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Polymorphism of the APEX nuclease 1 gene in keratoconus and Fuchs endothelial corneal dystrophy

  • Katarzyna A. Wojcik , Ewelina Synowiec , Anna Kaminska , Justyna Izdebska , Piotr Polakowski , Elzbieta Pawlowska , Janusz Blasiak , Jerzy Szaflik and Jacek P. Szaflik EMAIL logo
Published/Copyright: March 25, 2015
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Cellular and Molecular Biology Letters
From the journal Cellular and Molecular Biology Letters Volume 20 Issue 1

Abstract

Human APEX nuclease 1 (APEX1) plays an important role in the repair of oxidative DNA lesions through base excision repair. It may influence the development of oxidative stress-related diseases. The aim of this study was to determine the relationship between the genotypes of the c.444 T>G (rs1130409) and c.-468 T>G (rs1760944) polymorphisms in the APEX1 gene and the occurrence of two oxidative stress-related eye diseases: keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). The study involved 250 patients with KC, 209 patients with FECD, and 350 control subjects. All of the patients and control subjects underwent a detailed ophthalmic examination. The polymorphisms were genotyped by mismatch polymerase chain reaction restriction fragment length polymorphism (mismatch PCR-RFLP). We observed that the G/T and T/T genotypes of the c.-468 T>G polymorphism were respectively associated with a decreased occurrence of KC (OR 0.54, 95% CI 0.37-0.95; p = 0.030) and an increased occurrence of KC (OR 1.87, 95% CI 1.06-3.32; p = 0.032). None of these polymorphisms showed any association with FECD. Furthermore, no other association was observed, including haplotypes of the two polymorphisms. Our findings suggest that the c.-468 T>G polymorphism of the APEX1 gene may play a role in the pathogenesis of KC.

Keywords : Keratoconus; KC; Fuchs endothelial corneal dystrophy; FECD; APEX nuclease 1; APEX1; Oxidative stress

References

1. Rabinowitz, Y.S. Keratoconus. Surv. Ophthalmol. 42 (1998) 297-319.10.1016/S0039-6257(97)00119-7Search in Google Scholar

2. Moreira, L.B., Bardal, R.A. and Crisigiovanni, L.R. Contact lenses fitting after intracorneal ring segments implantation in keratoconus. Arq. Bras. Oftalmol. 76 (2013) 215-217.Search in Google Scholar

3. Vazirani, J. and Basu, S. Keratoconus: current perspectives. Clin. Ophthalmol. 7 (2013) 2019-2030.Search in Google Scholar

4. Romero-Jiménez, M, Santodomingo-Rubido, J. and Wolffsohn, J.S. Keratoconus: a review. Cont. Lens Anterior Eye 33 (2010) 157-166.10.1016/j.clae.2010.04.006Search in Google Scholar

5. Edwards, M., McGhee, C.N. and Dean, S. The genetics of keratoconus. Clin. Experiment. Ophthalmol. 29 (2001) 345-351.10.1046/j.1442-9071.2001.d01-16.xSearch in Google Scholar

6. Wang, Y., Rabinowitz, Y.S., Rotter, J.I. and Yang, H. Genetic epidemiological study of keratoconus: evidence for major gene determination. Am. J. Med. Genet. 93 (2000) 403-409.10.1002/1096-8628(20000828)93:5<403::AID-AJMG11>3.0.CO;2-ASearch in Google Scholar

7. McMahon, T.T., Shin, J.A., Newlin, A., Edrington, T.B., Sugar, J. and Zadnik, K. Discordance for keratoconus in two pairs of monozygotic twins. Cornea 18 (1999) 444-451.Search in Google Scholar

8. Hutchings, H., Ginisty, H., Le Gallo, M., Levy, D., Stoësser, F., Rouland, J.F., Arné, J.L., Lalaux, M.H., Calvas, P., Roth, M.P., Hovnanian, A. and Malecaze, F. Identification of a new locus for isolated familial keratoconus at 2p24. J. Med. Genet. 42 (2005) 88-94.Search in Google Scholar

9. Brancati, F., Valente, E.M., Sarkozy, A., Fehèr, J., Castori, M., Del Duca, P., Mingarelli, R., Pizzuti, A. and Dallapiccola, B. A locus for autosomal dominant keratoconus maps to human chromosome 3p14-q13. J. Med. Genet. 41 (2004) 188-192.Search in Google Scholar

10. Tang, Y.G., Rabinowitz, Y.S., Taylor, K.D., Li, X., Hu, M., Picornell, Y. and Yang, H. Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1. Genet. Med. 7 (2005) 397-405.Search in Google Scholar

