Kaswal M, Jeyyab M. A, Alzubi K, Alsarireh F, Fouad H, Mahgoub S. Association between Methylenetetrahydofolate Reductase C677T Polymorphisms, Plasma Homocysteine Levels, and Primary Open-Angle Glaucoma in Jordanian Patients. Biomed Pharmacol J 2025;18(4).

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Manuscript received on :18-09-2025
Manuscript accepted on :10-11-2025
Published online on: 20-11-2025

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Reviewed by: Dr. Sathyanarayana Namani and Dr. Karthikeyan Thangavelu
Second Review by: Dr. Dharakumari Patel
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Mahmoud Kaswal¹, Mohammad Abu-Jeyyab², Khalid Alzubi³, Fawaz Alsarireh⁴, Hala Fouad⁵ and Samir Mahgoub^6*

¹Hematology-Oncology Department, ST Bartholomew Hospital, Barts Health NHS Trust, London, UK,  

²Anesthesia and Intensive Care Department, Istishari hospital, Amman, Jordan.

³Special Surgeries Department, Faculty of Medicine, Mutah University, Al-Karak, Jordan.  

⁴Ophthalmology Department, AlQassim Hospital, AlQassim Saudi Arabia.  

⁵Department of Anatomy, Histology and Embryology, Faculty of Medicine, Mutah University, Al-Karak, Jordan.

⁶Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan.

Corresponding Author E-mail:samir_mhgb@yahoo.com

DOI : https://dx.doi.org/10.13005/bpj/3315

Abstract

Primary open-angle glaucoma (POAG) is a chronic, progressive optic neuropathy, recognized as the second most common cause of irreversible blindness globally. It is marked by the gradual degeneration of retinal ganglion cells, leading to optic nerve head cupping, optic disc excavation, and progressive visual field loss.The study aimedto investigate the relationship between POAG, methylenetetrahydofolate reductase (MTHFR) C677T polymorphism, and levels of plasma homocysteine,a well-known vascular risk factoramongstPOAG Jordanian patients.This case-control study included 183 participants: 89 POAG patients and 94 non-glaucomatous controls. In total, blood samples from allparticipants were analyzed for assessing plasma homocysteine levels and MTHFR C677T polymorphisms. Homocysteine levels were measured using ELISA, while the MTHFR C677T polymorphismswere identified through polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) analysis.Ourfindingsrevealed thatplasma homocysteine levels and hyperhomocysteinemia rate were significantly higher in POAG patients versus the controls (p<0.05). In contrast, no significant differences were identified in allelic frequency and MTHFR C677T polymorphismsdistribution between POAG patients and controls.Elevated homocysteine levels and a higher hyperhomocysteinemia prevalence have been observed in POAG patients, suggesting a potential role in the disease’s pathogenesis. Furthermore, a statistically significant association and increased risk linked to the CT and TT polymorphisms, as well as T allele, indicate that MTHFR C677T polymorphisms may contribute to POAG development in the Jordanian population.

Keywords

Alleles; Homocysteine; MTHFR C677T; Polymorphisms; POAG

Introduction

Glaucoma is an irreversible optic neuropathy that can cause permanent loss of the visual field.¹In 2010, an estimated 4.5 million and 3.9 million individuals with POAG and primary angle-closure glaucoma (PACG), were bilaterally blind,furthermoreby the year 2020, these figures had increased to 5.9 million and 5.3 million, respectively.^2-4

Higher intraocular pressure (IOP) is widely recognized as the most significant modifiable risk factorfor glaucoma onset and itsprogress,⁵particularly POAG. Among patients with primary glaucoma, IOP typically peaks in the morning and gradually decreases through the day in non-clinical settings.⁶

Primary glaucoma is broadly categorized into two main types: POAG,the most common oneand PACG.²The main risk factors for primary open-angle glaucoma (POAG) are elevated intraocular pressure (commonly above 21 mmHg), a thin central corneal thickness (under 500 μm), a family history of the disease, black ethnicity, and high levels of myopia..⁷

