Significant association between SCGB1D4 gene polymorphisms and susceptibility to adenoid hypertrophy in a pediatric population

Background/aim: Adenoid hypertrophy (AH) is chronic enlargement of the adenoid tissue. The pathophysiology of the disease is unclear. We analyzed SCGB1D4 gene polymorphisms in order to determine the effect of the variants or their genetic combinations on AH. Materials and methods: We genotyped the SCGB1D4 (IIS) gene in 167 participants (95 children with AH and 72 controls) by performing DNA sequencing in blood samples. Results: We genotyped three single nucleotide polymorphisms (SNPs). In the analysis, we found that in the presence of those SNPs and the minor alleles of individual SNPs four haplotypes were associated with an increased risk of AH. In addition, those SNPs were significantly associated with asthma, allergy, sleep-disordered breathing, AH grade +4, and a high level of IgE. As indicated on multifactor dimensionality reduction analysis, single-locus (rs35328961), two-locus (rs35328961_rs56196602), and three-locus models (rs200327820_rs35328961_rs56196602) had the highest synergistic interaction effect on AH. The three-factor model was also significantly associated with some genotypes of rs35328961 and allergic asthmatic AH. Conclusion: SNPs of SCGB1D4 and their combinations are associated with an increased risk for developing AH. We highlighted the importance of genetic factors on AH and AH-related clinical phenotypes.

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1. Wysocka J, Hassmann E, Lipska A, Musiatowicz M. Naïve and memory T cells in hypertrophied adenoids in children according to age. Int J Pediatr Otorhinolaryngol 2003; 67: 237-241.
2. Kenna MA. Tonsils and Adenoids. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson Textbook of Pediatrics, 16th ed. Philadelphia, PA, USA: WB Saunders; 2000.
3. Desager KN, Nelen V, Weyler JJ, De Backer WA. Sleep disturbance and daytime symptoms in wheezing school-aged children. J Sleep Res 2005; 14: 77-82.
4. Izu SC, Itamoto CH, Pradella-Hallinan M, Pizarro GU, Tufik S, Pignatari S, Fujita RR. Obstructive sleep apnea syndrome (OSAS) in mouth breathing children. Braz J Otorhinolaryngol 2010; 76: 552-556.
5. Modrzynski M, Zawisza E. An analysis of the incidence of adenoid hypertrophy in allergic children. Int J Pediatr Otorhinolaryngol 2007; 71: 713-719.
6. Diehl S, Rincón M. The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol 2002; 39: 531-536.
7. Harber M, Sundstedt A, Wraith D. The role of cytokines in immunological tolerance: potential for therapy. Exp Rev Mol Med 2000; 27: 1-20.
8. Borish LC, Steinke JW. Cytokines and chemokines. J Allergy Clin Immunol 2003; 111: 460-475.
9. 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.
10. Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 2008; 40: 695-701.
11. Jackson BC, Thompson DC, Wright MW, McAndrews M, Bernard A, Nebert DW, Vasiliou V. Update of the human secretoglobin (SCGB) gene superfamily and an example of evolutionary bloom of androgen-binding protein genes within the mouse Scgb gene superfamily. Hum Genomics 2011; 5: 691-702.
12. Mukherjee AB, Kundu GC, Mantile-Selvaggi G, Yuan CJ, Mandal AK, Chattopadhyay S, Zheng F, Pattabiraman N, Zhang Z. Uteroglobin: a novel cytokine?. Cell Mol Life Sci 1999; 55: 771-787.
13. Pala M, Özcan KM, Özdaş S, Köseoğlu S, Özdaş T, Erbek SS, Yıldırım E, Ensari S, Dere H. Investigation of SCGB3A1 (UGRP2) gene arrays in patients with nasal polyposis. Eur Arch Oto-rhino-l 2014; 27: 3209-3214.
14. Choi MS, Ray R, Zhang Z, Mukherjee AB. INF-gamma stimulates the expression of a novel secretoglobin that regulates chemotactic cell migration and invasion. J Immunol 2004; 172: 4245-4252.
