Methionine Synthase Reductase A66G Research Articles

Simultaneous Detection of Three Genotypes of Gene Methylene Tetrahydrofolate Reductase and Methionine Synthase Reductase Based on Multiplex Asymmetric Real-Time PCR-HRM Biosensing.

Genotyping of folate metabolism genes is of great importance in disease diagnosis and prevention. However, most current detection methods used for folate metabolism gene genotyping are based on sequencing and chips, which suffer from a high cost and laborious and time-consuming procedures. Herein, we reported a multiplex asymmetric PCR-HRM strategy for identifying genotypes of folate metabolism genes in a single tube. The proposed multiplex PCR-HRM assay has been successfully applied to identify the genotypes of folate metabolism genes, methylene tetrahydrofolate reductase (C677T, A1298C) and methionine synthase reductase A66G, on 1 μL of genomic DNA (gDNA) samples directly released from blood specimens, and the genotyping results were 100% consistent with the results of sequencing. The assay allows us to accurately detect the genotypes of gDNA with the detection limit down to 1 ng, which meets the clinical requirement. What is more, the capacity of resistance to aerosol pollution of the multiplex asymmetric PCR-HRM biosensing was first addressed and has been evaluated as it can withstand contamination of roughly 12.5-25% interfering nucleic acids. Because of the advantages of multiplex detection, high accuracy, and resistance to aerosol pollution and having no open tube procedure, this approach would pave the way for establishing a fast and cost-effective platform for folate metabolism gene genotyping and other SNP genotyping in clinical diagnostics.

3\u2019UTR polymorphism of Thymidylate Synthase gene increased the risk of persistence of pre-neoplastic cervical lesions

BackgroundCervical cancer is caused by high-risk Human Papillomavirus (hr-HPV) infection associated with cofactors that has been analyzed as predictors of the remission or persistence of cytological abnormalities remission or persistence. These cofactors can be either environmental, epigenetic, or genetic. Polymorphism in genes of enzymes that act on one-carbon metabolism alter their activity and also may be associated with cervical carcinogenesis because they affect DNA synthesis and repair, and gene expression. Therefore, this study aimed to analyze the risk of persistence of pre-neoplastic cervical lesions according to genetic polymorphisms involved in one-carbon metabolism.MethodsOur sample consisted of 106 women, divided into two groups – Remission (n = 60), i.e., with the presence of pre-neoplastic lesions at first meeting (T1) and normal cytology after 6 months of follow-up (T2), and Persistence (n = 46), i.e., with the presence of pre-neoplastic lesions at T1 and T2. We obtained cervical samples for cytological analysis (T1 and T2), HPV detection (T1), and evaluation of polymorphism C667T of Methylenetetrahydrofolate Reductase (MTHFR C677T), A2756G of Methionine Synthase (MS A2756G), A66G of Methionine Synthase Reductase (MTRR A66G), double or triple 28 bp tandem repeat in 5′-untranslated enhanced region of Thymidylate Synthase (TSER), and 6 bp deletion at nucleotide 1494 in TS 3′-untranslated region (TS3’UTR). To analyze all genetic polymorphisms simultaneously, we calculated the Genetic Risk Score (GRS).ResultsWe observed no differences between the Remission and Persistence groups regarding the GRS. Also, there were no differences in the genotypic and allelic distribution of MTHFR C677T and MS A2756G polymorphisms. However, the risk of persistence was higher among women with the heterozygote genotype - ins/del [OR (IC95%): 3.22 (1.19–8.69), p = 0.021], or the polymorphic genotype – del/del [OR (IC95%): 6.50 (1.71–24.70), p = 0.006] of TS3’UTR. Conclusions: The presence of the TS3’UTR polymorphism increased the risk of persistence of cervical abnormalities. This genetic variant could be a potential marker of cervical carcinogenesis and therefore assist the follow-up of women with persistent pre-neoplastic cervical lesions.

