Skip to main content
SpringerLink
Log in

MTHFR and MTHFD1 gene polymorphisms are not associated with pseudoexfoliation syndrome in South Indian population

  • Original Paper
  • Published:
International Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

Pseudoexfoliation syndrome (PEX) is a late onset disorder of extracellular matrix turnover, associated systemically with cardiovascular and cerebrovascular disease. To evaluate the suggested association of polymorphisms of homocysteine metabolism genes MTHFR (rs1801131, rs1801133) and MTHFD1 (rs8006686) with PEX.

Methods

A case–control association study was undertaken, comprising a total of 1472 individuals including 860 unrelated PEX cases and 612 ethnic-matched cataract controls (CC). All the study subjects were genotyped for three SNPs using the TaqMan allelic discrimination assay. Association and statistical analysis were performed with PLINK 1.07 and STATA 11.1.

Results

Among the three SNPs genotyped, MTHFR polymorphisms did not exhibit significant association with PEX (rs1801131; p = 0.549, rs1801133; p = 0.408). The intronic SNP rs8006686 showed nearly significant association (p = 0.069), and however did not remain significant after Bonferroni correction.

Conclusion

Our study suggests no significant genetic association of MTHFR (rs1801131, rs1801133) and MTHFD1 (rs8006686) polymorphisms in South Indian PEX patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lindberg JG (1917) Clinical studies of depigmentation of the pupillary margin and transillumination of the iris in cases of senile cataract and also in normal eyes in the aged. Thesis, Helsinki University, Helsinki

  2. Quigley HA (1996) Number of people with glaucoma worldwide. Br J Ophthalmol 80(5):389–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ritch R, Schlötzer-Schrehardt U (2001) Exfoliation syndrome. Surv Ophthalmol 45(4):265–315

    Article  CAS  PubMed  Google Scholar 

  4. Elhawy E, Kamthan G, Dong CQ, Danias J (2012) Pseudoexfoliation syndrome, a systemic disorder with ocular manifestations. Hum Genomics 6(1):1

    Article  Google Scholar 

  5. Arvind H, Raju P, Paul PG, Baskaran M, Ramesh SV, George RJ, Vijaya L (2003) Pseudoexfoliation in south India. Br J Ophthalmol 87(11):1321–1323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Krishnadas R, Nirmalan PK, Ramakrishnan R, Thulasiraj RD, Katz J, Tielsch JM, Robin AL (2003) Pseudoexfoliation in a rural population of southern India: the Aravind Comprehensive Eye Survey. Am J Ophthalmol 135(6):830–837

    Article  CAS  PubMed  Google Scholar 

  7. Thomas R, Nirmalan PK, Krishnaiah S (2005) Pseudoexfoliation in southern India: the Andhra Pradesh Eye Disease Study. Invest Ophthalmol Vis Sci 46(4):1170–1176

    Article  PubMed  Google Scholar 

  8. Ritch R (1994) Exfoliation syndrome-the most common identifiable cause of open-angle glaucoma. J Glaucoma 3(2):176–177

    CAS  PubMed  Google Scholar 

  9. Allingham RR, Loftsdottir M, Gottfredsdottir MS, Thorgeirsson E, Jonasson F, Sverisson T, Stefánsson E (2001) Pseudoexfoliation syndrome in Icelandic families. Br J Ophthalmol 85(6):702–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hardie JG, Mercieca F, Fenech T, Cuschieri A (2005) Familial pseudoexfoliation in Gozo. Eye 19(12):1280–1285

    PubMed  Google Scholar 

  11. Lemmela S, Forsman E, Sistonen P, Eriksson A, Forsius H, Järvelä I (2007) Genome-wide scan of exfoliation syndrome. Invest Ophthalmol Vis Sci 48(9):4136–4142

    Article  PubMed  Google Scholar 

  12. Lievers KJ, Kluijtmans LA, Blom HJ (2003) Genetics of hyperhomocysteinemia in cardiovascular disease. Ann Clin Biochem 40(1):46–59