Various genetic studies have revealed genetic polymorphismsofdifferent genes withuncertain effects that are linkedtoPOAG includingC677T polymorphisms ofMTHFR gene,⁸some variants of genes encoding formembrane palmitoylated protein ⁷ (MPP7), tumor protein p53,⁹ GRIN2B gene 421C/A, Arg72Pro,¹⁰ and soluble guanylate cyclase sGCα1.¹¹

MTHFR enzyme plays vital role in regulating folate,homocysteine (HCY) and methionine metabolism and in maintaining normal plasma HCY levels.¹² HCY is a key intermediate in the metabolism of methionine and cysteine, it is generated through the hydrolysis of S-adenosylhomocysteine in the cycle of methionine.MTHFR catalyzes 5,10- methylenetetrahydofolate reduction to 5 methylenetetrahydrofolate which is the main circulating form of folate and the donor of methyl groups forremethylatingHCY to methionine inareaction catalyzed by a B12-dependent methionine synthaseenzyme.¹³

A 677C/T mutation atposition222inexon 4 of MTHFR gene results in convertingalanine to valine codon. Asa consequence of this mutation, MTHFR enzymatic activityisreducedcomparable to the wild type (CC) enzyme¹⁴and the enzyme’s thermolabilityincreases, ¹⁵ thus, mutations ofMTHFR gene are associated with higher levels of HCY.¹⁶

Elevated plasma levels of HCY have been observed in glaucoma patients.¹⁷HCY has been implicated in vascular injury¹⁸alterations of the extracellular matrix,¹⁹ and neuronal cell death due toexcitotoxicity and apoptosis,²⁰also, hyperhomocysteinemia has also been associated with structural remodeling of connective tissues²¹ and various neurodegenerative disorders.²²

The aim of this study was to examine the potential link between MTHFR C677T polymorphisms and plasma HCY levels in individuals with POAG, with the objective of enhancing our understanding of the disease’s underlying pathogenic mechanisms. 

Materials and Methods

183 subjects participated in this study, amongthem 89 POAG patients and 94 non-glaucomatous individuals who served as the control group. All participants were recruited from the Outpatient Clinics of Special Surgeries Department /Ophthalmology Division at Al-Karak Governmental Hospital, Al-Karak, Jordan. The exclusion criteriafrom the study includedpatientswho had any ocular diseases other than glaucoma that could elevate IOP, or if they had cancer, diabetes mellitus, and chronic kidney disease, or patients who received immunosuppressants, antimicrobials, hormonal therapies, lipid-lowering drugs, vitamin supplements, anticonvulsants and antidepressants treatment within six months prior to the study. All participants (both patients and controls) weresubjectedto complete ophthalmic examination, includingtesting of visual acuity with the Humphrey 24-2 protocol, slit-lamp biomicroscopy, measurement ofIOP using a Goldmann applanation tonometer, assessment ofcentral corneal thickness via pachymetry, gonioscopy with a Goldmann 3-mirror lens, optic nerve imaging byOCT (optical coherence tomography).Patients were diagnosed with POAG based on optic nerve damage confirmed by OCT, along with an elevated IOP greater than 21 mmHg, and an open anterior chamber angle on gonioscopy according to Shaffer angle grading. The POAG group included 89 patients (51 males and 38 females), aged between40and74 years, with mean±SD 58.73 ± 9.47 years. Control group consisted of individuals with healthy-appearing optic discs, IOP below 21 mmHg, a cup-to-disc ratio less than 0.4, and normal visual field assessments in both eyes. None of the controls had a history of using IOP-lowering medications or a family history of glaucoma, the group included 94 participants (55 males and 39 females), with ages between 42 and 76 years with mean±SD 59.26 ± 10.39 years.

Biochemical Analyses

Plasma HCY assay

12 hours fasting blood sample was collected from eachparticipant inthe studyin EDTA-treated tubes for plasma HCYestimation,then,immediately centrifuged at 4°C, plasma fraction was withdrawnforstorage at –20°C until further analysis while,cellular portion was preserved for extraction ofDNA.

