Association of the methylene-tetrahydrofolate reductase gene rs1801133 C677T variant with serum homocysteine levels, and the severity of coronary artery disease.
ABSTRACT: 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:Plasma homocysteine (Hcy) level is associated with cardiovascular disease and may play an etiologic role in vascular damage, a precursor for atherosclerosis. We performed a genome-wide association study for Hcy in 1786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP) (rs7422339, P = 4.7 x 10(-13)) encodes Thr1405Asn in the gene CPS1 and explained 3.0% of variation in the Hcy level. The widely studied MTHFR C677T SNP (rs1801133) was also highly significant (P = 8.7 x 10(-10)) and explained 1.6% of the trait variation. We also genotyped these two SNPs in 1679 CLHNS young adult offspring. The MTHFR C677T SNP was strongly associated with Hcy (P = 1.9 x 10(-26)) and explained approximately 5.1% of the variation in the offspring. In contrast, the CPS1 variant was significant only in females (P = 0.11 in all; P = 0.0087 in females). Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with Hcy in the offspring (interaction P = 1.2 x 10(-5)). Furthermore, although there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring (interaction P = 0.0046), there was no significant evidence for an interaction in the mothers (P = 0.55). These data confirm a recent finding that CPS1 is a locus influencing Hcy levels in women and suggest that genetic effects on Hcy may differ across developmental stages.
Project description:BACKGROUND:Coronary artery disease (CAD) is a complex disease resulting from the cumulative and interactive effects of large number of genes along with environmental exposure. Therefore, the present study was envisaged as an effort to study the association of candidate genes ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with the risk of CAD, targeting the populations of Jammu (JandK). METHOD:A total of 400 confirmed CAD patients and 400 healthy controls were enrolled for the present study. Genotyping was done by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). RESULTS:ESR1 gene (rs9340799) polymorphism was found to be associated with CAD in all the genetic models. The haplotype analysis of ESR1 (rs2234693 and rs9340799) gene revealed that C-G haplotype was conferring approximately 5-fold risk and T-A haplotype was adding 1.4-fold risk towards the disease. 'T' allele of MTHFR rs1801133 SNP was observed to be responsible for development of CAD in our study population (p?<?0.0001). In case of MTHFR (rs1801133 and rs2274976) gene, the haplotype T-G was observed to confer 4.7-fold risk towards CAD whereas haplotype C-G provided nearly a 1.7 fold protection towards development of CAD. For MS gene, rs185087 was also found to be associated with CAD in a co-dominant (p =?0.003 and p =?0.03), dominant (p =?0.001) and allelic models (p?=?0.001). The gene-gene interaction revealed strong epistasis between single nucleotide polymorphisms (SNPs), ESR1 rs9340799 and MTHFR rs2274976. Furthermore, the dendrogram for gene-environment dataset indicated moderately synergistic interaction between CETP rs708272 and physical inactivity. CONCLUSION:In the study under reference, a significant association of ESR1-XbaI (rs9340799), MTHFR C677T (rs1801133) and MS A2756G (rs185087) gene polymorphisms with the susceptibility of CAD in the population of Jammu region (JandK) has been observed.
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.
Project description:Background and Goal. The aim was to examine the serum levels of homocysteine (Hcy) and their associations with the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in patients with schizophrenia and mood disorders as well as controls. Materials and Methods. There were 198 patients: 82 with schizophrenia spectrum disorders, 22 with mood disorders, and 94 controls. The level of Hcy was determined by an isocratic high-performance liquid chromatography system. MTHFR C677T polymorphism was analysed using the restriction fragment length polymorphism-polymerase chain reaction method. Results. The average level of Hcy was 11.94 ± 5.6??mol/L for patients with schizophrenia, 11.65 ± 3.3??mol/L for patients with affective disorders, versus 6.80 ± 2.93??mol/L in a control. The highest level of Hcy has been observed in patients with episodic-recurrent course of schizophrenia (11.30 ± 7.74??mol/L), paranoid schizophrenia continuous (12.76 ± 5.25??mol/L), and in patients with affective disorders (11.65 ± 3.26??mol/L). An association between the MTHFR gene C677T polymorphism and Hcy level was found by linear regression analysis (r = 1.41, P = 0.029). Conclusions. The data indicate a link between Hcy levels and schizophrenia and mood disorders. No associations between the level of Hcy in patients with schizophrenia and mood disorders and the MTHFR C677T polymorphism were found.
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:Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes a common polymorphism (rs1801133 or C677T), which is associated with enzyme activity. The T-allele of the C677T polymorphism has been associated with earlier age at onset of schizophrenia in a Scandinavian population, although no association was found in replication attempts in other populations. Extending the study to five Nordic samples consisting of 2,198 patients with schizophrenia, including the original Scandinavian samples, there was no significant association between MTHFR C677T polymorphism and age at onset in schizophrenia. The present results do not suggest that the investigated MTHFR polymorphism has any significant influence on age at onset of schizophrenia in the Nordic population.