11. Tyynismaa, H., Sistonen, P., Tuupanen, S., Tervo, T., Dammert, A., Latvala, T. and Alitalo, T. A locus for autosomal dominant keratoconus: linkage to 16q22.3-q23.1 in Finnish families. Invest. Ophthalmol. Vis. Sci. 43 (2002) 3160-3164.Search in Google Scholar

12. Burdon, K.P., Coster, D.J., Charlesworth, J.C., Mills, R.A., Laurie, K.J., Giunta, C., Hewitt, A.W., Latimer, P. and Craig, J.E. Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci. Hum. Genet. 124 (2008) 379-386.Search in Google Scholar

13. Hughes, A.E., Dash, D.P., Jackson, A.J., Frazer, D.G. and Silvestri, G. Familial keratoconus with cataract: linkage to the long arm of chromosome 15 and exclusion of candidate genes. Invest. Ophthalmol. Vis. Sci. 44 (2003) 5063-5066.Search in Google Scholar

14. Gajecka, M., Radhakrishna, U., Winters, D., Nath, S.K., Rydzanicz, M., Ratnamala, U., Ewing, K., Molinari, A., Pitarque, J.A., Lee, K., Leal, S.M. and Bejjani, B.A. Localization of a gene for keratoconus to a 5.6-Mb interval on 13q32. Invest. Ophthalmol. Vis. Sci. 50 (2009) 1531-1539.Search in Google Scholar

15. Fullerton, J., Paprocki, P., Foote, S., Mackey, D.A., Williamson, R. and Forrest, S. Identity-by-descent approach to gene localisation in eight individuals affected by keratoconus from north-west Tasmania, Australia. Hum. Genet. 110 (2002) 462-470.10.1007/s00439-002-0705-7Search in Google Scholar

16. Burdon, K.P. and Vincent, A.L. Insights into keratoconus from a genetic perspective. Clin. Exp. Optom. 96 (2013) 146-54.Search in Google Scholar

17. Yuen, H.K., Rassier, C.E., Jardeleza, M.S., Green, WR, de la Cruz, Z., Stark, W.J. and Gottsch, J.D. A morphologic study of Fuchs dystrophy and bullous keratopathy. Cornea 24 (2005) 319-327. Search in Google Scholar

18. Elhalis, H., Azizi, B. and Jurkunas, U.V. Fuchs endothelial corneal dystrophy. Ocul. Surf. 8 (2010) 173-184.Search in Google Scholar

19. Schmedt, T., Silva, M.M., Ziaei, A. and Jurkunas, U. Molecular bases of corneal endothelial dystrophies. Exp. Eye Res. 95 (2012) 24-34.Search in Google Scholar

20. Eghrari, A.O. and Gottsch, J.D. Fuchs’ corneal dystrophy. Expert. Rev. Ophthalmol. 5 (2010) 147-159.10.1586/eop.10.8Search in Google Scholar

21. Jurkunas, U.V., Bitar, M.S., Funaki, T. and Azizi, B. Evidence of oxidative stress in the pathogenesis of Fuchs endothelial corneal dystrophy. Am. J. Pathol. 177 (2010) 2278-2289.Search in Google Scholar

22. Iliff, B.W., Riazuddin, S.A. and Gottsch, J.D. The genetics of Fuchs’ corneal dystrophy. Expert. Rev. Ophthalmol. 7 (2012) 363-375.10.1586/eop.12.39Search in Google Scholar

23. Sundin, O.H., Broman, K.W., Chang, H.H., Vito, E.C., Stark, W.J. and Gottsch, J.D. A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32. Invest. Ophthalmol. Vis. Sci. 47 (2006) 3919-3926.Search in Google Scholar

24. Sundin, O.H., Jun, A.S., Broman, K.W., Liu, S.H., Sheehan, S.E., Vito, E.C., Stark, W.J. and Gottsch, J.D. Linkage of late-onset Fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest. Ophthalmol. Vis. Sci. 47 (2006) 140-145.Search in Google Scholar

25. Riazuddin, S.A., Zaghloul, N.A., Al-Saif, A., Davey, L., Diplas, B.H., Meadows, D.N., Eghrari, A.O., Minear, M.A., Li, Y.J., Klintworth, G.K., Afshari, N., Gregory, S.G., Gottsch, J.D. and Katsanis, N. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am. J. Hum. Genet. 86 (2010) 45-53.Search in Google Scholar

26. Riazuddin, S.A., Eghrari, A.O., Al-Saif, A., Davey, L., Meadows, D.N., Katsanis, N. and Gottsch, J.D. Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q33.1-q35.2. Invest. Ophthalmol. Vis. Sci. 50 (2009) 5667-5671.Search in Google Scholar