Plasma HCY levels were measured using ELISA, according to the method adopted by Engvall et al.²³. Hyperhomocysteinemia was defined as a HCY concentration exceeding 15 μmol/L.²⁴ 

MTHFR polymorphisms analysis

Basedon Lahiri and Nurnberger,²⁵ method,genomic DNA was extracted from leukocytes,then,MTHFR C677T polymorphisms in the gene wereanalyzed using PCR-RFLP technique, as reported in a previous study.²⁶ The sequences oftheprimers used for amplification ofa 198 bp fragment of the targeted DNA were: Forward: 5’-TGA AGG AGA AGG TGT CTG CGG GA-3’ Reverse: 5’-AGG ACG GTG CGG TGA GAG TG-3’.

PCR was initiated with denaturation at 94°C for 2 minutes, followed by 35 cycles of denaturation at 94°C for 30 seconds, annealing at 62°C for 30 seconds, and extension at 72°C for 30 seconds. A final extension was performed at 72°C for 7 minutes.

5 units of HinfI enzyme wereusedfordigestingPCR products for 12 hours at 37°C. Electrophoresis was performed on a 2% agarose gel. The digestion yielded a single 198 bp band for CC polymorphism (wild-type), two bands of 175 bp and 23 bp for CTpolymorphism(the heterozygous-type), and a 175 bp and 23 bp for TT polymorphism(homozygous mutant). The 23 bp fragment cannotbeseenbecause of itstoo small size. 

Statistical analysis

SPSS software package version 25.0was used for dataanalysiswhich were presented as mean±SD, while, variables in categorieswere expressed as percentages,student’s t-test wasappliedforthe assessmentof thedifferences between continuous variables,whereas Chi-square (χ²) test wasused to evaluate the differences between categorical variables and totest Hardy-Weinberg equilibrium by comparingthe observed and expected polymorphisms frequencies. A p-value less than 0.05 was regarded as statistically significant. 

Results

Table 1 shows insignificant differences between POAG patients and controls in terms of age, hypertension, diabetes mellitus, or cardiovascular disorders. However, the differences in plasma HCY levels and hyperhomocysteinemia rates were significant. 

Table 1: Thebiologicaland clinical characteristics of participants in POAG and control groups

* P >0.05 is insignificant versus the controls

** P <0.05 is significant when compared to the controls

Table 2 presents C677T polymorphisms’distribution and frequencies of alleles in POAG patients and controls. Among POAG patients, the polymorphisms distribution was 48.8% CC, 31.5% CT, and 19.7% TT. In the control group, the distribution was 57.9% CC, 26.3% CT, and 15.8% TT. Also, the results revealed significant association and positive risk ratio between CT, TT polymorphisms and T allele in POAG patients (OR=1.38, 95%CI=0.98-1.95), (OR=1.21, 95%CI=0.87-1.88) (OR=1.53, 95%CI=0.97-2.49), respectively, while, no significant risk ratio regarding CC polymorphism and C allele was detected. 

Table 2: Distribution of polymorphisms ofMTHFR C677T and allelic frequencies in POAG patientsand control groups

^*χ² test

^**CC (Cytosine-Cytosine), TT (Thymine-Thymine), CT (Cytosine-Thymine), C (Cytosine), T (Thymine). 

