Original Article

Tumor Necrosis Factor-α (-308G>A) Gene Polymorphism and Its Association with Asthma and Atopy Status


Asthma is one of the most prevalent chronic lung diseases that afflict genetically predisposed individuals. Certain cytokine gene polymorphisms have been associated with asthma. Tumor necrosis factor-alpha (TNF-α) is a potent inflammatory cytokine that can modulate nonspecific inflammation to influence asthma. This study aimed to define the relationship between the TNF gene polymorphism at position -308 and asthma susceptibility, as well as atopic and non-atopic asthma.
Using polymerase chain reaction with sequence-specific primers, we investigated genotype frequencies and alleles of a polymorphic gene coding for TNF-α in 86 pediatric patients with asthma and 470 healthy controls of the same race. Seventy-four patients underwent a skin prick test.
The homozygous AA variant (-308, rs1800629) was the most common genotype among patients, accounting for 63.3% of all cases. In contrast, homozygous GG (-308) was significantly less prevalent in the patient group compared to the control group. TNF A (-308) allele frequency was 85.5% among asthma patients and 16.6% among healthy controls. The genotype and allele frequencies of TNF (-308 A>G, rs1800629) did not differ between atopic and non-atopic asthma.
In conclusion, TNF (-308) AA and AG genotypes are associated with asthma susceptibility in Iranian children, although there was no significant difference in polymorphism between atopic and non-atopic asthma and no difference in asthma severity groups.

1. Rot A, Von Andrian UH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol. 2004;22:891-928.
2. March ME, Sleiman PM, Hakonarson H. Genetic polymorphisms and associated susceptibility to asthma. Int J Gen Med. 2013:253-65.
3. McLeish S, Turner S. Gene–environment interactions in asthma. Archives of disease in childhood. 2007;92(11):1032-5.
4. Turner S. Gene–environment interactions—what can these tell us about the relationship between asthma and allergy? Front Pediatr. 2017;5:118.
5. Sandford A, Weir T, Paré P. The genetics of asthma. Am J Respir Crit Care Med. 1996;153(6):1749-65.
6. Chang J-C, Wang L, Chen R-F, Liu C-A. Perinatal gene-gene and gene-environment interactions on IgE production and asthma development. Clin Dev Immunol. 2012;2012.
7. Britt Jr RD, Thompson MA, Sasse S, Pabelick CM, Gerber AN, Prakash Y. Th1 cytokines TNF-α and IFN-γ promote corticosteroid resistance in developing human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2019;316(1):L71-L81.