27. Wojcik, K.A., Kaminska, A., Blasiak, J., Szaflik, J. and Szaflik, J.P. Oxidative stress in the pathogenesis of keratoconus and fuchs endothelial corneal dystrophy. Int. J. Mol. Sci. 14 (2013) 19294-19308.Search in Google Scholar

28. Shoham, A., Hadziahmetovic, M., Dunaief, J.L., Mydlarski, M.B. and Schipper, H.M. Oxidative stress in diseases of the human cornea. Free Radic. Biol. Med. 45 (2008) 1047-55.10.1016/j.freeradbiomed.2008.07.021Search in Google Scholar

29. Kohen, R. and Nyska, A. Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol. Pathol. 30 (2002) 620-650.Search in Google Scholar

30. Behndig, A., Karlsson, K., Johansson, B.O., Brännström, T. and Marklund, S.L. Superoxide dismutase isoenzymes in the normal and diseased human cornea. Invest. Ophthalmol. Vis. Sci. 42 (2001) 2293-2296.Search in Google Scholar

31. Arnal, E., Peris-Martínez, C., Menezo, J.L., Johnsen-Soriano, S. and Romero, F.J. Oxidative stress in keratoconus? Invest. Ophthalmol. Vis. Sci. 52 (2011) 8592-8597. 10.1167/iovs.11-7732Search in Google Scholar

32. Kryston, T.B., Georgiev, A.B., Pissis, P. and Georgakilas, A.G. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat. Res. 711 (2011) 193-201.Search in Google Scholar

33. Kim, Y.J. and Wilson, D.M. 3rd. Overview of base excision repair biochemistry. Curr. Mol. Pharmacol. 5 (2012) 3-13.Search in Google Scholar

34. Pflugfelder, S.C., Liu, Z., Feuer, W. and Verm, A. Corneal thickness indices discriminate between keratoconus and contact lens-induced corneal thinning. Ophthalmology 109 (2002) 2336-2341.Search in Google Scholar

35. Holladay, J.T. Keratoconus detection using corneal topography. J. Refract. Surg. 25 (2009) S958-962.10.3928/1081597X-20090915-11Search in Google Scholar

36. Szaflik, J.P. Comparison of in vivo confocal microscopy of human cornea by white light scanning slit and laser scanning systems. Cornea 26 (2007) 438-445.Search in Google Scholar

37. Weiss, J.S., Møller, H.U., Lisch, W., Kinoshita, S., Aldave, A.J., Belin, M.W., Kivelä, T., Busin, M., Munier, F.L., Seitz, B., Sutphin, J., Bredrup, C., Mannis, M.J., Rapuano, C.J., Van Rij, G., Kim, E.K. and Klintworth, G.K. The IC3D classification of the corneal dystrophies. Cornea 27 (2008) Suppl. 2 S1-83.Search in Google Scholar

38. Haliassos, A., Chomel, J.C., Tesson, L., Baudis, M., Kruh, J., Kaplan, J.C. and Kitzis, A. Modification of enzymatically amplified DNA for the detection of point mutations. Nucleic Acids Res. 17 (1989) 3606.Search in Google Scholar

39. Haliassos, A., Chomel, J.C., Grandjouan, S., Kruh, J., Kaplan, J.C. and Kitzis, A. Detection of minority point mutations by modified PCR technique: a new approach for a sensitive diagnosis of tumor-progression markers. Nucleic Acids Res. 17 (1989) 8093-8099.Search in Google Scholar

40. Buddi, R., Lin, B., Atilano, S.R., Zorapapel, N.C., Kenney, M.C. and Brown, D.J. Evidence of oxidative stress in human corneal diseases. J. Histochem. Cytochem. 50 (2002) 341-51.Search in Google Scholar

41. Bawazeer, A.M., Hodge, W.G. and Lorimer, B. Atopy and keratoconus: a multivariate analysis. Br. J. Ophthalmol. 84 (2000) 834-836.Search in Google Scholar

42. Rahi, A., Davies, P., Ruben, M., Lobascher, D. and Menon, J. Keratoconus and coexisting atopic disease. Br. J. Ophthalmol. 61 (1977) 761-764.Search in Google Scholar

43. Nagarsheth, M., Singh, A., Schmotzer, B., Babineau, D.C., Sugar, J., Lee, W.B., Iyengar, S.K., Lass, J.H and Fuchs’ Genetics Multi-Center Study Group. Relationship between fuchs endothelial corneal dystrophy severity and glaucoma and/or ocular hypertension. Arch. Ophthalmol. 9 (2012) 1-5.Search in Google Scholar