    Article  CAS  PubMed  Google Scholar 

  13. van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051

    Article  PubMed  PubMed Central  Google Scholar 

  14. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113

    Article  CAS  PubMed  Google Scholar 

  15. Lalouschek W, Aull S, Serles W, Wolfsberger M, Deecke L, Pabinger-Fasching I, Mannhalter C (2000) The relation between erythrocyte volume and folate levels is influenced by a common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (C.665C>T). J Invest Med 48(1):14–20

    CAS  Google Scholar 

  16. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64(3):169–172

    Article  CAS  PubMed  Google Scholar 

  17. Miller SA, Dykes DD, Polesky HFRN (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ritch R (2016) Systemic associations of exfoliation syndrome. Asia-Pac J Ophthalmol 5(1):45–50

    Article  Google Scholar 

  20. Kang JH, Wiggs JL, Pasquale LR (2014) Relation between time spent outdoors and exfoliation glaucoma or exfoliation glaucoma suspect. Am J Ophthalmol 158(3):605–614

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pasquale LR, Jiwani AZ, Zehavi-Dorin T, Majd A, Rhee DJ, Chen T, Gardiner M (2014) Solar exposure and residential geographic history in relation to exfoliation syndrome in the United States and Israel. JAMA Ophthalmol 132(12):1439–1445

    Article  PubMed  PubMed Central  Google Scholar 

  22. Stein JD, Pasquale LR, Talwar N, Kim DS, Reed DM, Nan B, Richards JE (2011) Geographic and climatic factors associated with exfoliation syndrome. Arch Ophthalmol 129(8):1053–1060

    Article  PubMed  PubMed Central  Google Scholar 

  23. Pasquale LR, Wiggs JL, Willett WC, Kang JH (2012) The relationship between caffeine and coffee consumption and exfoliation glaucoma or glaucoma suspect: a prospective study in two cohorts relationship between caffeine and exfoliation glaucoma. Invest Ophthalmol Vis Sci 53(10):6427–6433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Thorleifsson G, Magnusson KP, Sulem P, Walters GB, Gudbjartsson DF, Stefansson H, Masson G (2007) Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 317(5843):1397–1400

    Article  CAS  PubMed  Google Scholar 

  25. Aung T, Ozaki M, Mizoguchi T, Allingham RR, Li Z, Haripriya A, Lee MC (2015) A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet 47(4):387–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dubey SK, Hejtmancik JF, Krishnadas SR, Sharmila R, Haripriya A, Sundaresan P (2014) Lysyl oxidase-like 1 gene in the reversal of promoter risk allele in pseudoexfoliation syndrome. JAMA Ophthalmol 132(8):949–955

    Article  PubMed  Google Scholar 

  27. Angeline T, Jeyaraj N, Granito S, Tsongalis GJ (2004) Prevalence of MTHFR gene polymorphisms (C.665C>T and C.1286A>C) among Tamilians. Exp Mol Pathol 77(2):85–88

    Article  CAS  PubMed  Google Scholar 

  28. Dayakar S, Goud KI, Reddy TPK, Rao SP, Sesikeran SB, Sadhnani M (2011) Sequence variation of the methylene tetrahydrofolate reductase gene (677C>T and 1298 A>C) and traditional risk factors in a South Indian population. Genetic testing and molecular biomarkers 15(11):765–769

    Article  CAS  PubMed  Google Scholar 

  29. Kumar J, Das SK, Sharma P, Karthikeyan G, Ramakrishnan L, Sengupta S (2005) Homocysteine levels are associated with MTHFR C.1286A>C polymorphism in Indian population. J Hum Genet 50(12):655–663

    Article  CAS  PubMed  Google Scholar 

  30. Mukherjee M, Joshi S, Bagadi S, Dalvi M, Rao A, Shetty KR (2002) A low prevalence of the C.665C>T mutation in the methylenetetrahydrofolate reductase gene in Asian Indians. Clin Genet 61(2):155–159

    Article  CAS  PubMed  Google Scholar 

  31. Leibovitch I, Kurtz S, Shemesh G, Goldstein M, Sela BA, Lazar M, Loewenstein A (2003) Hyperhomocystinemia in pseudoexfoliation glaucoma. J Glaucoma 12(1):36–39