Methionine Synthase Reductase-A66G and -C524T Single Nucleotide Polymorphisms and Prostate Cancer: A Case-Control Trial

Purpose:Some variations in the sequence of methionine synthase reductase (MTRR) gene can increase the risk of various cancers such as prostate cancer. The aim of this study was to investigate the association between prostate cancer and the MTRR A66G and C524T gene single nucleotide polymorphisms (SNPs) using an in silico analysis.Methods:In this case-control study, 218 Iranian men, including 108 men with prostate cancer and 110 prostate cancer-free men, were enrolled. The MTRR A66G and C524T genotyping was performed by PCR-RFLP. Some of the bioinformatics tools were employed for the evaluation of polymorphism on the molecular aspects of the MTRR.Results:With regard to the MTRR A66G polymorphism, the genotype AG (OR: 0.85, 95% CI: 0.47-1.54, p= 0.6014), genotype GG (OR: 0.89, 95% CI: 0.42-1.87, p= 0.7512), and allele G (OR: 0.92, 95% CI: 0.63-1.35, p= 0.6686) were not associated with prostate cancer risk. However, the data for C524T SNP showed that the genotype CT was associated with prostate cancer risk (OR: 1.92, 95% CI: 1.06-3.47, p= 0.0308). Further, carriers of the allele T (OR: 1.80, 95% CI: 1.04-3.13, p= 0.0358) were associated with high risk of prostate cancer. In addition, bioinformatics analysis revealed that C524T SNP could affect some molecular aspects of the protein structure, while having no effect on the mRNA structure.Conclusion:The MTRR C524T is a genetic risk factor for prostate cancer; however, the MTRR A66G is not suggested as a suitable biomarker for prostate cancer. To obtain more reliable results, further studies are recommended to use larger sample sizes and investigate the effects of environmental factors.

Association between Methionine Synthase Reductase A66G Polymorphism and Male Infertility: A Meta-Analysis

The aim of this meta-analysis was to assess the methionine synthase reductase (MTRR) gene 66A>G polymorphism and male infertility susceptibility. Studies were identified in PubMed and Embase databases. An odds ratio (OR) was used to assess the relationship between MTRR 66A>G polymorphism and male infertility risk. A total of seven case-control studies containing 1438 patients and 1363 controls were enrolled in the meta-analysis. Our results showed that no association exists between the MTRR 66A>G polymorphism and male infertility risk in the total population (GG vs. AA: OR = 1.29, 95% confidence interval [CI] = 1.00-1.66; GA vs. AA: OR = 1.09, 95% CI = 0.92-1.30; dominant model: OR = 1.13, 95% CI = 0.96-1.34; recessive model: OR = 0.83, 95% CI = 0.67-1.03). In a subgroup analysis by nationality, the 66A>G polymorphism was not associated with male infertility in both Asians and Caucasians. In a subgroup analysis stratified by male infertility type, significant association was found with oligoasthenozoospermia (OAT) (GG vs. AA: OR = 1.83, 95% CI = 1.24-269; GA vs. AA: OR = 1.36, 95% CI = 0.88-2.11; dominant model: OR = 1.51, 95% CI = 1.13-2.01; recessive model: OR = 0.62, 95% CI = 0.46-0.85). In summary, the present meta-analysis suggests that MTRR 66A>G polymorphism may be associated with OAT risk.

Association between methionine synthase reductase A66G polymorphism and primary infertility in Chinese males.

We examined the association between the methionine synthase reductase (MTRR A66G), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), and methionine synthase (MS A2756G) genotypes and non-obstructive male infertility in a Chinese population. This case-control study included 162 infertile Chinese patients with azoospermia (N = 100) or oligoasthenozoospermia (N = 62) and 120 fertile men as controls. The polymorphisms MTRR A66G, MTHFR C677T, A1298C, and MS A2756G were identified by direct DNA sequencing and the results were statistically analyzed. We found no association between the incidence of any of these variants in azoospermia patients and control populations. The frequency of the MTRR66 polymorphic genotypes (AG, AG+GG) was significantly higher in the oligoasthenozoospermia group compared to the controls (P = 0.013, 0.012). Our findings revealed an association between the single-nucleotide polymorphism A66G in the MTRR gene and male infertility, particularly in oligoasthenozoospermia males, suggesting that this polymorphism is a genetic risk factor for male infertility in Chinese men.