Discussion

Glaucoma represents a group of chronic eye disorders distinguished by the progressive loss of retinal ganglion cells (RGCs), thinning of the retinal nerve fiber layer, and a gradual decline in visual field. Among these conditions, POAG is the most common type and has been the focus of extensive research.The etiology of POAG is complex and multifactorial, encompassing interactions between environmental influences and significant genetic predisposition. Family linkage analyses have revealed at least 17 genetic loci associated with the disease. Within this framework, MTHFR gene emerges as a compelling candidate due to its critical function in one-carbon metabolism and its regulatory role in maintaining HCY levels.^{9,  27}

Our findings demonstrated that plasma homocysteine (HCY) levels were significantly elevated in Jordanian patients with primary open-angle glaucoma (POAG) compared to healthy controls. This observation suggests a potential association between hyperhomocysteinemia and POAG, indicating that elevated HCY may contribute to the disease’s pathogenesis. Consistent with this hypothesis, Leibovitch et al. ²⁸ reported a higher prevalence of hyperhomocysteinemia and increased mean plasma HCY levels in glaucoma patients, accompanied by vascular abnormalities that may play a role in disease progression. Similarly, Bleich et al. ²⁹ observed a twofold increase in HCY concentrations in the aqueous humor of glaucoma patients, suggesting a possible intraocular contribution of HCY to the disease mechanism. Moreover, Roedl et al. ³⁰ found elevated HCY levels in tear fluid, providing additional evidence of its pathogenic involvement. Collectively, these observations strengthen the hypothesis that HCY may act as a biochemical mediator in glaucomatous optic nerve damage.Nonetheless, previous studies have yielded divergent outcomes. Wang et al.³¹ observed no significant difference in plasma HCY levels between patients with POAG and healthy controls. Likewise, Tongabay et al.³² found elevated HCY concentrations only in individuals with pseudoexfoliation glaucoma (PEXG), but not in those with POAG. Consistently, Turaçli et al.³³ also reported no significant variation in HCY levels between PEXG patients and control subjects, despite a high overall prevalence of hyperhomocysteinemia in both groups.

These discrepancies may be attributed to methodological variations, differences in study design, limited sample sizes, or the influence of ethnic and dietary factors. Specifically, variations in dietary intake of folate and B vitamins key regulators of HCY metabolism as well as differences in the analytical methods used to measure plasma HCY levels, could account for population-specific differences observed across studies.

Our study revealed no significant differences in the MTHFR C677T polymorphism between POAG patients and controls, in terms of both polymorphisms and allele frequencies. The distributions of CT and TT polymorphisms, as well as the C and T alleles, were nearly identical across the two groups. Consistently, odds ratio analysis showed no significant association between this polymorphism and the risk of developing POAG.

These findings align with several previous studies. George et al.³⁴ reported no significant association between MTHFR C677T polymorphisms and either POAG or pseudoexfoliation glaucoma. Similarly, Mabuchi et al.³⁵ observed no differences in polymorphism frequencies between patients and controls. A study conducted in a Pakistani population³⁶ also found no significant link between MTHFR C677T polymorphisms and POAG; however, they did report a significant association between the TT genotype and primary closed-angle glaucoma (PCAG), suggesting that the influence of this polymorphism may vary depending on the glaucoma subtype.

Our results indicate that MTHFR C677T polymorphisms modulate HCY levels; however, they do not appear to be a significant risk factor for POAG in our population. It is likely that the pathogenic role of hyperhomocysteinemia in POAG arises from a complex interplay of genetic predisposition, environmental factors, and nutritional status, rather than a single genetic mutation.

In our Jordanian cohort, the T allele frequency of the MTHFR C677T polymorphism was 18% among POAG patients. By comparison, previous studies have reported frequencies of 24% in Brazilians, 9% in West Africans, 55% in Mainland Chinese, and 33% in Turks³⁷^–⁴⁰, highlighting significant global variation. These differences may affect statistical power and influence the strength of genetic associations reported across populations.

Moreover, other polymorphisms within the MTHFR gene or in genes involved in the HCY metabolic pathway such as MTR, MTRR, or CBS may exert a greater influence in our population, potentially through gene-gene or gene-environment interactions. 