15. Chien CY, Chen AM, Hwang CF, Su CY. The clinical significance of adenoid-choanae area ratio in children with adenoid hypertrophy. Int J Pediatr Otorhinolaryngol 2005; 69: 235-239.
16. Parikh SR, Coronel M, Lee JJ, Brown SM. Validation of a new grading system for endoscopic examination of adenoid hypertrophy. Otolaryngol Head Neck Surg 2006; 135: 684-687.
17. Gozal D, Kheirandish-Gozal L. Neurocognitive and behavioral morbidity in children with sleep disorders. Curr Opin Pulm Med 2007; 13: 505-509.
18. Busse WW. Asthma diagnosis and treatment: filling in the information gaps. J Allergy Clin Immunol 2011; 28: 740-750.
19. Position paper: allergen standardization and skin tests, The European Academy of Allergology and Clinical Immunology Allergy 1993; 48: 48-82.
20. Wittig HJ, Belloit J, De Fillippi I, Royal G. Age-related serum immunoglobulin E levels in healthy subjects and in patients with allergic disease. J Allergy Clin Immunol 1980; 66: 305- 313.
21. Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JPA. Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 2006; 163: 300-309.
22. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 2006; 22: 1928-1929.
23. Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction for detecting gene-gene interactions. Bioinformatics 2002; 19: 376-382.
24. Moore JH, White BC. Exploiting expert knowledge in genetic programming for genome-wide genetic analysis. Lect Notes Comp Sci 2006; 4193: 969-977.
25. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001; 69: 138-147.
26. Ritchie MD, Hahn LW, Moore JH. Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 2003; 24: 150-157.
27. The 1000 Genome Consortium, A map of human genome variation from population-scale sequencing. Nature 2010; 467: 1061-1073.
28. Moore JH. A global view of epistasis. Nat Genet 2005; 37: 13- 14.
29. Capon F, Allen MH, Ameen M, Burden AD, Tillman D, Barker JN, Trembath RC. A synonymous SNP of the gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet 2004; 13: 2361-2368.
30. Jarjanazi H, Savas S, Pabalan N, Dennis JW, Ozcelik H. Biological implications of SNPs in signal peptide domains of human proteins. Proteins 2008; 1: 394-403.
31. Choi JW, Park CS, Hwang M, Nam HY, Chang HS, Park SG, Han BG, Kimm K, Kim HL, Oh B et al. A common intronic variant of CXCR3 is functionally associated with gene expression levels and the polymorphic immune cell responses to stimuli. J Allergy Clin Immunol 2008; 122: 1119-1126.
32. Krawczak M, Reiss J, Cooper DN. The mutational spectrum of single base-pair substitutions in messenger RNA splice junctions of human genes-causes and consequences. Hum Genet 1992; 90: 41-54.
33. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nature Rev Genetics 2005; 6: 95-108.
34. Ersu R, Arman AR, Save D, Karadag B, Karakoc F, Berkem M, Dagli E. Prevalence of snoring and symptoms of sleep disordered breathing in primary school children in Istanbul. Chest 2004; 126: 19-24.
35. Kheirandish-Gozal L, Gozal D. Obesity, asthma, and sleepdisordered breathing. J Pediatr 2012; 160: 713-714.
36. Marcus CL, McColley SA, Carroll JL, Loughlin GM, Smith PL, Schwartz AR. Upper airway collapsibility in children with obstructive sleep apnea syndrome. J Appl Physiol 1994; 77: 918-924.
37. Kim J, Bhattacharjee R, Dayyat E, Snow AB, KheirandishGozal L, Goldman JL, Li RC, Serpero LD, Clair HB, Gozal D. Increased cellular proliferation and inflammatory cytokines in tonsils derived from children with obstructive sleep apnea. Pediatr Res 2009; 66: 423-428.
38. Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nature Reviews Genetics 2010; 11: 499- 511.
39. Grasso DL, Guerci VI, Zocconi E, Milanese M, Segat L, Crovella S. MBL2 genetic polymorphisms in Italian children with adenotonsillar hypertrophy. Int J Pediatr Otorhinolaryngol 2007; 71: 1013-1016.