44. Durik, M., Kavousi, M., van der Pluijm, I., Isaacs, A., Cheng, C., Verdonk, K., Loot, A.E., Oeseburg, H., Bhaggoe, U.M., Leijten, F., van, Veghel, R., de, Vries, R., Rudez, G., Brandt, R., Ridwan, Y.R., van, Deel, E.D., de, Boer, M., Tempel, D., Fleming, I., Mitchell, G.F., Verwoert, G.C., Tarasov, K.V., Uitterlinden, A.G., Hofman, A., Duckers, H.J., van, Duijn, C.M., Oostra, B.A., Witteman, J.C., Duncker, D.J., Danser, A.H., Hoeijmakers, J.H. and Roks, A.J. Nucleotide excision DNA repair is associated with age-related vascular dysfunction. Circulation 126 (2012) 468-478. Search in Google Scholar

45. Abbotts, R. and Madhusudan, S. Human AP endonuclease 1 (APE1): from mechanistic insights to druggable target in cancer. Cancer Treat. Rev. 36 (2010) 425-435.Search in Google Scholar

46. Wilson, D.M. 3rd. Properties of and substrate determinants for the exonuclease activity of human apurinic endonuclease Ape1. J. Mol. Biol. 330 (2003) 1027-1037.Search in Google Scholar

47. Izumi, T., Hazra, T.K., Boldogh, I., Tomkinson, A.E., Park, M.S., Ikeda, S. and Mitra, S. Requirement for human AP endonuclease 1 for repair of 3’-blocking damage at DNA single-strand breaks induced by reactive oxygen species. Carcinogenesis 21 (2000) 1329-1334.Search in Google Scholar

48. Fan, J. and Wilson, D.M. 3rd. Protein-protein interactions and posttranslational modifications in mammalian base excision repair. Free Radic. Biol Med. 38 (2005) 1121-1138.Search in Google Scholar

49. Evans, A.R., Limp-Foster, M. and Kelley, M.R. Going APE over ref-1. Mutat. Res. 461 (2000) 83-108.Search in Google Scholar

50. Au, W.W., Salama, S.A. and Sierra-Torres, C.H. Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays. Environ. Health Perspect. 111 (2003) 1843-1850.Search in Google Scholar

51. Lo, Y.L., Jou, Y.S., Hsiao, C.F., Chang, G.C., Tsai, Y.H., Su, W.C., Chen, K.Y., Chen, Y.M., Huang, M.S., Hu, C.Y., Chen, C.J. and Hsiung, C.A. A polymorphism in the APE1 gene promoter is associated with lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 18 (2009) 223-229.Search in Google Scholar

52. Lu, J., Zhang, S., Chen, D., Wang, H., Wu, W., Wang, X., Lei, Y., Wang, J., Qian, J., Fan, W., Hu, Z., Jin, L., Shen, H., Huang, W., Wei, Q. and Lu, D. Functional characterization of a promoter polymorphism in APE1/Ref-1 that contributes to reduced lung cancer susceptibility. FASEB J. 23 (2009) 3459-3469. Search in Google Scholar

Received: 2014-7-23
Accepted: 2014-12-24
Published Online: 2015-3-25
Published in Print: 2015-3-1

© 2015 University of Wrocław, Poland

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https://doi.org/10.1515/cmble-2015-0001
Keywords for this article
Keratoconus; KC; Fuchs endothelial corneal dystrophy; FECD; APEX nuclease 1; APEX1; Oxidative stress

Articles in the same Issue

  1. Identification of drought-induced transcription factors in Sorghum bicolor using GO term semantic similarity
  2. Evaluation of the potential of alkylresorcinols as superoxide anion scavengers and sox-regulon modulators using nitroblue tetrazolium and bioluminescent cell-based assays
  3. Cyclic phosphatidic acid induces G0/G1 arrest, inhibits AKT phosphorylation, and downregulates cyclin D1 expression in colorectal cancer cells
  4. Polymorphism of the APEX nuclease 1 gene in keratoconus and Fuchs endothelial corneal dystrophy
  5. FE65: Roles beyond amyloid precursor protein processing
  6. Single nucleotide polymorphisms in the STAT3 gene influence AITD susceptibility, thyroid autoantibody levels, and IL6 and IL17 secretion
  7. Antioxidant effect of a fermented powder of Lady Joy bean in primary rat hepatocytes
  8. Oncogene-dependent survival of highly transformed cancer cells under conditions of extreme centrifugal force – implications for studies on extracellular vesicles
  9. Changes in cell death of peripheral blood lymphocytes isolated from children with acute lymphoblastic leukemia upon stimulation with 7 Hz, 30 mT pulsed electromagnetic field
  10. Flow cytometric analysis of apoptosis in cryoconserved chicken primordial germ cells
  11. GGeneration of an efficient artificial promoter of bovine skeletal muscle alpha-actin gene (ACTA1) through addition of cis-acting element
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