Association Between Methionine Synthase Reductase A66G Polymorphism and the Risk of Congenital Heart Defects: Evidence From Eight Case–Control Studies

Methionine synthase reductase (MTRR) plays a major role in hyperhomocysteinemia, a risk factor related to the occurrence of congenital heart defects (CHDs). However, the associations between MTRR polymorphism and CHDs have been inconclusive. Thus, a metaanalysis of eight case-control studies was conducted to investigate 3,592 cases and 3,638 control subjects for MTRR A66G polymorphism to identify the association. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. The results showed that MTRR A66G polymorphism was associated with a higher CHD risk in the allele comparison (G vs A: OR 1.163; 95 % CI 1.016-1.330; P heterogeneity = 0.004), the homozygote comparison (GG vs AA: OR 1.332; 95 % CI 1.020-1.740; P heterogeneity = 0.035), and the dominant model (GG/AG vs AA: OR 1.218; 95 % CI 1.001-1.482; P heterogeneity = 0.001). In the subgroup analysis, this polymorphism was associated with CHDs in Asians in the homozygote comparison (GG vs AA: OR 1.427; 95 % CI 1.017-2.001; P heterogeneity = 0.019) and the allele comparison (G vs A: OR 1.203; 95 % CI 1.018-1.422; P heterogeneity = 0.002). In summary, the metaanalysis demonstrated that MTRR A66G polymorphism is a risk factor for CHDs. Further studies should be performed to investigate the association of plasma homocysteine levels, enzyme activity, parental genotypes, and vitamin complex intakes with the risk of CHDs.

The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes.

The aim of this study was to investigate the association between polymorphisms in folic acid metabolism-related genes and idiopathic recurrent early pregnancy loss (REPL). A prospective case-control study was performed on a cohort of 82 REPL patients and 166 healthy controls. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C was assessed by applying polymerase chain reaction for amplification followed by DNA sequencing, for methionine synthase reductase A66G, solute carrier family 19, member 1 (SLC19A1) G80A and C696T, and genotyping was done by utilizing the Sequenom MassARRAY system. The results revealed a significant association between MTHFR A1298C polymorphism and idiopathic REPL. Haplotype analysis indicated that the MTHFR 677C-MTHFR 1298C allele combination was associated with REPL (P<0.001). The MTHFR 677C-MTHFR 1298A and SLC19A1 80G-SLC19A1 696C allele combinations had lower frequencies in patients with REPL, but with P>0.05 (P=0.093 and P=0.084, respectively).

Methionine Synthase Reductase A66G Polymorphism is not Associated with Breast Cancer Susceptibility - a Meta-analysis

Several studies have investigated the association between methionine synthase reductase (MTRR) A66G polymorphism and breast cancer risk, but controversial results were yielded. Therefore, we performed a meta-analysis to provide a more robust estimate of the effect of this polymorphism on susceptibility to breast cancer. Case-control studies investigating the relationship between MTRR A66G polymorphism and breast cancer risk were included by searching PubMed, EMBASE, China National Knowledge Infrastructure and Wanfang Database. Either fixed-effects or random-effects models were applied to calculate odds ratios(ORs) and 95% confidence intervals (CIs) by RevMan5.2 software. A total of 9 studies bearing 7,097 cases and 7,710 controls were included in the meta-analysis. The results were that the combined ORs and 95%CIs of MTRR 66AG, GG, (AG+GG) genotypes were 0.98(0.91-1.05), 1.06(0.97-1.16) and 1.02(0.94-1.10), respectively with p=0.52, 0.19 and 0.65. We also performed subgroup analysis by specific ethnicity. The results of the combined analysis of MTRR 66AG, GG, (AG+GG) genotypes and breast cancer in Asian descent were Z=0.50, 0.53 and 0.21, with p all>0.05; for breast cancer in Caucasian descent, the results were Z=1.14, 1.65 and 0.43, with p all>0.05. Our findings suggested that MTRR A66G polymorphism was not associated with breast cancer susceptibility.

Methionine synthase reductase A66G polymorphism and leukemia risk: evidence from published studies

Methionine synthase reductase (MTRR) is required for the reductive methylation of cobalamin, which is the functional cofactorial form of methionine synthase (MS) in the remethylation of homocysteine to methionine. The MTRR A66G (rs1801394) polymorphism is found to be associated with decreased enzyme affinity for MTR, the gene that encodes MS, and has been widely investigated for cancer risk, including leukemia. However, the conclusions of epidemiological studies have always been contradictory. To further clarify the association of MTRR A66G polymorphism with the risk of leukemia, this meta-analysis was performed for 2913 cases and 4764 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Pooled ORs were determined for the co-dominant model (GG vs. AA, AG vs. AA), dominant model (GG + AG vs. AA) and recessive model (GG vs. AA+ AG), respectively. No significant associations were found for all comparisons in the overall pooled analysis. However, the results of stratified analyses revealed that MTRR A66G GG genotype was associated with decreased leukemia risk in the Caucasian population, in children and for acute lymphoblastic leukemia (ALL). In contrast, increased risk was observed in the Asian population and for acute myeloid leukemia (AML). This meta-analysis suggests that MTRR A66G GG is associated with decreased risk of leukemia in a Caucasian population and in children, especially for ALL.

