TNF-α Gene Polymorphisms and Primary Open Angle Glaucoma in Romanian Population / Polimorfisme ale genei TNF-α în populația română cu glaucom primar cu unghi deschis

Open access


Primary open-angle glaucoma (POAG) represents the most common form of a heterogeneous group of glaucomatous optic neuropathies which are a worldwide cause of irreversible blindness. Immune dysregulation and the genetic background are considered important risk factors. The influence on susceptibility to POAG of single nucleotide polymorphisms (SNPs) of tumor necrosis factor-α (TNF-α) was intensively studied, mostly on Asian population. We investigated the possible association of two TNF-α SNPs (-308G/A and -857C/T) with susceptibility to POAG and its clinical characteristics. A case-control association study of aforementioned TNF-α SNPs was performed on 197 POAG patients (divided into two subgroups: high-tension and normal-tension glaucoma - HTG/ NTG) versus 208 ethnically matched controls. This is the first study performed on Romanian population. No significant differences were found in terms of allelic frequencies, genotype distribution of the studied SNPs, or their haplotypes between POAG and healthy control groups. In the subgroup analysis, TT genotype of TNF-α -857T-allele was found to be associated with higher values of central corneal thickness (CCT) in NTG subgroup (p-value 0.032). In order to confirm the association between -857C/T SNP of TNF-α and CCT in NTG subgroup of POAG patients, additional studies on different populations should be performed.

1. Quigley HA, Broman A. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophtalmol. 2006 Mar;90(3):262-7. DOI: 10.1136/bjo.2005.081224

2. Allingham RR. Chronic Open-Angle Glaucoma and Normal Tension Glaucoma. Shields textbook of Glaucoma, 6th ed.; Lippincott Williams & Wilkins. 2011. Section II, chapter 11, pg 176.

3. American Academy of Ophthalmology Glaucoma Panel; Preferred Practice Pattern® Guidelines. Primary Open-Angle Glaucoma. San Francisco, CA: American Academy of Ophthalmology; 2010.

4. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC. Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey. Arch Ophthalmol. 1994 Jan;112(1):69-3. DOI: 10.1001/archopht. 1994.01090130079022

5. Shastry BS. Genetic susceptibility to normal tension glaucoma. Br J Med Med Res. 2013 Jan;3(2):372-82. DOI: 10.9734/BJMMR/2013/2655

6. Wolfs RC; Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Genetic risk of primary open angle glaucoma. Population based familial aggregation study. Arch Ophthalmol. 1998 Dec;116(12):1640-45. DOI: 10.1001/archopht.116.12.1640

7. Gemenetzi M, Yang Y, Lotery AJ. Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment. Eye. 2012 Mar;26(3):355-69. DOI: 10.1038/eye.2011.309

8. Wiggs JL. Genetic Etiologies of Glaucoma. Arch Ophthalmol. 2007 Jan;125(1):30-7. DOI: 10.1001/archopht. 125.1.30

9. Yuan L.; Neufeld AH. TNF-α: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia. 2000 Oct;32(1):42-50. DOI: 10.1002/1098-1136(200010)32:1<42::AIDGLIA40> 3.3.CO;2-V

10. Tezel G, Wax MB. Increased production of TNF-α by glia cell exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J Neurosci. 2000 Dec 1;20(23):8693-700.

11. Tezel G, Li LY, Patil RV, Wax MB. TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 2001 Jul;42(8):1787-1794.

12. Gupta N, Ang LC, Noel de TL, Bidaisee L, Yucel YH. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophtalmol. 2006 Jun;90(6):674-78. DOI: 10.1136/bjo.2005.086769

13. (accessed on 15 august 2014).

14. European Glaucoma Society. Terminology and Guidelines for Glaucoma, 4th ed.;, printed manuscript, 2014.

15. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006 Aug;22(15):1928-29. DOI: 10.1093/bioinformatics/btl268

16. Generalitat de Catalunya. Institut catala d’Oncologia. Accesed on 05 August 2014; Available from:

17. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet. 2007 Sep;81(3):559-75. DOI: 10.1086/519795\

18. Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T, She H. et al. Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci. 2006 Dec 6;26(49):12633-41. DOI: 10.1523/ JNEUROSCI.2801-06.2006

19. Tezel G, Chauhan BC, LeBlanc RP, Wax MB. Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest Ophthalmol Vis Sci. 2003 Jul;44(7):3025-33.

20. Tezel G, Yang X, Luo C, Peng Y, Sun SL, Sun D. Mechanisms of immune system activation in glaucoma: oxidative stress-stimulated antigen presentation by the retina and optic nerve head glia. Invest Ophthalmol Vis Sci. 2007 feb;48(2):705-14. DOI: 10.1167/iovs.06-0810

21. Xin X, Gao L, Wu T, Sun F. Roles of tumor necrosis factor alpha gene polymorphisms, tumor necrosis factor alpha level in aqueous humor, and the risks of open angle glaucoma: a meta-analysis. Mol Vis. 2013;19:526-35.

