Effect of TXNRD2 rs35934224, FOXC1 rs2745599 and rs984253 genetic polymorphisms combinations on the development of primary open-angle glaucoma and their degree of association with the disease

  • N. V. Malachkova National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • S. P. Veretelnyk National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • P. P. Slobodian National Pirogov Memorial Medical University, Vinnytsya, Ukraine
Keywords: primary open-angle glaucoma, chromosome, genotype, polymorphism, TXNRD2 gene, FOXC1 gene, allele, heterozygote.


Primary open-angle glaucoma (POAG) is a complex disease caused by numerous genetic and environmental factors, as well as their interaction. In recent studies, the effect of genetic polymorphisms combinations and non-equilibrium linkage of allele genes related to the development of POAG has been proved. The aim of the study was to determine the effect of TXNRD2 rs35934224, FOXC1 rs2745599 and rs984253 genetic polymorphisms combinations on the development of primary open-angle glaucoma and their degree of association with the disease. The study included 93 patients (185 eyes) with POAG stage I-IV and 89 volunteers (178 eyes) control subjects without any types of glaucoma. The patients were divided into four groups according to the degree of perimetric changes (Nesterov A. P., 2008). All patients performed visometry, computer perimetry, tonometry, biomicroscopy, ophthalmoscopy, gonioscopy, keratopahymetry, optical coherent tomography of the optic nerve. Analysis of the TXNRD2 rs35934224, FOXC1 rs2745599 and rs984253 genetic polymorphism with POAG was performed in real time using a polymerase chain reaction (PCR) in Gene Amp® PCR System 7500 (Applied Biosystems, USA) automatic amplifier. In the first stage of the study, the genomic DNA from whole venous blood was isolated using the standard reagents PureLink® Genomic DNA Kit for purification of genomic DNA, manufactured by INVITROGEN (USA). The analysis of polymorphism was carried out using unified test systems of TaqMan Mutation Detection Assays Life-Technology (USA). It was determined that the association with POAG had the genotype C/T*A/A*T/A as by comparing control with all patients, and by stratification – with the 1st, 2nd and 3rd groups of patients. The obtained results showed the evidentiary effect of this genotype combinations on the appearance of POAG, and on its progression by the stages of perimetric changes. The risk of the occurrence of POAG in carriers of genotypes C/T*A/A*T/A was increased by 2.8 times (p<0.001). In this combination, the two polymorphisms had heterozygous genotypes (rs35934224 – C/T, rs984253 – T/A), and the genotype rs2745599 – a mutant homozygote A/A. A combination of genotypes C/C*G/A*T/A was also important for the progression of the disease till stage II, which increased the risk of development of the POAG stage II by 2.9 times (p<0.01) compared to control. The risk of occurrence of the POAG in general and development of stage IV increased the presence of combinations of three minor genotypes T/T*A/A*A/A, which was encountered only in patients with POAG (in stage II – f = 0.025, in the third stage – f = 0.036, and in IV – f = 0.071). In our opinion, it confirmed the proposed working hypothesis of the study and showed that the more genotype combinations have the mutant alleles, the stronger this genotype affects the development of POAG.


[1] Bailey, J. N., Loomis, S. J., Kang, J. H., Allingham, R. R., Gharahkhani, P., Khor, C. C., … Wiggs, J. L. (2016). Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open angle glaucoma. Nat. Genet., 48(2), 189-194. doi: 10.1038/ng.3482

[2] Caprioli J, Munemasa, Y., Kwong, J. M., & Piri, N. (2009). Overexpression of thioredoxins 1 and 2 increases retinal ganglion cell survival after pharmacologically induced oxidative stress, optic nerve transection, and in experimental glaucoma. Trans. Am. Ophthalmol. Soc., 107, 161-165. PMID: 20126492

[3] Carelli, V., Ross-Cisneros, F. N., & Sadun, A. A. (2004). Mitochondrial dysfunction as a cause of optic neuropathies. Prog. Retin. Eye. Res., 23(1), 53-89. doi: /10.1016/j.preteyeres.2003.10.003

[4] Chen, Y., Cai, J., & Jones, D. P. (2006). Mitochondrial thioredoxin in regulation of oxidant-induced cell death. FEBS Lett, 580(28-29), 6596-6602. doi: 10.1016/j.febslet.2006.11.007

[5] Chrysostomou, V., Rezania, F., Trounce, I. A., & Crowston, J. G. (2013). Oxidative stress and mitochondrial dysfunction in glaucoma. Curr. Opin. Pharmacol., 13(2), 12-15. doi: org/10.1016/j.exer.2010.07.015

[6] Cook, C. (2009). Glaucoma in Africa: size of the problem and possible solutions. J. Glaucoma, 18(2), 124-128. doi: 10.1097/IJG.0b013e318189158c

[7] Gong, G., Kosoko-Lasaki, S., Haynatzki, G., Lynch, H. T., Lynch, J. A., & Wilson, M. R. (2007). Inherited, familial and sporadic primary open-angle glaucoma. J. Natl. Med. Assoc., 99(5), 559-563. PMID: 17534014

