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Correlation between the COL4A3, MMP-9, and TIMP-1 polymorphisms and risk of keratoconus

  • Clinical Investigation
  • Published:
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Abstract

Purpose

Keratoconus (KC) is thinning of the central cornea. Its etiology is unknown, but it may result from degrading of collagen type IV. The major protein in the cornea is collagen. Matrix metalloproteinase-9 (MMP-9) is able to degrade collagen type IV from the basement membrane and extracellular matrix (ECM). MMP-9 enzymatic activity is inhibited by the tissue inhibitor of metalloproteinase-1 (TIMP-1). In the present study, we sought to investigate and evaluate the effects of single nucleotide polymorphisms in COL4A3, MMP-9, and TIMP-1 on the risk of KC in an Iranian population sample.

Methods

This case–control study was performed on 140 KC patients and 150 healthy controls. Genotyping of the COL4A3 rs55703767, MMP-9 rs17576, and TIMP-1 rs6609533 polymorphisms was done using amplification refractory mutation system polymerase chain reaction (ARMS-PCR).

Results

Our findings showed that the rs55703767G/T polymorphism decreased the risk of KC (OR = 0.26, 95% CI = 0.08–0.82, P = 0.022). rs17576A/G, associated with KC and the A allele, was significantly overrepresented in healthy individuals. rs6609533A/G (X-chromosome) increased the risk of KC in females (OR = 2.27, 95% CI = 1.06–4.76, P = 0.036). In males, the allele frequency was not associated with KC risk/protection.

Conclusions

This study indicates that in our population, the COL4A3 rs55703767 polymorphism decreased the risk of KC. However, the TIMP-1 rs6609533 polymorphism was associated with an increased risk of KC.

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References

  1. Arnal E, Peris-Martinez C, Menezo JL, Johnsen-Soriano S, Romero FJ. Oxidative stress in keratoconus? Invest Ophthalmol Vis Sci. 2011;52:8592–7.

    Article  CAS  PubMed  Google Scholar 

  2. Sahebjada S, Fenwick EK, Xie J, Snibson GR, Daniell MD, Baird PN. Impact of keratoconus in the better eye and the worse eye on vision-related quality of life. Investig Ophthalmol Vis Sci. 2014;55:412–6.

    Article  Google Scholar 

  3. Liskova P, Hysi PG, Waseem N, Ebenezer ND, Bhattacharya SS, Tuft SJ. Evidence for keratoconus susceptibility locus on chromosome 14: a genome-wide linkage screen using single-nucleotide polymorphism markers. Arch Ophthalmol. 2010;128:1191–5.

    Article  CAS  PubMed  Google Scholar 

  4. Georgiou T, Funnell CL, Cassels-Brown A, O’Conor R. Influence of ethnic origin on the incidence of keratoconus and associated atopic disease in asians and white patients. Eye (Lond). 2004;18:379–83.

    Article  CAS  Google Scholar 

  5. Nowak DM, Gajecka M. The genetics of keratoconus. Middle East Afr J Ophthalmol. 2011;18:2–6.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Balasubramanian SA, Pye DC, Willcox MD. Are proteinases the reason for keratoconus? Curr Eye Res. 2010;35:185–91.

    Article  CAS  PubMed  Google Scholar 

  7. Hasanian-Langroudi F, Saravani R, Validad MH, Bahari G, Yari D. Association of lysyl oxidase (lox) polymorphisms with the risk of keratoconus in an Iranian population. Ophthalmic Genet. 2014;36(4):309–14.

    Article  PubMed  Google Scholar 

  8. Heon E, Greenberg A, Kopp KK, Rootman D, Vincent AL, Billingsley G, et al. Vsx1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet. 2002;11:1029–36.

    Article  CAS  PubMed  Google Scholar 

  9. Guan T, Liu C, Ma Z, Ding S. The point mutation and polymorphism in keratoconus candidate gene TGFBI in Chinese population. Gene. 2012;503:137–9.

