MTHFR C677T Predisposes to POAG but Not to PACG in a North Indian Population: A Case Control Study

Abstract

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.

Association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with primary glaucoma in Saudi population

“…Similar to our findings, no association of MTHFR C677T polymorphism has been found with the susceptibility to PACG in Nepalese and Australian [31], and Indian [15]. Contrary to these findings one report from Pakistan indicates that the MTHFR C677T polymorphism is associated with PACG.…”

“…The prevalence of MTHFR C677T polymorphism has been reported to be high in POAG patients [4, 14, 15]. However, earlier reports on the association between MTHFR C677T polymorphism and glaucoma risk are inconclusive and conflicting [6, 7, 16–20].…”

The genetic mechanisms of primary angle closure glaucoma

“…Rather this study found that this variant is associated with POAG. 84 This may suggest that the pathogenic effect of MTHFR mutations is primarily related to homocysteine toxicity leading to RGC loss, which is a characteristic feature of all types of glaucoma.…”

Association of MTHFR C677T and A1298C Polymorphisms with Glaucoma Risk: a Systematic Review Meta-Analysis based 42 Case-Control Studies

“…Among the remaining studies, 84 articles were excluded because they were review articles, letters to editors, previous meta-analyses, not relevant to MTHFR C677T and A1298C, not casecontrol studies, evaluated other diseases instead of glaucoma, case reports, and other polymorphisms of MTHFR gene. Finally, a total of 42 case-control studies including 33 studies (in 19 publications) with 3,504 cases and 2,525 controls for MTHFR C677T [9][10][11][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and nine studies (in six publications) with 1,073 cases and 775 controls for A1298C [11,[19][20][21]23,29] were selected. The main characteristics of studies included in the current meta-analysis are presented in Tables 1 and 2.…”