Associations of Polymorphisms in MTHFR Gene with the Risk of Age-Related Cataract in Chinese Han Population: A Genotype-Phenotype Analysis.
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.
Project description:Stroke is currently the leading cause of functional impairments worldwide. Folate supplementation is inversely associated with risk of ischemic stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism. The aim of this study is to examine whether genetic variants in MTHFR gene are associated with the risk of ischemic stroke and fasting total serum homocysteine (tHcy) level. We genotyped nine tag SNPs in the MTHFR gene in a case-control study, including 543 ischemic stroke cases and 655 healthy controls in China. We found that subjects with the rs1801133 TT genotype and rs1801131 CC genotype had significant increased risks of ischemic stroke (adjusted odds ratio (OR)=1.82, 95% confidence interval (CI): 1.27-2.61, p=0.004; adjusted OR=1.99, 95% CI: 1.12-3.56, p=0.01) compared with subjects with the major alleles. Haplotype analysis also found that carriers of the MTHFR CTTCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had a significant reduced risk of ischemic stroke (adjusted OR=0.53, 95% CI: 0.35-0.82) compared with those with the CTTTGA haplotype. Besides, the MTHFR rs1801133 and rs9651118 were significantly associated with serum levels of tHcy in healthy controls (p<0.0001 and p=0.02). These findings suggest that variants in the MTHFR gene may influence the risk of ischemic stroke and serum tHcy.
Project description:Diabetes is a global public health crisis, and the prevalence is increasing rapidly. Folate supplementation is proved to be effective in reducing the risk of diabetes or improving its symptoms. Methylenetetrahydrofolate reductase is an important enzyme involved in folate metabolism. The aim of this study is to examine whether polymorphisms in the MTHFR gene are associated with risk of type 2 diabetes mellitus (T2DM) and fasting total serum homocysteine (tHcy) levels. We genotyped nine tagging SNPs in the MTHFR gene in a case-control study, including 595 T2DM cases and 681 healthy controls in China. We found that C allele of rs9651118 had significant decreased risk of T2DM (adjusted odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.55-0.87, P = 0.002) compared with T allele. Haplotype analysis also showed that MTHFR CTCCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had significant reduced risk of T2DM (adjusted OR = 0.71, 95% CI: 0.58-0.87, P = 0.001) compared with CTTTGA haplotype. Besides, the MTHFR rs1801133 was significantly associated with serum levels of tHcy in healthy controls (P = 0.0002). These associations were still significant after Bonferroni corrections (P < 0.0056). These findings suggest that variants in the MTHFR gene may influence the risk of T2DM and tHcy levels.
Project description:Polymorphisms in one-carbon metabolism genes may influence the susceptibility to hepatocellular carcinoma (HCC). In the present study, we studied methylenetetrahydrofolate reductase (MTHFR) tagging polymorphisms in 584 HCC cases and 923 controls. Polymerase chain reaction was harnessed to detect MTHFR genotype. Overall, our results showed that genotype distribution of MTHFR rs4846048 and rs4845882 polymorphisms was not different between HCC patients and controls. MTHFR rs9651118 and rs1801133 loci were protective factors for HCC (rs9651118: CT vs. TT: adjusted odds ratio (OR) = 0.67, 95% confidence interval (CI): 0.49-0.90, P=0.008 and TC/CC vs. TT: adjusted OR = 0.70, 95% CI: 0.53-0.93, P=0.015; rs1801133: GA vs. GG: adjusted OR = 0.72, 95% CI: 0.54-0.97, P=0.031, AA/GA vs. GG: adjusted OR = 0.76, 95% CI: 0.57-0.99, P=0.045). However, MTHFR rs3753584 locus was a candidate for susceptibility to HCC (CT vs. TT: adjusted OR = 1.67, 95% CI: 1.20-2.32, P=0.003 and TC/CC vs. TT: adjusted OR = 1.59, 95% CI: 1.15-2.20, P=0.005). Results of haplotype analysis suggested that MTHFR Grs1801133Trs3753584Grs4845882Ars4846048Trs9651118 was associated with the risk of HCC (OR = 1.55, 95% CI: 1.16-2.07, P=0.003). The power of our study also confirmed these associations (the value of power >0.80). In summary, our findings suggested that MTHFR rs3753584, rs9651118 and rs1801133 polymorphisms may affect the risk of HCC in Chinese Han population. In future, our findings should be further validated in additional case-control studies.