    Article  PubMed  Google Scholar 

  32. Vessani RM, Ritch R, Liebmann JM, Jofe M (2003) Plasma homocysteine is elevated in patients with exfoliation syndrome. Am J Ophthalmol 136(1):41–46

    Article  CAS  PubMed  Google Scholar 

  33. Bleich S, Roedl J, Von Ahsen N, Schlötzer-Schrehardt U, Reulbach U, Beck G, Jünemann AG (2004) Elevated homocysteine levels in aqueous humor of patients with pseudoexfoliation glaucoma. Am J Ophthalmol 138(1):162–164

    Article  CAS  PubMed  Google Scholar 

  34. Puustjärvi T, Blomster H, Kontkanen M, Punnonen K, Teräsvirta M (2004) Plasma and aqueous humour levels of homocysteine in exfoliation syndrome. Graefe’s Arch Clin Exp Ophthalmol 242(9):749–754

    Article  Google Scholar 

  35. Altintaş Ö, Maral H, Yüksel N, Karabaş VL, Dillioğlugil MÖ, Çağlar Y (2005) Homocysteine and nitric oxide levels in plasma of patients with pseudoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open-angle glaucoma. Graefe’s Arch Clin Exp Ophthalmol 243(7):677–683

    Article  Google Scholar 

  36. Cumurcu T, Sahin S, Aydin E (2006) Serum homocysteine, vitamin B 12 and folic acid levels in different types of glaucoma. BMC Ophthalmol 6(1):1

    Article  Google Scholar 

  37. Saricaoglu S, Karakurt A, Sengun A, Hasiripi H (2006) Plasma homocysteine levels and vitamin B status in patients with pseudoexfoliation syndrome. Saudi Med J 27(6):833–837

    PubMed  Google Scholar 

  38. Turgut B, Kaya M, Arslan S, Demir T, Güler M, Kaya MK (2010) Levels of circulating homocysteine, vitamin B6, vitamin B12, and folate in different types of open-angle glaucoma. Clin Interv Aging 5:133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Türkcü FM, Köz OG, Yarangümeli A, Oner V, Kural G (2012) Plasma homocysteine, folic acid, and vitamin B12 levels in patients with pseudoexfoliation syndrome, pseudoexfoliation glaucoma, and normotensive glaucoma. Medicina (Kaunas, Lithuania) 49(5):214–218

    Google Scholar 

  40. Yaghoubi G, Heydari B, Raza MM, Zohre B (2007) Homocysteine levels in plasma of cataract patients with and without pseudoexfoliation syndrome. Middle East Afr J Ophthalmol 14(1):22

    Google Scholar 

  41. Vardhan A et al (2016) Serum homocysteine levels in Indian patients with ocular pseudoexfoliation. US-ARVO abstract, poster no: 1988-B0068

  42. Bleich S, Jünemann A, Von Ahsen N, Lausen B, Ritter K, Beck G, Kornhuber J (2002) Homocysteine and risk of open-angle glaucoma. J Neural Transm 109(12):1499–1504

    Article  CAS  PubMed  Google Scholar 

  43. Jünemann AG, von Ahsen N, Reulbach U, Roedl J, Bönsch D, Kornhuber J, Bleich S (2005) C.665C>T variant in the methylentetrahydrofolate reductase gene is a genetic risk factor for primary open-angle glaucoma. Am J Ophthalmol 139(4):721–723

    Article  PubMed  Google Scholar 

  44. Turaçli ME, Tekeli O, Özdemir F, Akar N (2005) Methylenetetrahydrofolate reductase 677 C–T and homocysteine levels in Turkish patients with pseudoexfoliation. Clin Exp Ophthalmol 33(5):505–508

    Article  PubMed  Google Scholar 

  45. Mossbock G, Weger M, Faschinger C, Steinbrugger I, Temmel W, Schmut O, Stanger O (2006) Methylenetetrahydrofolatereductase (MTHFR) 677C>T polymorphism and open angle glaucoma. Mol Vis 12:356–359

    CAS  PubMed  Google Scholar 

  46. Roedl JB, Bleich S, Reulbach U, Rejdak R, Naumann GOH, Kruse FE, Jünemann AGM (2007) Vitamin deficiency and hyperhomocysteinemia in pseudoexfoliation glaucoma. J Neural Transm 114(5):571–575