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

Physical exercise induces adaptive changes leading to a muscle phenotype with enhanced performance. We first investigated whether genetic polymorphisms altering enzymes involved in DNA methylation, probably responsible of DNA methylation deficiency, are present in athletes' DNA. We determined the polymorphic variants C667T/A1298C of 5,10-methylenetetrahydrofolate reductase (MTHFR), A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR), G742A of betaine:homocysteine methyltransferase (BHMT), and 68-bp ins of cystathionine β-synthase (CBS) genes in 77 athletes and 54 control subjects. The frequency of MTHFR (AC), MTR (AG), and MTRR (AG) heterozygous genotypes was found statistically different in the athletes compared with the control group (P=0.0001, P=0.018, and P=0.0001), suggesting a reduced DNA methylating capacity. We therefore assessed whether DNA hypomethylation might increase the expression of myogenic proteins expressed during early (Myf-5 and MyoD), intermediate (Myf-6), and late-phase (MHC) of myogenesis in a cellular model of hypomethylated or unhypomethylated C2C12 myoblasts. Myogenic proteins are largely induced in hypomethylated cells [fold change (FC)=Myf-5: 1.21, 1.35; MyoD: 0.9, 1.47; Myf-6: 1.39, 1.66; MHC: 1.35, 3.10 in GMA, DMA, respectively] compared with the control groups (FC=Myf-5: 1.0, 1.38; MyoD: 1.0, 1.14; Myf-6: 1.0, 1.44; MHC: 1.0, 2.20 in GM, DM, respectively). Diameters and length of hypomethylated myotubes were greater then their respective controls. Our findings suggest that DNA hypomethylation due to lesser efficiency of polymorphic MTHFR, MS, and MSR enzymes induces the activation of factors determining proliferation and differentiation of myoblasts promoting muscle growth and increase of muscle mass.

Methionine synthase reductase A66G polymorphism contributes to tumor susceptibility: evidence from 35 case–control studies

Methionine synthase reductase (MTRR) gene is involved in tumorigenesis by regulating DNA methylation through activation of methionine synthase (MTR). MTRR is polymorphic at nucleotide 66 (A-to-G) and the resulting variant enzyme has a lower affinity for MTR. The reported associations of MTRR A66G polymorphism with cancer risk are contradictory. Therefore, we performed a meta-analysis to better assess the associations, including 18,661 cases and 27,678 controls from 35 studies. Crude ORs with 95% CIs were used to assess the strength of association between the MTRR A66G polymorphism and cancer risk. The pooled ORs were performed for homozygote model (GG vs. AA), heterozygote model (GG vs. GA), recessive genetic model (GG vs. GA + AA), and dominant genetic model (GG + GA vs. AA), respectively. Overall, results indicated that the G allele and GG variant genotypes were associated with a significantly increased cancer risk (G vs. A: OR, 1.039; 95% CI, 1.009-1.078; homozygote model: OR, 1.094; 95% CI, 1.006-1.191). In subgroup analysis by ethnicity, significant increased risks were found among Asians with G allele (G vs. A: OR, 1.063; 95% CI, 1.011-1.119; homozygote model: OR, 1.189; 95% CI, 1.055-1.341; recessive model: OR, 1.197; 95% CI, 1.068-1.341). For stratification analysis, the cancer types with fewer than three studies were categorized into "other cancers", and the results indicated that there was a significant elevated cancer risk in "other cancers" in all genetic models, not in colorectal cancer, lymphoid leukemia or breast cancer. In summary, our study suggests that the MTRR A66G polymorphism is a potential biomarker for cancer risk.