Project description:The aim of this case-control study was to assess the relationship between the tagging polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene and the susceptibility to colorectal cancer (CRC) in a Chinese Han population. A custom-by-design 48-Plex SNPscan Kit was used to determine the genotypes of MTHFR rs3753584 T>C, rs9651118 T>C, rs1801133 G>A, rs4846048 A>G and rs4845882 G>A polymorphisms in 387 CRC patients and 1,536 non-cancer controls. The results revealed that MTHFR rs1801133 G>A polymorphism was associated with a decreased risk of overall CRC. While MTHFR rs4845882 G>A polymorphism conferred an increased risk to overall CRC. In a stratified analysis by CRC region, we found MTHFR rs3753584 T>C and rs9651118 T>C polymorphisms were associated with the increased risk of colon cancer. In addition, a significantly increased risk of rectum cancer associated with MTHFR rs3753584 T>C polymorphism was overt. However, MTHFR rs1801133 G>A polymorphism conferred a decreased risk to colon cancer. In conclusion, findings of the present study reveal that the tagging polymorphisms in MTHFR gene (rs3753584 T>C, rs9651118 T>C and rs4845882 G>A) are associated with the increased risk of CRC. However, MTHFR rs1801133 G>A polymorphism confers a decreased risk to CRC. Additional studies with larger sample size are needed to confirm these findings.
Project description:Previous reports implicated 5,10-ethylenetetrahydrofolate reductase (MTHFR) polymorphisms acted as a potential risk factor for several cancers. In order to explore the effect of MTHFR SNPs on non-small cell lung cancer (NSCLC), we selected MTHFR tagging single nucleotide polymorphisms (SNPs) and carried out a case-control study to determine the potential relationship of MTHFR SNPs with NSCLC risk. Our study consisted of 521 NSCLC patients and 1,030 non-cancer controls. MTHFR SNPs were genotyped by SNPscanTM genotyping assay. Using four genetic models (additive, Homozygote, dominant, recessive), the genotype frequencies were compared using the chi-squared (?2) test. Crude/adjusted odds ratios (ORs) with their 95% confidence intervals (CIs) were used to assess the difference for the genotype distribution. We found that MTHFR rs1801133 G>A polymorphism decreased the risk of overall NSCLC. In a subgroup analysis, MTHFR rs1801133 G>A polymorphism also decreased NSCLC risk in female, < 60 years and never smoking subgroups. However, we identified that MTHFR rs4845882 G>A polymorphism was associated with the development of NSCLC in female subgroup. In addition, MTHFR rs9651118 T>C polymorphism increased the risk of NSCLC in < 60 years, never smoking and BMI < 24 kg/m2 subgroups. In conclusion, the current study highlights MTHFR rs1801133 G>A variants decreases the risk of NSCLC. Nevertheless, MTHFR rs4845882 G>A and rs9651118 T > C polymorphisms may be associated with NSCLC susceptibility. Well-designed large-scale studies are needed to confirm these findings and explore the interactions of gene-gene and gene-environment involved in MTHFR SNPs and NSCLC.
Project description:In this study, we aimed to determine the potential association of MTHFR tagging single nucleotide polymorphisms (SNPs) with risk of developing esophagogastric junction adenocarcinoma (EGJA). MTHFR rs1801133 G>A, rs3753584 T>C, rs4845882 G>A, rs4846048 A>G and rs9651118 T>C polymorphisms were genotyped in 1,677 healthy individuals and 1,063 patients with EGJA. We found that MTHFR rs1801133 G>A polymorphism was significantly associated with the risk of developing EGJA (AA vs. GG: adjusted P = 0.001; GA/AA vs. GG: adjusted P = 0.007 and AA vs. GA/GG: adjusted P = 0.001). However, for MTHFR rs4845882 G>A polymorphism, the decreased risk of EGJA was found in two genetic models (AA vs. GG: adjusted P = 0.002 and AA vs. GA/GG: adjusted P = 0.005). In addition, for MTHFR rs3753584 T>C and rs9651118 T>C polymorphisms, a tendency to decreased risk of EGJA was noted. In a subgroup analysis, a significantly decreased risk of EGJA in <64 years subgroup was identified. We found that MTHFR Grs1801133Trs3753584Grs4845882Ars4846048Crs9651118, Grs1801133Crs3753584Ars4845882Ars4846048Trs9651118 and Grs1801133Trs3753584Ars4845882Grs4846048Trs9651118 haplotypes significantly decreased the risk of EGJA (P = 0.002, P < 0.001 and P = 0.038, respectively). In conclusion, our study demonstrates that MTHFR rs1801133 G>A may be associated with the increased risk of EGJA. Meanwhile, MTHFR rs3753584 T>C, rs4845882 G>A and rs9651118 T>C polymorphisms and haplotypes may decrease the risk of EGJA in Eastern Chinese Han population. Further studies with large sample size and detailed gene-environmental data are needed to validate our conclusion.