Conclusion

This study demonstrates significantly elevated HCY levels and higher rates of hyperhomocysteinemia in Jordanian POAG patients compared to controls, suggesting a contributory role in disease pathogenesis.MTHFR C677T polymorphisms distribution and C allele frequency were higher among individuals with the homozygous CC polymorphisms compared to those with CT or TT polymorphisms and T allele. Furthermore, the results indicate that elevated HCY levels rather than MTHFR polymorphisms are associated with the severity of POAG. This suggests that MTHFR C677T polymorphisms are unlikely to be a significant independent risk factor for POAG. Clinically, this suggests that elevated HCY levels regardless of genetic background warrant further investigation be carried out on a larger number of populations as a potentially modifiable biochemical risk factor in glaucoma management.

Acknowledgement

The authors would like to thank all staff members in the Special Surgeries Department /Ophthalmology Division, Faculty of Medicine, Mutah University and all participants in the study.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The author(s) do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Clinical Trial Registration

This research does not involve any clinical trials

Permission to reproduce material from other sources

Not Applicable

Author contributions

Mahmoud Kaswal: Conceptualization, visualization,

Mohammad Abu-Jeyyab: Data collection, analysis,

Khalid Alzubi: Supervision, methodology, editing,

Fawaz Alsarireh: Supervision, methodology, editing,

Hala Fouad: Project administration, supervision,

Samir Mahgoub: Project administration, methodology, writing – original draft, writing – review & editing 

References

1. The Japanese Archive of Multicentral Database in Glaucoma (JAMDIG) construction group. A novel method to predict visual field progression more accurately, using intraocular pressure measurements in glaucoma patients. Sci. Rep.  2016, 6,31728-31735.https://doi.org/10.1038/srep31728
   CrossRef
2. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 2006, 90, 262-267.DOI: 10.1136/bjo.2005.081224
   CrossRef
3. Friedman DS, Foster PJ, Aung T, He M. Angle closure and angle-closure glaucoma: what we are doing now and what we will be doing in the future. Clin. Exp. Ophthalmol. 2012, 40, 381-387.doi: 10.1111/j.1442-9071.2012.02774.x
   CrossRef
4. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology2014,121, 2081-2090.doi: 10.1016/j.ophtha.2014.05.013.
   CrossRef
5. The Japan Glaucoma Society guidelines for glaucoma (3rd edition). Nippon GankaGakkaiZasshi 2012, 116 (1), 3–46.PMID: 22352070
6. Shaoying T, Nafees B, Linda H, et al. Comparison of self-measured diurnal intraocular pressure profiles using rebound tonometry between primary angle closure glaucoma and primary open angle glaucoma patients. PLoS ONE 2017,12(3),  e0173905.doi: 10.1371/journal.pone.0173905
   CrossRef
   
7. Janssen SF, Gorgels TG, Ramdas WD, et al. The vast complexity of primary open angle glaucoma: disease genes, risks, molecular mechanisms and pathobiology. ProgRetin Eye Res. 2013, 37, 31–67.doi: 10.1016/j.preteyeres.2013.09.001.
   CrossRef
8. Al-Shahrani H, Al-Dabbagh N, Al-Dohayan N, et al. Association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with primary glaucoma in Saudi population. BMC Ophthalmol. 2016, 16(1),  156.doi: 10.1186/s12886-016-0337-7
   CrossRef
   