    Article  CAS  PubMed  Google Scholar 

  10. Wang Y, Jin T, Zhang X, Wei W, Cui Y, Geng T, et al. Common single nucleotide polymorphisms and keratoconus in the Han Chinese population. Ophthalmic Genet. 2013;34:160–6.

    Article  PubMed  Google Scholar 

  11. Sahebjada S, Schache M, Richardson AJ, Snibson G, Daniell M, Baird PN. Association of the hepatocyte growth factor gene with keratoconus in an Australian population. PLoS One. 2014;9:e84067.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Saravani R, Hasanian-Langroudi F, Validad MH, Yari D, Bahari G, Faramarzi M, et al. Evaluation of possible relationship between Col4a4 gene polymorphisms and risk of keratoconus. Cornea. 2015;34:318–22.

    Article  PubMed  Google Scholar 

  13. Nie XC, Wang JP, Zhu W, Xu XY, Xing YN, Yu M, et al. COL4A3 expression correlates with pathogenesis, pathologic behaviors, and prognosis of gastric carcinomas. Hum Pathol. 2013;44:77–86.

    Article  CAS  PubMed  Google Scholar 

  14. Mariyama M, Zheng K, Yang-Feng TL, Reeders ST. Colocalization of the genes for the alpha 3(IV) and alpha 4(IV) chains of type IV collagen to chromosome 2 bands q35-q37. Genomics. 1992;13:809–13.

    Article  CAS  PubMed  Google Scholar 

  15. Collier SA. Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clin Exp Ophthalmol. 2001;29:340–4.

    Article  CAS  PubMed  Google Scholar 

  16. Abalain JH, Dossou H, Colin J, Floch HH. Levels of collagen degradation products (telopeptides) in the tear film of patients with keratoconus. Cornea. 2000;19:474–6.

    Article  CAS  PubMed  Google Scholar 

  17. Critchfield JW, Calandra AJ, Nesburn AB, Kenney MC. Keratoconus: I. Biochemical studies. Exp Eye Res. 1988;46:953–63.

    Article  CAS  PubMed  Google Scholar 

  18. Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML. Matrix metalloproteinase-9: many shades of function in cardiovascular disease. Physiol (Bethesda). 2013;28:391–403.

    CAS  Google Scholar 

  19. Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci. 2006;11:1696–701.

    Article  CAS  PubMed  Google Scholar 

  20. Farina AR, Mackay AR. Gelatinase B/MMP-9 in tumour pathogenesis and progression. Cancers (Basel). 2014;6:240–96.

    Article  Google Scholar 

  21. Groblewska M, Siewko M, Mroczko B, Szmitkowski M. The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer. Folia Histochem Cytobiol. 2012;50:12–9.

    Article  PubMed  Google Scholar 

  22. Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta. 2010;1803:55–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kenney MC, Chwa M, Atilano SR, Tran A, Carballo M, Saghizadeh M, et al. Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role in this disorder. Invest Ophthalmol Vis Sci. 2005;46:823–32.

    Article  PubMed  Google Scholar 

  24. Micheal S, Yousaf S, Khan MI, Akhtar F, Islam F, Khan WA, et al. Polymorphisms in matrix metalloproteinases MMP1 and MMP9 are associated with primary open-angle and angle closure glaucoma in a Pakistani population. Mol Vis. 2013;19:441–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Awadalla MS, Burdon KP, Kuot A, Hewitt AW, Craig JE. Matrix metalloproteinase-9 genetic variation and primary angle closure glaucoma in a Caucasian population. Mol Vis. 2011;17:1420–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Karasneh JA, Bani-Hani ME, Alkhateeb AM, Hassan AF, Thornhill MH. Association of MMP but not TIMP-1 gene polymorphisms with recurrent aphthous stomatitis. Oral Dis. 2014;20:693–9.