Effect of methionine synthase A2756G and methionine synthase reductase A66G gene polymorphisms in male infertility

Effect of methionine synthase A2756G and methionine synthase reductase A66G gene polymorphisms in male infertility

Uttar Pradesh Methionine Synthase Reductase A66g Polymorphism in Rural Population of Uttar Pradesh (India)

Uttar Pradesh Methionine Synthase Reductase A66g Polymorphism in Rural Population of Uttar Pradesh (India)

Impact of Coagulation-Balance Gene Predictors on Efficacy of Photodynamic Therapy for Choroidal Neovascularization in Pathologic Myopia

To investigate whether different coagulation-balance genetic backgrounds might explain the variable clinical outcomes detected, after a single photodynamic therapy with verteporfin (PDT-V), in Caucasian patients with subfoveal choroidal neovascularization (CNV) secondary to pathologic myopia (PM). Retrospective, consecutive, nonrandomized, interventional cases series. Two hundred thirty-four patients exclusively treated with standardized PDT-V for the presence of PM-related classic CNV. The enrolled patients were subdivided as responders or nonresponders based on CNV responsiveness to the first PDT-V over a 3-month period. Three common gene polymorphisms, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, and methionine synthase reductase A66G, were genotyped by polymerase chain reaction in each patient. The measures of CNV responsiveness to PDT-V were the changes, respect to baseline, of fluorescein angiography CNV leakage, greatest linear dimension, and area of the lesion. Logistic regression analyses were performed to explore the predictive role of phenotypic (patient's age, baseline visual acuity, and baseline CNV area) and genotypic (all the mentioned mutations) variables regarding PDT-V efficacy. Responders to PDT-V were overrepresented within carriers of methylenetetrahydrofolate reductase 677 T-allele (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.8-5.4; P = 0.001) and, to a minor extent, among patients with better visual acuity at baseline (OR, 11.8; 95% CI, 1.6-88.0; P = 0.02). However, predictors of PDT-V lack of efficacy were patient's age (OR, 0.73; 95% CI, 0.62-0.86; P = 0.01) and, especially, factor XIII-A 185 GT/TT genotypes (OR, 0.19; 95% CI, 0.11-0.35; P = 0.0001). All the other considered predictive factors did not significantly influence the CNV responsiveness to PDT-V. These findings document the presence of pharmacogenetic correlations between common coagulation-balance gene polymorphisms and different CNV responsiveness to PDT-V in Caucasian patients with neovascular PM.

Coagulation Gene Predictors of Photodynamic Therapy for Occult Choroidal Neovascularization in Age-Related Macular Degeneration

To determine whether different coagulation-balance genetic polymorphisms explain the variable clinical outcomes of photodynamic therapy with verteporfin (PDT-V) in Caucasian patients with occult subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). The clinical records of consecutive patients with AMD-related occult CNV, treated with PDT-V for evidence of disease progression, were retrospectively examined. Eighty-four eligible subjects were subdivided into responders and nonresponders based on CNV responsiveness to the first PDT-V over a 3-month period. Six gene polymorphisms (i.e., factor V G1691A, prothrombin G20210A, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, methionine synthase A2756G, and methionine synthase reductase A66G) were genotyped in each patient. Logistic regression analyses were performed to explore the predictive role of phenotypic and genotypic variables for PDT-V effectiveness. Regression models documented that PDT-V nonresponders were more frequently patients with the hyperfibrinolytic G185T mutation of factor XIII-A (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11-0.73; P < 0.01). Univariate logistic regression was indicative of an overrepresentation of PDT-V responders among the combined carriers of thrombophilic factor V 1691A and prothrombin 20210A alleles (OR = 3.8; 95% CI: 0.94-15.6; P = 0.07). All the other predictors considered did not significantly influence the short-term CNV responsiveness to PDT-V. These data provide evidence of the presence of a pharmacogenetic relationship between peculiar coagulation-balance genetic backgrounds and different levels of PDT-V effectiveness in patients with AMD with occult CNV.

Predictive role of coagulation-balance gene polymorphisms in the efficacy of photodynamic therapy with verteporfin for classic choroidal neovascularization secondary to age-related macular degeneration