9. Mansi V, Anchal S, Lalit K, et al. Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma. BMC Medical Genomics 2016, 9, 15.doi: 10.1186/s12920-016-0177-6.
   CrossRef
10. Alicja N, Karolina P, Katarzyna S, Jerzy S, Jacek PS, Ireneusz M. The relationship of TP53 and GRIN2B gene polymorphisms with risk of occurrence and progression of primary open-angle glaucoma in a Polish Population. Pol J Pathol. 2014, 65 (4), 313-321.DOI:10.5114/pjp.2014.48193
    CrossRef
11. Buys ES, Ko YC, Alt C, et al.  Soluble guanylate cyclase α1-deficient mice: a novel murine model for primaryopen angle glaucoma.PloS One 2013, 8(3), e60156.doi: 10.1371/journal.pone.0060156
    CrossRef
12. Wilson CP, Mcnulty H, Scott JM, Strain JJ, Ward M.  Postgraduate symposium: the MTHFR C677T polymorphism, B-vitamins and blood pressure. ProcNutrSoc.2010, 69,156–165. DOI: 10.1017/S0029665109991728
    CrossRef
13. Huang T, Wahlqvist ML, Li D. Effect of n-3 polyunsaturated fatty acid on gene expression of the critical enzymes involved in homocysteine metabolism. Nutr J.2012, 11, 6.doi: 10.1186/1475-2891-11-6
    CrossRef
14. TaioliE, Garza MA, Ahn YO, et al. Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review. Am J Epidemiol.2009, 170, 1207–1221.doi: 10.1093/aje/kwp275.
    CrossRef
15. Zonouzi AP, ChaparzadehN, Estiar AM,et al. Methylene tetrahydrofolate reductase C677T and A1298C mutations in women with recurrent spontaneous abortions in the Northwest of Iran. ISRN ObstetGynecol. 2012, 2012, 945486. doi: 10.5402/2012/945486.
    CrossRef
    
16. Xu H, Liu C, Wang Q. Plaque image characteristics, hyperhomocysteinemia, and gene polymorphism of homocysteine metabolism-related enzyme (MTHFR C677T) in acute coronary syndrome. Cell BiochemBiophys.2013, 66, 403–407.doi: 10.1007/s12013-012-9483-6
    CrossRef
    
17. Bleich S, Junemann A, von Ahsen N, et al. Homocysteine and risk of open-angle glaucoma. J Neural Transm. 2002, 109, 1499-504.doi: 10.1007/s007020200097
    CrossRef
    
18. McCully KS. Chemical pathology of homocysteine. I.Atherogenesis. Ann Clin Lab Sci. 1993, 23, 477-93.PMID: 8291902
19. Tyagi SC. Homocysteine redox receptor and regulation of extracellular matrix components in vascular cells. Am J Physiol. 1998, 274, C396-405. doi: 10.1152/ajpcell.1998.274.2.C396
    CrossRef
    
20. Moore P, El-sherbeny A, RoonP, Schoenlein PV, Ganapathy V, Smith SB. Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res. 2001, 73, 45-57.doi: 10.1006/exer.2001.1009
    CrossRef
    
21. Mujumdar VS, Tummalapalli CM, Aru GM, Tyagi SC. Mechanism of constrictive vascular remodeling by homocysteine: role of PPAR. Am J Physiol Cell Physiol. 2002, 282, C1009-15.doi: 10.1152/ajpcell.00353.2001
    CrossRef
    
22. Brustolin S, Giugliani R, Fe´lix TM. Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res. 2010, 43, 1–7.doi: 10.1590/s0100-879×2009007500021.
    CrossRef
    
23. Engvall E,JonssonK,PerlmannP. Enzyme- Linked Immunosorbent Assay. II. Quantitative assay of protein antigen, immunoglobulin G, by means of enzyme-labeled antigen and antibody-coated tubes. Biochim. Biophys.Acta 1971, 251, 427-434.doi: 10.1016/0005-2795(71)90132-2
    CrossRef
24. Borson-Chazot F, HartheC, Teboul F, et al.  Occurrence of Hyperhomocysteinemia 1 Year afterGastroplasty for Severe Obesity. J ClinEndocrinolMetab. 1999, 84(2), 541-5.doi: 10.1210/jcem.84.2.5476
    CrossRef
    
25. Lahiri DK, Nurnberger JI Jr. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res.1991, 19, 5444.doi: 10.1093/nar/19.19.5444
    CrossRef
    
26. Papoutsakis C, Yiannakouris N, Manios Y, et al.Plasma Homocysteine Concentrations in Greek Children Are Influenced by an Interaction between the Methylenetetrahydrofolate Reductase C677T Genotype and Folate Status. J Nutr. 2005, 135(3), 383-8. doi: 10.1093/jn/135.3.383
    CrossRef
    
