Hyperhomocysteinemia induced by the C677T genetic variant in MTHFR (methylenetetrahydrofolate reductase) has been implicated in neuronal cell death of retinal ganglion cells (RGC), which is a characteristic feature of glaucoma. However, association of MTHFR C677T with glaucoma has been controversial because of inconsistent results across association studies. Association between MTHFR C677T and glaucoma has not been reported in Indian population. Therefore, with a focus on neurodegenerative death of RGC in glaucoma, the current study aimed to investigate association of MTHFR C677T with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a North Indian population. A total of 404 participants (231 patients and 173 controls) were included in this study. Genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. A few random samples were also tested by direct sequencing. Genotypic and allelic distributions of the POAG and PACG cohorts were compared to that of controls by chi-square test and odds ratios were reported with 95% confidence intervals. Genotypic and allelic distributions between POAG cases and controls were significantly different (p = 0.03 and p = 0.01 respectively). Unlike POAG, we did not find significant difference in the genotypic and allelic distributions of C677T between PACG cases and controls (p>0.05). We also observed a higher proportion of TT associated POAG in females than that in males. However, this is a preliminary indication of gender specific risk of C677T that needs to be replicated in a larger cohort of males and females. The present investigation on MTHFR C677T and glaucoma reveals that the TT genotype and T allele of this polymorphism are significant risk factors for POAG but not for PACG in North Indian population. Ours is the first report demonstrating association of MTHFR C677T with POAG but not PACG in individuals from North India.
References
[1]
Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90: 262–267. doi: 10.1136/bjo.2005.081224
[2]
Liu Y, Allingham RR (2011) Molecular genetics in glaucoma: a review. Exp Eye Res 93: 331–339. doi: 10.1016/j.exer.2011.08.007
[3]
Allingham RR, Liu Y, Rhee DJ (2009) The genetics of primary open-angle glaucoma: A review. Exp Eye Res 88: 837–844. doi: 10.1016/j.exer.2008.11.003
[4]
Allingham RR, Shields MB (2011) Shields' Textbook of Glaucoma. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Health.
[5]
Osborne NN, Wood JPM, Chidlow G, Bae JH, Melena J, et al. (1999) Ganglion cell death in glaucoma: what do we really know?. Br J Ophthalmol 83: 980–986. doi: 10.1136/bjo.83.8.980
[6]
Nickells RW (1999) Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death. Surv Ophthalmol (suppl 1): 151–161.
[7]
Garcia-Valenzuela E, Shareef S, Walsh J, Sharma SC (1995) Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res 61: 33–44. doi: 10.1016/s0014-4835(95)80056-5
[8]
Moore P, El-sherbeny A, Roon P, Schoenlein PV, Ganapathy V, et al. (2011) Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 73: 45–57. doi: 10.1006/exer.2001.1009
[9]
Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22: 195–201. doi: 10.1016/s0165-6147(00)01675-8
[10]
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, et al. (1995) A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111–113. doi: 10.1038/ng0595-111
Brustolin S, Giugliani R, Félix TM (2010) Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res 43: 1–7. doi: 10.1590/s0100-879x2010000100001
[13]
Bleich S, Junemann A, von Ahsen N, Lausen B, Ritter K, et al. (2002) Homocysteine and risk of open-angle glaucoma. J Neural Transm 109: 1499–1504. doi: 10.1007/s007020200097
[14]
Roedl JB, Bleich S, Reulbach U, Rejdak R, Naumann GO, et al. (2007) Vitamin deficiency and hyperhomocysteinemia in pseudoexfoliation glaucoma. J Neural Transm 114: 571–575. doi: 10.1007/s00702-006-0598-z
[15]
Turgut B, Kaya M, Arslan S, Demir T, Guler M, et al. (2010) Levels of circulating homocysteine, vitamin B6, vitamin B12, and folate in different types of open-angle glaucoma. Clin Inter Aging 5: 133–139. doi: 10.2147/cia.s9918
[16]
Mossbock G, Weger M, Faschinger C, Steinbrugger I, Temmel M, et al. (2006) Methylenetetrahydrofolatereductase (MTHFR) 677C>T polymorphism and open angle glaucoma. Mol Vis 12: 356–359.
[17]
Mabuchi F, Tang S, Kashiwagi K, Yamagata Z, Iijima H, et al. (2006) Methylenetetrahydrofolate reductase gene polymorphisms c.677C/T and c.1298A/C are not associated with open angle glaucoma. Mol Vis 12: 735–739.
[18]
Zetterberg M, Tasa G, Palmer SM, Jurone E, Toover E, et al. (2007) Methylenetetrahydrofolate reductase genetic polymorphisms in patients with primary open-angle glaucoma. Ophthalmic Genet 28: 47–50. doi: 10.1080/13816810701329046
[19]
Fingert JH, Kwon YH, Moore PA, Johnston RM, Kim KY, et al. (2006) The C677T variant in the methylenetetrahydrofolate reductase gene is not associated with disease in cohorts of pseudoexfoliation glaucoma and primary open-angle glaucoma patients from Iowa. Ophthalmic Genet 27: 39–41. doi: 10.1080/13816810600677883
[20]
Woo SJ, Kim JY, Kim DM, Park SS, Ko HS, et al. (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. doi: 10.1038/sj.eye.6702920
[21]
Micheal S, Qamar R, Akhtar F, Khan MI, Khan WA, et al. (2009) MTHFR gene C677T and A1298C polymorphisms and homocysteine levels in primary open angle and primary closed angle glaucoma. Mol Vis 15: 2268–2278.