Age-related macular degeneration (AMD) represents the leading cause of blindness in Western populations. The majority of severe vision loss occurs in the exudative form of AMD, characterized by the development of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) represents one of the most largely employed modality that maybe achieves the subfoveal CNV inactivation in AMD patients. Although several ocular factors have been hitherto investigated as predictors, these researches have weakly contributed to PDT-V optimization. As PDT-V benefit is determined by CNV photothrombosis, we have retrospectively studied several coagulation-balance gene polymorphisms as predictors of PDT-V efficacy. Ninety Caucasian patients with neovascular AMD were subdivided in responder and nonresponder, on the basis of CNV responsiveness to PDT-V application. Six gene polymorphisms, that is factor V G1691A, prothrombin G20210A, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, methionine synthase A2756G, and methionine synthase reductase A66G, were genotyped in the entire cohort. Logistic regression models showed that PDT-V responders were more prevalent within patients with prothrombin G20210A mutation [odds ratio (OR)=5.6, 95% confidence interval (CI) (1.2, 27.2), P=0.03], and within methylenetetrahydrofolate reductase 677T carriers [OR=6.9, 95% CI (2.7, 18.1), P<0.001]. Conversely, PDT-V nonresponders were overrepresented in carriers for factor XIII-A 185T [OR=0.13, 95% CI (0.05, 0.36), P<0.001]. These results provide evidences for the presence of pharmacogenetic relationship between peculiar coagulation-balance gene polymorphisms and different levels of PDT-V effectiveness in patients with AMD-related CNV.

Polymorphism C776G in the transcobalamin II gene and homocysteine, folate and vitamin B 12 concentrations. Association with MTHFR C677T and A1298C and MTRR A66G polymorphisms in healthy children

One of the etiologies of hyperhomocysteinemia is decreased vitamin B 12. Genetic variation in the transcobalamin II gene, the transporter of vitamin B 12 to the cells, may produce altered homocysteine levels. We determined transcobalamin II C776G polymorphism, homocysteine, folate and vitamin B 12 levels and analyzed the interactive effect with the methylenetetrahydrofolate reductase C677T and A1298C and methionine synthase reductase A66G polymorphisms in 207 healthy Brazilian children. The prevalence of GG genotype of transcobalamin II C776G polymorphism in this Brazilian population, a highly miscigeneous population was 12.5% and the statistical analysis showed that this population is in Hardy–Weinberg equilibrium, it could be considered representative of the general population. We observed a significant increase in homocysteine in the 776GG vs. 776CC genotype, corroborating the influence of age as a determinant of homocysteine in relation to this polymorphism. When we analyzed vitamin B 12 and its relationship with the C776G polymorphism, we found no significant differences. Only 776CG/66AA or 776GG/66AG genotypes presented a significant increase in homocysteine when compared with other groups. In the multivariate analysis, transcobalamin II C776G (CC/CG vs. GG), methylenetetrahydrofolate reductase C677T (CC/CT vs. TT), folate, gender and age presented statistical significance in relation to the homocysteine. These can be considered independent risk factors for hyperhomocysteinemia in this children group. Our results, if confirmed in other populations, highlight the necessity for investigation of the transcobalamin II C776G polymorphism in the research for hyperhomocysteinemia risk factors.

Association of MTRR A66G polymorphism (but not of MTHFR C677T and A1298C, MTR A2756G, TCN C776G) with homocysteine and coronary artery disease in the French population

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) is an established determinant of homocysteine plasma level (t-Hcys) while its association with coronary artery disease (CAD) seems to be more limited. In contrast, the association of the substitutions A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR) and C776G of transcobalamin (TCN) to both t-Hcys and CAD needs to be evaluated further. The objective was to evaluate the association of these polymorphisms with t-Hcys and CAD in a French population. We investigated the individual and combined effects of these polymorphisms and of vitamin B12 and folates with t-Hcys in 530 CAD patients and 248 matched healthy controls. t-Hcys was higher in the CAD group than in controls (11.8 vs 10.4 microM, P < 0.0001) and in carriers of MTRRAA and MTHFR 677TT than in those carrying the most frequent allele of both polymorphisms (13.8 vs 11.4 microM, P = 0.0102 and 12.5 vs 11.0 mM, P = 0.0065 respectively). The frequency of MTRR A allele was higher in CAD patients than in controls (0.48 [95% CI: 0.44-0.52] vs 0.38 [95% CI: 0.32-0.44], P = 0.0081) while no difference was observed for MTHFR 677T frequency. In multivariate analysis, t-Hcys > median and MTRRAA genotype were two significant independent predictors of CAD with respective odds ratios of 3.1 (95 % CI: 1.8-5.1, P < 0.0001) and 4.5 (95% CI: 1.5-13.1, P = 0.0051). In conclusion, in contrast to North Europe studies, MTRRAA genotype is a genetic determinant of moderate hyperhomocysteinemia associated with CAD in a French population without vitamin fortification.