Project description:Background:Methylenetetrahydrofolate reductase (MTHFR) is indispensable for the conversion of homocysteine (Hcy) to methionine. The single nucleotide polymorphism (SNP) of MTHFR gene (rs1801133, C667T) is correlated with decreased enzyme activity that eventually results in elevated plasma Hcy levels. Hyperhomocysteinemia has been confirmed to be involved in the pathogenesis of stroke, cerebral small vessel disease (CSVD), various metabolic disorders and so on. However, the relationship between the MTHFR gene polymorphisms, Hcy, and CSVD has not been investigated. In this study, the relationship between SNPs of MTHFR gene and CSVD was determined after adjusting for cardiovascular risk factors, and the potential mechanism based on Hcy levels was explored. Methods:A total of 163 consecutive CSVD patients were collected as the case group. In the corresponding period, 326 healthy people were selected as the control group, who were matched to these cases according to age (±2 years) and gender at a ratio of 2:1. SNPs of MTHFR rs1801133, rs1801131, rs2274976, rs4846048, rs4846049, rs13306561 and rs3737964, were genotyped with TaqMan Pre-Designed SNP Genotyping Assays. Plasma Hcy levels were detected using Hcy reagent through enzymatic cycling assay. Multivariate analysis was used to identify the SNPs associated with CSVD susceptibility. Plasma Hcy levels were compared between different genotypes. Results:The MTHFR rs1801133 TT and CT genotype had increased risk for CSVD, and the OR was higher in the TT genotype than in the CT genotype (2.307 vs 1.473). The plasma Hcy levels of different genotypes showed the tendency of the TT genotype > CT genotype > CC genotype (19.91 ± 8.73 pg/ml vs 17.04 ± 5.68 pg/ml vs 14.96 ± 4.85 pg/ml). Conclusions:The SNP of MTHFR rs1801133 was correlated with CSVD, and the TT and CT genotypes had increased risk for CSVD compared to the CC genotype. The potential mechanism was associated with elevated Hcy levels.
Project description:This study aimed to investigate whether the single nucleotide polymorphism C677T (rs1801133) of the methylene-tetrahydrofolate reductase (MTHFR) gene was associated with the risk of coronary artery disease (CAD) and circulating homocysteine (Hcy) levels in Tunisian population. 310 angiografically diagnosed CAD patients and 210 controls were enrolled in this study. The MTHFR C677T (rs1801133) polymorphism was genotyped, and the Hcy concentrations were measured. The severity of CAD was evaluated using the Gensini scoring system. Compared to the CC genotype, the TT genotype confers a higher risk for CAD severity with an OR?=?9.07 and 95% CI?=?3.78-21.8. The T allele was the predisposing allele for CAD and that it was probably associated with CAD severity. The area under the ROC curve for Hcy was 0.764 (95% CI 0.660 to 0.868, p?=?0.001). The receiver operating characteristics curve (ROC) for Hcy showed its useful prediction of CAD. Hcy levels were not significantly associated with CAD severity expressed by Gensini Score (GS). The MTHFR C677T (rs1801133) polymorphism influences circulating Hcy levels. The MTHFR C677T polymorphism and hyperhomocysteinemia could have an important role in the prediction of the presence and not the severity expressed by GS of CAD.
Project description:Folate metabolism has been associated with cancers via alterations in nucleotide synthesis, DNA methylation, and DNA repair. We hypothesized that genetic variants in methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate metabolism, would affect the prognosis of prostate cancer. Three haplotype-tagging single-nucleotide polymorphisms (SNPs) across the MTHFR gene region were genotyped in a cohort of 458 patients with clinically localized prostate cancer treated with radical prostatectomy. One SNP, rs9651118, was associated with disease recurrence, and the association persisted after multivariate analyses adjusting for known risk factors. Public dataset analyses suggested that rs9651118 affects MTHFR expression. Quantitative real-time polymerase chain reaction analysis revealed that MTHFR expression is significantly upregulated in prostate tumor tissues when compared with adjacent normal tissues. Furthermore, overexpression of MTHFR correlates with cancer recurrence and death in two independent publicly available prostate cancer datasets. In conclusion, our data provide rationale to further validate the clinical utility of MTHFR rs9651118 as a biomarker for prognosis in prostate cancer.
Project description:The aim of this study was to investigate the relationship between the combined effect of MTHFR C677T (rs1801133) and EPHX2 G860A (rs751141) polymorphism and ischemic stroke in Chinese T2DM patients. This case-control study included a total of 626 Chinese T2DM patients (236 T2DM patients with ischemic stroke and 390 T2DM patients without ischemic stroke). The rs1801133 and rs751141 were genotyped using real-time polymerase chain reaction. Statistical analysis was performed with SPSS 17.0. Results showed that the combined effect of MTHFR TT and EPHX2 GG or GA + AA genotype has a higher risk of ischemic stroke compared with the control group (combined effect of MTHFR CC and EPHX2 GA + AA genotypes; OR = 3.46 and OR = 3.42, resp.; P = .001 and P = .002, resp.). The A allele showed marked association with a lower risk of ischemic stroke in patients with the lowest Hcy levels under additive, recessive, and dominant genetic models (OR = 0.45, OR = 0.11, and OR = 0.44, resp.; P = .002, P = .035, and P = .008, resp.), which was not observed in medium or high Hcy level groups. In conclusion, the T allele of rs1801133 and the G allele of rs751141 may be risk factors of ischemic stroke in the Chinese T2DM population.