[22]
Junemann AG, von Ahsen N, Reulbach U, Roedl J, Bonsch D, et al. (2005) C677T variant in the methylentetrahydrofolate reductase gene is a genetic risk factor for primary open-angle glaucoma. Am J Ophthalmol 139(4): 721–723. doi: 10.1016/j.ajo.2004.09.081
[23]
Burdon KP, Macgregor S, Hewitt AW, Sharma1 S, Chidlow G, et al (2011) Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 43(6): 574–580. doi: 10.1038/ng.824
[24]
van Koolwijk LME, Ramdas WD, Ikram MK, Jansonius NM, Pasutto F, et al. (2012) Common genetic determinants of intraocular pressure and primary open-angle glaucoma. PLoS Genet 8(5): e1002611. doi: 10.1371/journal.pgen.1002611
[25]
Takamoto M, Kaburaki T, Mabuchi A, Araie M, Amano S, et al. (2012) Common variants on chromosome 9p21 are associated with normal tension glaucoma. PLoS ONE 7(7): e40107. doi: 10.1371/journal.pone.0040107
[26]
Nakano M, Ikeda Y, Tokuda Y, Fuwa M, Omi N, et al. (2012) Common variants in CDKN2B-AS1 associated with optic-nerve vulnerability of glaucoma identified by genome-wide association studies in Japanese. PLoS ONE 7(3): e33389. doi: 10.1371/journal.pone.0033389
[27]
Gibson J, Griffiths H, Salvo GD, Cole M, Jacob A, et al. (2012) Genome-wide association study of primary open angle glaucoma risk and quantitative traits. Mol Vis 18: 1083–1092.
[28]
Shannon B, Gnanasampanthan S, Beilby J, Iacopetta B (2002) A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability. Gut 50: 520–524. doi: 10.1136/gut.50.4.520
[29]
Sukla KK, Raman R (2011) Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population. Eur J Clin Nutri 1–8.
[30]
Ali A, Singh SK, Raman R (2009) MTHFR 677TT alone and IRF6 820GG together with MTHFR 677CT, but not MTHFR A1298C, are risks for nonsyndromic cleft lip with or without cleft palate in an Indian population. Gene Test Mol Biomarkers 13: 1–6. doi: 10.1089/gtmb.2008.0115
[31]
Singh K, Singh SK, Sah R, Singh I, Raman R (2005) Mutation C677T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population. Inter J Andro 28: 115–119. doi: 10.1111/j.1365-2605.2004.00513.x
[32]
Indian Genome Variation Consortium (2008) Genetic landscape of the people of India: a canvas for disease gene exploration. J Genet 87: 3–20. doi: 10.1007/s12041-008-0002-x
[33]
Huo Y, Zou H, Lang M, Ji S, Yin X, et al. (2012) Association between MTHFR C677T polymorphism and primary open-angle glaucoma: A meta-analysis. Gene 512: 179–184. doi: 10.1016/j.gene.2012.10.067
[34]
McLean E, Benoist B, Allen LH (2008) Review of the magnitude of folate and vitamin B12 deficiencies worldwide. Food Nutr Bull (Suppl 2): 38–51.
[35]
Elmadfa I, Singer I (2009) Vitamin B-12 and homocysteine status among vegetarians: a global perspective. Am J Clin Nutr 89(suppl): 1693–1698. doi: 10.3945/ajcn.2009.26736y
[36]
Rai AK, Singh S, Mehta S, Kumar A, Pandey LK, et al. (2006) MTHFR C677T and A1298C are risk factors for Down's syndrome in Indian mothers. J Hum Genet 51: 278–283. doi: 10.1007/s10038-005-0356-3
[37]
Nair RR, Khanna A, Singh K (2012) MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reprod Sci 19(2): 210–215. doi: 10.1177/1933719111417888
[38]
Gueant-Rodriguez RM, Gueant JL, Debard R, Thirion S, Hong LX, et al. (2006) Prevalence of methylentetrahydrofolate reductase 677T and 1298C alleles and folate status: a compatative study in Mexican, West African and European populations. Am J Clin Nutr 83: 701–707.
[39]
Rosenberg N, Murata M, Ikeda Y, Opare-Sem O, Zivelin A, et al. (2002) The Frequent 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphism is associated with a common haplotype in whites, Japanese and Africans. Am J Hum Genet 70: 758–762. doi: 10.1086/338932
[40]
Zee RY, Mora S, Cheng S, Erlich HA, Lindpaintner K, et al. (2007) Homocysteine, 5,10-Methylenetetrahydrofolate Reductase C677T polymorphism, nutrient intake and incidence of cardiovascular disease in 24968 Initially Healthy Woman. Clin Chem 53: 845–851. doi: 10.1373/clinchem.2006.083881