22. Abraham LJ, Kroeger KM. Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukon Biol. 1999;66(4):562-6.

23. Agarwal P, Oldenburg MC, Czarneski JE, Morse RM, Hameed MR, Cohen S, et al. Comparison study for identifying promoter allelic polymorphism in interleukin 10 and tumor necrosis factor alpha genes. Diagn Mol Pathol. 2000 Sep;9(3):158-64. DOI: 10.1097/00019606-200009000-00006

24. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation. Proc Natl Acad Sci. 1997 Apr 1;94(7):3195-9. DOI: 10.1073/pnas.94.7.3195

25. Allen RD. Polymorphism of the human TNF-alpha promoter random variation or functional diversity? Mol Immunol. 1999 Oct-Nov; 36(15-16), 1017-27. DOI: 10.1016/S0161-5890(99)00127-3

26. Mossbock G, Weger M, Moray M, Renner W, Haller- Schober EM, Mattes D, et al. TNF-a promoter polymorphisms and primary open-angle glaucoma. Eye. 2006 Sep; 20(9):1040-3. DOI: 10.1038/sj.eye.6702078

27. Bozkurt B, Mesci L, Irkec M, Ozdag BB, Sanal O, Arslan U, et al. Association of tumour necrosis factor-alpha -308 G/A polymorphism with primary open-angle glaucoma. Clin Exp Ophthalmol. 2012 May-Jun;40(4):156-62. DOI: 10.1111/j.1442-9071.2011.02595.x

28. Lin HC, Tsai FJ, Chen WC, Shi YR, Hsu Y, Tsai SW. Association of tumor necrosis factor alpha -308 gene polymorphism with primary open-angle glaucoma in Chinese. Eye. 2003 Jan;17(1):31-4. DOI: 10.1038/sj. eye.6700227

29. Fan BJ, Liu K, Wang DY, Tham CC, Tam PO, Lam DS, et al. Association of polymorphisms of tumor necrosis factor and tumor protein p53 with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2010 Aug;51(8):4110-6. DOI: 10.1167/iovs.09-4974

30. Funayama T, Ishikawa K, Ohtake Y, Tanino T, Kurosaka D, Kimura I, et al. Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4359-67. DOI: 10.1167/iovs.03-1403

31. Middleton D, Gonzalez-Galarza FF, Jones AR, Takeshita L. Allele*Frequencies in Worldwide Populations. The Royal Liverpool and Broadgreen University Hospitals, 2014;accesed on 20 August 2014; www.allelefrequencies. net.

32. Yu QQ, Yao Y. A detailed meta-analysis shows no association between TNF-alpha -308 G/A polymorphism and different forms of glaucoma. Ophthalmic Res. 2012; 47(1):47-51. DOI: 10.1159/000328631

33. Brandt JD, Beiser JA, Kass MA, Gordon MO. Central corneal thickness in the Ocular Hypertension Treatment Study Group (OHTS). Ophthalmology. 2001 Oct;108(10):1779-88. DOI: 10.1016/S0161-6420(01)00760-6

34. Gordon MO, Beiser JA, Brandt JD. The ocular treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002 Jun;120(6):714-20. DOI: 10.1001/archopht.120.6.714

35. Toh TY, Liew MSHM, Hewitt AW, MacKinnon JR, Poulsen JL, Spector TD, et al. High heritability of Central Corneal Thickness- The Twin Eye Studies. Invest Ophthalmol Vis Sci. 2005 Oct;46(10):3718-22. DOI: 10.1167/iovs.04-1497

36. Freeman EE, Roy-Gagnon MH, Descovich D, Masse H, Lesk MR. The heritability of Glaucoma-related traits corneal hysteresis, central corneal thickness, intraocular pressure and choroidal blood flow pulsatility. PloS One. 2013;8(1):e55573. DOI: 10.1371/journal. pone.0055573

37. Brandt JD, Beiser JA, Gordon MO, Lin SC, Alexander MY, Kass MA. Changes in central corneal thickness over time: The Ocular Hypertension Treatment Study. Ophthalmology. 2008 Sep;115(9):1550-6. DOI: 10.1016/j.ophtha.2008.02.001

38. Lesk MR, Hafez AS, Descovich D. Relationship between central corneal thickness and changes of optic nerve head topography and blood flow after intraocular pressure reduction in open-angle glaucoma and ocular hypertension. Arch Ophthalmol. 2006 Nov;124(11):1568-72. DOI: 10.1001/archopht. 124.11.1568

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2017: 0.400
5-year IMPACT FACTOR: 0.320

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2017: 0.144
Source Normalized Impact per Paper (SNIP) 2017: 0.195


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 149 149 55
PDF Downloads 105 105 66