27. Jünemann AG, von Ahsen N, Reulbach U, et al. C677T variant in the methylenetetrahydofolate reductase gene is a genetic risk factor for primary open-angle glaucoma. Am J Ophthalmol. 2005, 139, 721-3.doi: 10.1016/j.ajo.2004.09.081
    CrossRef
    
28. Leibovitch I, Kurtz S, Shemesh G, et al.  Hyperhomocysteinemia in pseudoexfoliation glaucoma. Journal of Glaucoma 2003, 12(1), 36-39.doi: 10.1097/00061198-200302000-00007
    CrossRef
    
29. Bleich S, Roedl J, Ahsen VN, et al. ElevatedHomocysteine levels in aqueous humor of patients with pseudoexfoliation glaucoma. American Journalof Ophthalmology 2004, 138(1), 162–164.doi: 10.1016/j.ajo.2004.02.027
    CrossRef
    
30. Roedl JB, Bleich S, Reulbach U, et al. Homocysteine in tear fluid of patients with pseudoexfoliation glaucoma. J. Glaucoma 2007, 16, 234-9. doi: 10.1097/IJG.0b013e31802d6942
    CrossRef
    
31. WangG, MedeirosFA, BarshopBA, Weinreb RN. Total plasma homocysteine and primary open-angle glaucoma. American Journal of Ophthalmology 2004, 137(3), 401-406.doi: 10.1016/j.ajo.2003.09.041
    CrossRef
    
32. Tongabay C, Semsettin S, Erdinc A. Serum homocysteine, vitamin b12 and folic acid levels in different types of glaucoma. BMC Ophthalmology 2006, 6, 6.doi: 10.1186/1471-2415-6-6
    CrossRef
    
33. Turaçli ME, Tekeli O, ÖzdemirF,Akar N. Methylenetetrahydrofolate reductase 677 C-T and homocysteine levels in Turkish patients with pseudoexfoliation. Clinical and Experimental Ophthalmology 2005, 33, 505–508.doi: 10.1111/j.1442-9071.2005.01070.x
    CrossRef
    
34. George M, Martin W, Christoph F, et al. Methylenetetrahydrofolatereductase (MTHFR) 677C>Tpolymorphismand open angle glaucoma. Molecular Vision 2006, 12, 356-9.PMID: 16636653
35. Mabuchi F, Tang S, Kashiwagi K, Yamagata Z, Iijima H, TsukaharaS.Methylenetetrahydrofolatereductase gene polymorphisms c.677c/t and c.1298a/c are not associated with open angle glaucoma. Mol Vis. 2006, 12, 735-9.PMID: 16862068
36. Shazia M, Raheel Q, Farah A, Muhammad IK, WajidAK,Asifa A. MTHFR gene c677t and a1298c polymorphisms and homocysteine levels in primary open angle and primary closed angle glaucoma. Molecular vision2009, 15, 2268-2278.PMID: 19936026
37. Franco RF, Araújo AG, Guerreiro JF, Elion J, Zago MA. Analysisof the 677 C→T mutation of the methylenetetrahydrofolate reductase gene in different ethnic groups. ThrombHaemost.1998, 79, 119-121.DOI: 10.1055/s-0037-1614230
    CrossRef
38. Sazci A, Ergul E, Kaya G, Kara I. Genotype and allele frequencies of the polymorphic methylenetetrahydofolate reductase gene in Turkey. CellBiochemFunct. 2005, 23, 51-54.doi: 10.1002/cbf.1132
    CrossRef
    
39. Angeline T, Jeyaraj N, Granito S, Tsongalis GJ. Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians. ExpMolPathol.2004, 77, 85-88. doi: 10.1016/j.yexmp.2004.04.006
    CrossRef
    
40. Mohsin Y, Naushad M, Siddiqa P, Bushra C, Iqbal A, Mohammad PI. Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population.PLoS ONE 2012, 7(3), e33222.doi: 10.1371/journal.pone.0033222
    CrossRef