    Article  CAS  PubMed  Google Scholar 

  27. Kokolakis NS, Gazouli M, Chatziralli IP, Koutsandrea C, Gatzioufas Z, Peponis VG, et al. Polymorphism analysis of COL4A3 and COL4A4 genes in Greek patients with keratoconus. Ophthalmic Genet. 2014;35:226–8.

    Article  CAS  PubMed  Google Scholar 

  28. Stabuc-Silih M, Ravnik-Glavac M, Glavac D, Hawlina M, Strazisar M. Polymorphisms in COL4A3 and COL4A4 genes associated with keratoconus. Mol Vis. 2009;15:2848–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hashemi M, Amininia S, Ebrahimi M, Hashemi SM, Taheri M, Ghavami S. Association between hTERT polymorphisms and the risk of breast cancer in a sample of Southeast Iranian population. BMC Res Notes. 2014;7:895.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Newton CR, Graham A, Heptinstall LE, Powell SJ, Summers C, Kalsheker N, et al. Analysis of any point mutation in DNA: the amplification refractory mutation system (ARMS). Nucl Acids Res. 1989;17:2503–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Crawford A, Fassett RG, Geraghty DP, Kunde DA, Ball MJ, Robertson IK, et al. Relationships between single nucleotide polymorphisms of antioxidant enzymes and disease. Gene. 2012;501:89–103.

    Article  CAS  PubMed  Google Scholar 

  32. Abreu-Velez AM, Howard MS. Collagen IV in normal skin and in pathological processes. N Am J Med Sci. 2012;4:1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bai X, Dilworth DJ, Weng YC, Gould DB. Developmental distribution of collagen IV isoforms and relevance to ocular diseases. Matrix Biol. 2009;28:194–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nielsen K, Hjortdal J, Pihlmann M, Corydon TJ. Update on the keratoconus genetics. Acta Ophthalmol. 2013;91:106–13.

    Article  CAS  PubMed  Google Scholar 

  35. Fullerton J, Paprocki P, Foote S, Mackey DA, Williamson R, Forrest S. Identity-by-descent approach to gene localisation in eight individuals affected by keratoconus from north-west Tasmania, Australia. Hum Genet. 2002;110:462–70.

    Article  CAS  PubMed  Google Scholar 

  36. Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol. 2011;12:233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol. 2002;37:375–536.

    Article  PubMed  Google Scholar 

  38. Johnson MD, Kim HR, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol. 1994;160:194–202.

    Article  CAS  PubMed  Google Scholar 

  39. Lee JE, Oum BS, Choi HY, Lee SU, Lee JS. Evaluation of differentially expressed genes identified in keratoconus. Mol Vis. 2009;15:2480–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Brown D, Chwa MM, Opbroek A, Kenney MC. Keratoconus corneas: increased gelatinolytic activity appears after modification of inhibitors. Curr Eye Res. 1993;12:571–81.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded with a dissertation grant (MSc thesis of Davood Yari) from the Deputy for Research, Zahedan University of Medical Sciences.

Conflicts of interest

R. Saravani, None; D. Yari, Grant (Deputy for Research, Zahedan University of Medical Sciences); S. Saravani, None; F. H. Langroudi, None.

Author information

Authors and Affiliations

  1. Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran

    Ramin Saravani & Davood Yari

  2. Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

    Ramin Saravani, Davood Yari & Farzaneh Hasanian-Langroudi

  3. Department of Molecular Genetics, University of Zabol, Zabol, Iran

    Samira Saravani

Authors
  1. Ramin Saravani
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  2. Davood Yari
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  3. Samira Saravani
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  4. Farzaneh Hasanian-Langroudi
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Correspondence to Davood Yari.

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Saravani, R., Yari, D., Saravani, S. et al. Correlation between the COL4A3, MMP-9, and TIMP-1 polymorphisms and risk of keratoconus. Jpn J Ophthalmol 61, 218–222 (2017). https://doi.org/10.1007/s10384-017-0503-3

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  • DOI: https://doi.org/10.1007/s10384-017-0503-3

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