8. Busse PJ, Zhang TF, Schofield B, Kilaru S, Patil S, Li X-M. Decrease in airway mucous gene expression caused by treatment with anti-tumor necrosis factor α in a murine model of allergic asthma. Ann Allergy Asthma Immunol. 2009;103(4):295-303.
9. Nabe T. Tumor necrosis factor alpha-mediated asthma? Int Arch Allergy Immunol. 2013;160(2):111-3.
10. Matera MG, Calzetta L, Cazzola M. TNF-α inhibitors in asthma and COPD: we must not throw the baby out with the bath water. Pulm Pharmacol Ther. 2010;23(2):121-8.
11. Berry M, Brightling C, Pavord I, Wardlaw AJ. TNF-α in asthma. Curr Opinion Pharmacol. 2007;7(3):279-82.
12. Shin HD, Park BL, Kim LH, Jung JH, Wang HJ, Kim YJ, et al. Association of tumor necrosis factor polymorphisms with asthma and serum total IgE. Hum Mol Genetics. 2004;13(4):397-403.
13. Pillai P, Corrigan CJ, Ying S. Airway epithelium in atopic and nonatopic asthma: similarities and differences. Int Scholarly Res Notices. 2011;2011.
14. Pekkanen J, Lampi J, Genuneit J, Hartikainen A-L, Järvelin M-R. Analyzing atopic and non-atopic asthma. Europ J Epidemiol. 2012;27(4):281-6.
15. Pekkanen J, Pearce N. Defining asthma in epidemiological studies. Europ Respiratory Journal. 1999;14(4):951-7.
16. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax. 2008;63(11):974-80.
17. Court C, Cook D, Strachan D. The descriptive epidemiology of house dust mite‐specific and total immunoglobin E in England using a nationally representative sample. Clin Exp Allergy. 2002;32(7):1033-41.
18. Castro-Rodriguez JA, Ramirez AM, Toche P, Pavon D, Perez MA, Girardi G, et al. Clinical, functional, and epidemiological differences between atopic and nonatopic asthmatic children from a tertiary care hospital in a developing country. Ann Allergy Asthma Immunol. 2007;98(3):239-44.
19. Darweesh MF, Kadhem EJ, editors. The Impact of Genetic variation at TNF-α-308 G>A on their serum production and severity of Asthma disease. Journal of Physics: Conference Series; 2019: IOP Publishing.
20. Mahdaviani SA, Rezaei N, Moradi B, Dorkhosh S, Amirzargar AA, Movahedi M. Proinflammatory cytokine gene polymorphisms among Iranian patients with asthma. J Clin Immunol. 2009;29(1):57-62.
21. Gao J, Shan G, Sun B, Thompson PJ, Gao X. Association between polymorphism of tumour necrosis factor α-308 gene promoter and asthma: a meta-analysis. Thorax. 2006;61(6):466-71.
22. Zhang Y, Zhang J, Tian C, Xiao Y, He C, Li X, et al. The− 308 G>A polymorphism in TNF-α gene is associated with asthma risk: an update by meta-analysis. J Clin Immunol. 2011;31(2):174-85.
23. Daneshmandi S, Pourfathollah AA, Pourpak Z, Heidarnazhad H, Kalvanagh PA. Cytokine gene polymorphism and asthma susceptibility, progress and control level. Mol Biol Reports. 2012;39(2):1845-53.
24. Qidwai T, Khan F. Tumour necrosis factor gene polymorphism and disease prevalence. Scand J Immunol. 2011;74(6):522-47.
25. Bilolikar H, Nam A, Rosenthal M, Davies J, Henderson D, Balfour-Lynn I. Tumour necrosis factor gene polymorphisms and childhood wheezing. Eur Respir J. 2005;26(4):637-46.
26. Kang SW, Kim SK, Han YR, Hong D, Chon J, Chung J-H, et al. Promoter polymorphism (− 308G>A) of tumor necrosis factor-alpha (TNF-α) gene and asthma risk: an updated meta-analysis. Genet Test Mol Biomarkers. 2019;23(6):363-72.
27. Despotovic M, Stoimenov TJ, Stankovic I, Pavlovic D, Sokolovic D, Cvetkovic T, et al. Gene polymorphisms of tumor necrosis factor alpha and antioxidant enzymes in bronchial asthma. Advances in Clinical and Experimental Medicine. 2015;24(2):251-6.
28. JimÊnez-Morales S, VelÂzquez-Cruz R, RamÎrez-Bello J, Bonilla-GonzÂlez E, Romero-Hidalgo S, Escamilla-Guerrero G, et al. Tumor necrosis factor–α is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population. Hum Immunol. 2009;70(4):251-6.
29. Becker AB, Abrams EM. Asthma guidelines: the Global Initiative for Asthma in relation to national guidelines. Current opinion in allergy and clinical immunology. 2017;17(2):99-103.
30. Tsuo K, Zhou W, Wang Y, Kanai M, Namba S, Gupta R, et al. Multi-ancestry meta-analysis of asthma identifies novel associations and highlights the value of increased power and diversity. Cell Genomics. 2022;2(12).
31. Amal S, Shalaby SM, Abdel-Nour HM, Sarhan WM, Gehad MH, Yousif YM. Impact of cytokines genes polymorphisms and their serum levels on childhood asthma in Egyptian population. Cytokine. 2022;157:155933.
32. Eyerich S, Metz M, Bossios A, Eyerich K. New biological treatments for asthma and skin allergies. Allergy. 2020;75(3):546-60.
33. De Volder J, Vereecke L, Joos G, Maes T. Targeting neutrophils in asthma: a therapeutic opportunity? Biochem Pharmacol. 2020;182:114292.
34. Alyasin S, Kanannejad Z, Esmaeilzadeh H, Nabavizadeh H, Amin R. Cytokine levels and polymorphisms in childhood asthma among the iranian population. J Ped Rev. 2021;9(1):19-26.
35. Hong S-J, Kim H-B, Kang M-J, Lee S-Y, Kim J-H, Kim B-S, et al. TNF-α (− 308 G>A) and CD14 (− 159T/C) polymorphisms in the bronchial responsiveness of Korean children with asthma. J Allergy Clin Immunol. 2007;119(2):398-404.
36. Kamali-Sarvestani E, Kiany S, Gharesi-Fard B, Robati M. Association study of IL-10 and IFN-γ gene polymorphisms in Iranian women with preeclampsia. J Reprod Immunol. 2006;72(1-2):118-26.
37. Babic Z, Pipinic IS, Varnai VM, Kezic S, Macan J. Associations of TNF [alpha]-308G> A, TNF [alpha]-238G> A, IL-1 [alpha]-889C> T and IL-10-1082G> A Genetic Polymorphisms with Atopic Diseases: Asthma, Rhinitis and Dermatitis. International Archives of Allergy and Immunology. 2016;169(4):231-41.
38. Saba N, Yusuf O, Rehman S, Munir S, Bashir N, Mansoor A, et al. Association of tumor necrosis factor alpha 308 G>A polymorphism with asthma in Pakistani population. Iran J Allergy Asthma Immunol. 2015:287-91.
39. Despotovic M, Stoimenov TJ, Stankovic I, Pavlovic D, Sokolovic D, Cvetkovic T, et al. Gene polymorphisms of tumor necrosis factor alpha and antioxidant enzymes in bronchial asthma. Adv Clin Exp Med. 2015;24(2):251-6.
40. Yang Y-H, Liu Y-Q, Zhang L, Li H, Li X-B, Ouyang Q, et al. Genetic polymorphisms of the TNF-α-308G>A are associated with metabolic syndrome in asthmatic patients from Hebei province, China. Int J Clin Exp Pathol. 2015;8(10):13739.
41. Zedan M, Settin A, Farag MK, El-Bayoumi M, El Regal ME, El Baz R, et al. Gene polymorphisms of tumor necrosis factor alpha-308 and interleukin-10-1082 among asthmatic Egyptian children. Allergy Asthma proc. 2008;29(3):268-73.
IssueVol 22 No 4 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v22i4.13606
Asthma Atopy Gene polymorphism PCR-SSP Single nucleotide polymorphism Tumor necrosis factor-alpha

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Razaghian A, Parvaneh N, Amirzargar AA, Gharagozlou M. Tumor Necrosis Factor-α (-308G>A) Gene Polymorphism and Its Association with Asthma and Atopy Status. Iran J Allergy Asthma Immunol. 2023;22(4):337-344.