Abstract
Homocysteine (Hcy) is a potential risk factor for age-related cataract (ARC). Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for Hcy metabolism, and variants of MTHFR may affect MTHFR enzyme activity. This study mainly evaluated the associations between variants in MTHFR gene, plasma MTHFR enzyme activity, total Hcy (tHcy) levels and ARC risk in Chinese population. Four single nucleotide polymorphisms (SNPs) in MTHFR gene were genotyped using the high-resolution melting (HRM) method in 502 ARC patients (mean age, 70.2 [SD, 9.0], 46.0% male) and 890 healthy controls (mean age, 67.1 [SD, 11.1], 47.6% male). The plasma MTHFR activity, folic acid (FA), vitamins B12 and B6 levels were detected by enzyme-linked immunosorbent assays (ELISA). The plasma tHcy levels were measured by an automated enzymatic assay. After the Bonferroni correction, the minor allele T of SNP rs1801133 showed a significant association with an increased risk of overall ARC (OR = 1.26, P = 0.003). Consistent association was also found between SNP rs1801133 and cortical ARC risk (OR = 1.44, P = 0.003). Haplotype analyses revealed an adverse effect of the haplotype "C-A-T-C" (alleles in order of SNPs rs3737967, rs1801131, rs1801133 and rs9651118) on ARC risk (OR = 1.55, P = 0.003). Moreover, in a joint analysis of SNPs rs9651118 and rs1801133, subjects with two unfavorable genotypes had a 1.76-fold increased risk of ARC compared with the reference group, and a statistically significant dose-response trend (Ptrend = 0.001) was also observed. Further, in healthy controls and patients with cortical ARC, the allele T of SNP rs1801133 and the increasing number of unfavorable genotypes were significantly correlated with decreased MTHFR activity as well as increased tHcy levels. However, there was no significant association between FA, vitamins B12, B6 levels and MTHFR variants. Our data indicated that variants in MTHFR gene might individually and jointly influence susceptibility to ARC by affecting MTHFR enzyme activity and tHcy levels.
Highlights
Cataract is the leading cause of visual impairment and blindness [1], affecting about 16 million people worldwide [2]
In genetic association analyses adjusted for covariates, significantly increased risks of age-related cataract (ARC) were found for single nucleotide polymorphisms (SNPs) rs1801133 under both additive (OR = 1.25, 95%CI = 1.07–1.47, P = 0.006) and dominant models (OR = 1.44, 95%CI = 1.12– 1.85, P = 0.004), and for SNP rs9651118 (OR = 1.32, 95%CI = 1.04–1.67, P = 0.020) assuming a dominant model
Results from analyses of covariance (ANCOVA) (Fig 1 and Table 7) models indicated that the minor allele T of SNP rs1801133 was significantly associated with decreased Methylenetetrahydrofolate reductase (MTHFR) activity and increased total Hcy (tHcy) levels under both additive and dominant models in healthy controls and patients with cortical ARC
Summary
Cataract is the leading cause of visual impairment and blindness [1], affecting about 16 million people worldwide [2]. An increase in ROS can lead to DNA damage and formation of urea-insoluble proteins in the lens epithelium, and these processes are involved in cataract formation [4, 5]. Molecular studies have demonstrated that raised Hcy induced apoptosis by increasing ROS generation through activation of p38 MAPK [8], and down-regulating antioxidant enzymes such as heme oxygenase-1 and glutathione peroxidase [9, 10]. Elevated plasma total Hcy (tHcy) levels were found to be associated with increased risk of ARC in two clinical studies [11, 12]. It has been reported that two variants (rs1801133 and rs1801131) in MTHFR gene might lead to a change of enzyme activity, which influenced the levels of tHcy [14, 15]
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