    Article  CAS  PubMed  Google Scholar 

  47. DelBono E, Haines JL, Fan B, Chen TCC, Grosskreutz CL, Pasquale L, Wiggs JL (2008) Lack of association of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma

  48. Talebnejad MR, Mosallaei M, Azarpira N (2009) Methylenetetrahydrofolate reductase gene polymorphism and homocysteine level in patients with pseudoexfoliation and pseudoexfoliation glaucoma in southern Iran. Iran Red Crescent Med J 11(4):445

    Google Scholar 

  49. Nilforoushan N, Aghapour S, Raoofian R, Rad SS, Greene WK, Fakhraie G, Heidari M (2012) Lack of association between the C.665C>T single nucleotide polymorphism of the MTHFR gene and glaucoma in Iranian patients. Acta Med Iran 50(3):208

    CAS  PubMed  Google Scholar 

  50. Clement CI, Goldberg I, Healey PR, Graham SL (2009) Plasma homocysteine, MTHFR gene mutation, and open-angle glaucoma. J Glaucoma 18(1):73–78

    Article  PubMed  Google Scholar 

  51. Woo SJ, Kim JY, Kim DM, Park SS, Ko HS, Yoo T (2009) Investigation of the association between 677C>T and 1298A>C 5, 10-methylenetetra-hydrofolate reductase gene polymorphisms and normal-tension glaucoma. Eye 23(1):17–24

    Article  CAS  PubMed  Google Scholar 

  52. Xu F, Zhang L, Li M (2012) Plasma homocysteine, serum folic acid, serum vitamin B12, serum vitamin B6, MTHFR and risk of pseudoexfoliation glaucoma: a meta-analysis. Graefe’s Arch Clin Exp Ophthalmol 250(7):1067–1074

    Article  CAS  Google Scholar 

  53. Zacharaki F, Hadjigeorgiou GM, Koliakos GG, Morrison MA, Tsezou A, Chatzoulis DZ, DeAngelis MM (2014) Plasma homocysteine and genetic variants of homocysteine metabolism enzymes in patients from Central Greece with primary open-angle glaucoma and pseudoexfoliation glaucoma. Clin Ophthalmol (Auckland NZ) 8:1819

    Article  CAS  Google Scholar 

  54. Cardon LR, Bell JI (2001) Association study designs for complex diseases. Nat Rev Genet 2(2):91–99

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all the patients for their kind cooperation in this study. We like to express our gratitude to Mr. Vijayakumar, Biostatistician, Aravind Eye Hospital for his assistance on statistical analysis. We also thank Mr. Saravanan, Senior Technician and lab coordinators: Mrs. Kalarani, Mrs. Muthuselvi for their kind help during genotyping experiment and sample collection, respectively.

Author information

Authors and Affiliations

  1. Department of Genetics, Aravind Medical Research Foundation, Dr G. Venkataswamy Eye Research Institute, Anna Nagar 1, Madurai, Tamil Nadu, 625020, India

    Prakadeeswari Gopalakrishnan & Periasamy Sundaresan

  2. Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, India

    Aravind Haripriya

Authors
  1. Prakadeeswari Gopalakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aravind Haripriya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Periasamy Sundaresan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Periasamy Sundaresan.

Ethics declarations

Conflict of interest

The authors declare no financial or proprietary interest in any of the methods or materials discussed in this manuscript.

Ethical approval

All the procedures performed in this study involving human participants were in accordance with the ethical standards of the Institutionary Ethics Committee of Aravind Eye Hospital and with 1964 Helsinki Declaration and its amendments or comparable ethical standards.

Funding

This study was financially supported by the Alcon APEX-Aravind Eye Hospital project.

Informed consent

Written informed consent was obtained from all the individual participants included in this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gopalakrishnan, P., Haripriya, A. & Sundaresan, P. MTHFR and MTHFD1 gene polymorphisms are not associated with pseudoexfoliation syndrome in South Indian population. Int Ophthalmol 38, 599–606 (2018). https://doi.org/10.1007/s10792-017-0498-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-017-0498-2

Keywords

Search

Navigation