Project description:We investigated the interaction of MTHFR C677T polymorphism (rs1801133) with smoking in susceptibility to diabetic nephropathy (DN) in Chinese men with type 2 diabetes mellitus (T2DM). We studied 655 Chinese men with T2DM, who were divided into two groups (321 with DN and 334 without DN). The genotype of MTHFR C677T polymorphism was detected by real-time polymerase chain reaction. MTHFR TT genotype carried a higher risk of DN compared with the CC genotype (OR = 2.05; P = 0.002). The T allele showed marked association with DN development in patients who smoked, using additive, recessive, and dominant models (OR = 1.60, 1.83, and 1.88, respectively; P = 0.006, 0.002, and 0.04, respectively), which was not observed in the nonsmoking group. Patients with TT and CT genotypes, who smoked had a higher risk of DN compared with the control group (non-smoking with CC genotype; OR = 3.73 and 2.28, respectively; P < 0.001 and P = 0.004, respectively), whereas the other groups were not observed. In conclusion, the T allele of rs1801133 may be a risk factor for DN in Chinese men with T2DM, and synergy appears to exist between the MTHFR rs1801133 and smoking in susceptibility to DN.
Project description:<h4>Background</h4>Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy), folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism on risk of cancer overall.<h4>Method</h4>Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs) and mean differences and presented with 95% confidence intervals (95% CIs) and 2-sided probability values.<h4>Results</h4>We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC) polymorphism was positively associated with overall risk of cancer.<h4>Conclusion</h4>Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer.
Project description:INTRODUCTION:Methylenetetrahydrofolate reductase (MTHFR) is essential in mediating folate metabolism, and thus plays an important role in diabetes and diabetic complications. MTHFR C677T (rs1801133 C>T) polymorphism has been proposed to be linked with type 2 diabetes mellitus (T2DM) susceptibility. However, the conclusions are inconsistent. Therefore, we rechecked their linkage aiming to obtain a more reliable estimation by performing an updated meta-analysis. METHODS:We searched electronic databases PubMed, EMBASE, CNKI, and Wanfang to obtain studies updated to October 2019. RESULTS:After carefully screening, we finally incorporated 68 studies with 10,812 cases and 8,745 controls. The genotype frequency of C677T polymorphism was analyzed pooled to generate odds ratios (ORs) and 95% confidence intervals (CIs). Pooled results presented that MTHFR C677T polymorphism was significantly associated with T2DM under homozygous (OR = 1.64, 95% CI = 1.39-1.94), heterozygous (OR = 1.38, 95% CI = 1.20-1.59), recessive (OR = 1.41, 95% CI = 1.23-1.61), dominant (OR = 1.47, 95% CI = 1.27-1.70), and allele (OR = 1.37, 95% CI = 1.23-1.52) genetic models. Stratified analysis demonstrated that C677T genotype was associated with T2DM in Asian populations, but not Caucasian and African populations. CONCLUSION:Our results indicated that MTHFR C677T polymorphism confers to T2DM, especially in Asian populations. Much more large-scale case-control studies are needed to strengthen such conclusion in the future.
Project description:Osteoporosis is an age-related bone disease, affecting mainly postmenopausal women, characterized by decreased bone mineral density (BMD) and consequent risk of fractures. Homocysteine (Hcy), a sulfur-aminoacid whose serum level is regulated by methylenetrahydrofolate reductase (MTHFR) activity and vitamin B12 and folate as cofactors, is a risk factor for inflammatory diseases. Literature data concerning the link between Hcy and osteoporosis are still debated. The aim of our study was to assess the relationship among Hcy and BMD, inflammation, vitamin status and bone turnover in postmenopausal osteoporosis. In 252 postmenopausal women, BMD was measured by dual-energy X-ray absorptiometry (DXA). In addition to serum Hcy, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and bone turnover markers (bone alkaline phosphatase-BAP, osteocalcin-OC, C-terminal telopeptide of type I collagen (CTX), vitamin deficiencies and MTHFR-C677T polymorphism were evaluated. Hcy, inflammation, bone resorption markers and prevalence of C677T polymorphism were higher, whereas vitamin D, B12, folate, and bone formation markers were lower in women with decreased BMD compared to those with normal BMD. Our results suggest a significant association between Hcy, BMD and inflammation in postmenopausal osteoporosis. The regulation of Hcy overproduction and the modulation of the inflammatory substrate could represent additional therapeutic approaches for osteoporosis prevention.