[8] Gong, G., Kosoko-Lasaki, О., Haynatzki, G. R., & Wilson, M. R. (2004). Genetic dissection of myocilin glaucoma. Hum. Mol. Genet., 13(1), R91-R102. doi: 10.1093/hmg/ddh074

[9] Hysi, P. G., Cheng, C. Y., Springelkamp, H., Macgregor, S., Bailey, J. N., Wojciechowski, R., … Aung, T. (2014). Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat. Genet., 46(10), 1126-1130. doi: 10.1038/ng.3087

[10] Lascaratos, G., Garway-Heath, D. F., Willoughby, C. E., Chau, K. Y., & Schapira, A. H. (2012). Mitochondrial dysfunction in glaucoma: understanding genetic influences. Mitochondrion., 12(2), 202-212. doi: org/10.1016/j.mito.2011.11.004

[11] Lehmann, O. J., Tuft, S., Brice, G., Smith, R., Blixt, A., Bell, R., … Bhattacharya, S. S. (2003). Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function. Invest. Ophthalmol. Vis. Sci., 44(6), 2627-2633. doi: 10.1167/iovs.02-0609

[12] Lee, S., Van Bergen, N. J., & Kong, G. Y. (2011). Mitochondrial dysfunction in glaucoma and emerging bioenergetic therapies. Exp. Eye. Res., 93(2), 204-212. doi: org/10.1016/j.exer.2010.07.015

[13] Lin, M. T., & Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443, 787-795. doi: 10.1038/nature05292

[14] Lu, T., Zullo, J., & Aron, L. (2014). REST and stress resistance in ageing and Alzheimer’s disease. Nature, 507, 448-454. doi: 10.1038/nature13163

[15] Malachkova N. V., & Veretelnyk S. P. (2018). Correlation of rs35934224 polymorphism of TXNRD2 gene with primary open-angle glaucoma. Archive of Ukrainian ophthalmology, 6(3), 21-25.

[16] Mirzayans, F., Gould, D. B., Héon, E., Billingsley, G. D., Cheung, J. C., Mears, A. J., & Walter, M. A. (2000). Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25. Eur. J. Hum. Genet., 8(1), 71-74. doi: 10.1038/sj.ejhg.5200354

[17] Nesterov, A. P. (2008). Glaucoma. М.: ООО «Medical information agency».

[18] Nishimura, D. Y., Swiderski, R. E., Alward, W. L., Searby, C. C., Patil, S. R., Bennet, S. R., … Sheffield, V. C. (1998). The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat. Genet., 19(2), 140-147. doi: 10.1038/493

[19] Osborne, N. N., & del Olmo-Aguado, S. (2013). Maintenance of retinal ganglion cell mitochondrial functions as a neuroprotective strategy in glaucoma. Curr. Opin. Pharmacol., 13(1), 16-22. doi: 10.1016/j.coph.2012.09.002

[20] Ozel, A. B., Moroi, S. E., Reed, D. M., Nika, M., Schmidt, C. M., Akbari, S., … Li, J. Z. (2014) Genome-wide association study and meta-analysis of intraocular pressure. Hum. Genet., 133(1), 41-57. doi: 10.1007/s00439-013-1349-5

[21] Park, S., Jamshidi, Ya., Vaideanu, D., Fraser, S., & Sowden, J. C. (2012). Common TGFβ2, BMP4, and FOXC1 variants are not associated with primary open-angle glaucoma. Mol. Vis., 18, 1526-1539. PMID: 22736943

[22] Quigley, H. A., & Broman, A.T. (2006). The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol., 90(3), 262-267. doi: 10.1136/bjo.2005.081224

[23] Serdyuk, V. M. (2015). Clinical and experimental substantiation of neuroprotection in the complex treatment of patients with primary open-angle glaucoma (Doctoral dissertation). http://www.irbis-nbuv.gov.ua/

[24] Shields, M. B. (1983). Axenfeld-Rieger syndrome: a theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans. Am. Ophthalmol. Soc., 81, 736-784.

[25] Smith, R. S., Zabaleta, A., Kume, T., Savinova, O. V., Kidson, S. H., Martin, J. E., … John, S. W. (2000). Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum. Mol. Genet., 9(7), 1021-1032.

[26] van der Merwe, E. L., & Kidson, S. H. (2016). Wholemount imaging reveals abnormalities of the aqueous outflow pathway and corneal vascularity in Foxc1 and Bmp4 heterozygous mice. Exp. Eye. Res., 146, 293-303. doi: 10.1016/j.exer.2016.04.003

[27] Vitovsʹka, O. P., & Rykov, S. O. (2012). Organization of ophthalmologycal care for patients with glaucoma and its normative-legal support. Modern medical technology, 2), 46-50.

[28] Wiggs, J. L., & Pasquale, L. R. (2017). Genetics of glaucoma. Hum. Mol. Genet., 26(R1), R21-R27. doi: 10.1093/hmg/ddx184
How to Cite
Malachkova, N. V., Veretelnyk, S. P., & Slobodian, P. P. (2018). Effect of TXNRD2 rs35934224, FOXC1 rs2745599 and rs984253 genetic polymorphisms combinations on the development of primary open-angle glaucoma and their degree of association with the disease. Biomedical and Biosocial Anthropology, (33), 12-17. https://doi.org/https://doi.org/10.31393/bba33-2018-2