MTHFR gene polymorphisms in diabetes mellitus.

The methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) are three regulatory enzymes in the folic acid (FA) cycle play a critical role in the balance of methionine and homocysteine. MTHFR and MTRR gene polymorphisms affect the biochemical activities of enzymes, impairing the remethylation of homocysteine to methionine. In 1972, severe MTHFR deficiency resulting in homocystinuria was first reported, suggesting MTHFR involvement in the disease. MTHFR C677T polymorphism can independently increase the risk of high homocysteine (HHcy) in plasma. Elevation of homocysteine levels could increase the risk of microvascular damage, thrombosis, heart disease, etc. Vascular complications were regarded as a leading major cause of diabetes mortality, and disability increases individual health and economic burden. Diabetes mellitus (DM) is a chronic inflammatory disease, and conventional medications do not provide a complete cure for diabetes. It was essential to identify other risk factors for the intervention and prevention of diabetes. MTHFR gene polymorphism is an emerging risk factor in diabetes. Recent studies have shown that polymorphisms of the MTHFR gene play a significant role in the pathophysiology of diabetes, including inflammation and insulin resistance. This review summarizes the association between MTHER gene polymorphism and diabetes.

Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?

Methionine synthase reductase deficiency (cblE) is a rare autosomal recessive inborn error of cobalamin metabolism caused by pathogenic variants in the methionine synthase reductase gene (MTRR). Patients usually exhibit early-onset bone marrow failure with pancytopenia including megaloblastic anemia. The latter can remain isolated or patients may present developmental delay and rarely macular dysfunction. Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation. We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH >11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by hydroxocobalamin dose escalation. There was no obvious trigger apart from a parvovirus B19 infection in one of the patients. This is the first report of such complications in adulthood. The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage. Bone marrow infection with parvovirus B19 can complicate this genetic disease with erythroblastopenia even in the absence of an immunocompromised status, as in other congenital hemolytic anemias. The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation.

Association of maternal methionine synthase reductase gene polymorphisms with the risk of congenital heart disease in offspring: a hospital-based case-control study.

BACKGROUND: Evidence suggests that periconceptional folic acid supplementation may prevent congenital heart disease (CHD). Methionine synthase reductase (MTRR) is one of the key regulatory enzymes in the folate metabolic pathway. This study aimed to comprehensively evaluate the association of single nucleotide polymorphisms (SNPs) in the maternal MTRR gene with CHD risk in offspring. METHODS: A hospital-based case-control study involving 740 mothers of CHD cases and 683 health controls was conducted. RESULTS: The study showed that maternal MTRR gene polymorphisms at rs1532268 (C/T vs. C/C: aOR = 1.524; T/T vs. C/C: aOR = 3.178), rs1802059 (G/A vs. G/G: aOR = 1.410; A/A vs. G/G: aOR = 3.953), rs2287779 (G/A vs. G/G: aOR = 0.540), rs16879334 (C/G vs. C/C: aOR = 0.454), and rs2303080 (T/A vs. T/T: aOR = 0.546) were associated with the risk of CHD. And seven haplotypes were observed to be associated with the risk of CHD, T-G-A haplotype (OR = 1.298), C-A-C-C (OR = 4.824) and A-G haplotype (OR = 1.751) were associated with increased risk of CHD in offspring; A-A-A (OR = 0.773), T-A-A (OR = 0.557), G-A-C-C (OR = 0.598) and G-C (OR = 0.740) were associated with decreased risk of CHD in offspring. CONCLUSIONS: Maternal MTRR gene polymorphisms were associated with CHD in offspring, and its haplotypes have affected the occurrence of CHD. Furthermore, given the complexity and heterogeneity of CHD, the mechanisms by which these factors influence offspring cardiac development remain unknown, and studies in larger samples in an ethnically diverse population are needed.

Genetic Polymorphisms of Gene Methionine Synthase Reductase (MTRR) and Risk of Urinary Bladder Cancer.

Methionine synthase reductase (MTRR) gene involved in the signaling for production of enzyme called methionine synthase reductase that use for the synthesis of methionine, which further used in DNA replication and repair. Genetic variation in MTRR gene may alter the susceptibility of developing urinary bladder cancer. The present study undertaken to identify the contribution of genetic polymorphisms in the MTRR gene on the selected polymorphic sites including c.66A>G and c.524C>T towards urinary bladder cancer risk. Direct-DNA sequencing method was applied for the observation of genotyping distribution of MTRR c.66A>G and c.524C>T polymorphisms in 232 histopathological confirmed cases of transitional cell carcinoma (TCC) of urinary bladder cancer and 250 age-, sex- and ethnicity-matched cancer free controls. With significant difference (p = 0.05) of genotype analysis further corresponding Odds ratio (OR) and 95% confidence interval (CI) were calculated. Multivariable logistic regression analysis was applied for adjusting significant confounder variables. Haploview software (version 4.2) was used to perform pairwise Linkage Disequilibrium (LD) analysis. Age (p = 0.01), Habit of smoking (p = 0.05), tobacco consumption (p = 0.001) and diet (p = 0.02) were significantly differed between cases and controls. Both the MTRR substitution showed higher risk of developing urinary bladder cancer (p = <0.001), although this effect alters in multivariable logistic regression analysis in a protective association for both the substitution. No LD observed between the c.66A>G and c.524C>T substitutions. In conclusion, MTRR c.66A>G and c.524C>T substitutions showed a joint effect with the other associated risk factors. Further studies with a greater number of subjects of different ethnicity and polymorphisms are recommended for the better understanding urinary bladder cancer etiology and to screen the population who are at higher risk of developing urinary bladder cancer.

Role of folate metabolizing genes and homocysteine in mothers of Down syndrome children.

Objectives: Folates are essential nutrients required for the synthesis of DNA/RNA in cell division and segregation. Folates are reduced and methylated in the liver with the help of enzymes such as methylenetetrahydrofolate reductase (MTHFR), MTR MTRR, reduced folate carrier 1, and cystathionine-ß-synthase. Variants in the genes encoding these enzymes may lead to hypomethylation, resulting in nondisjunction which in turn increases the risk for Down syndrome (DS). The present study was conducted to genotype these genes and to see their association with homocysteine levels. Materials and Methods: A total of 213 mothers having DS children and 220 mothers having normal children were enrolled in the study. Genomic DNA was isolated from lymphocytes followed by polymerase chain reaction/Restriction Fragment Length Polymorphism for genotyping. Homocysteine levels were checked by chemoassay utilizing coumarin-based fluorescent probe. Results: Genotypic frequency of MTHFR 1298 A > C polymorphism was significantly different among cases and controls (χ 2 = 5.83, P = 0.01), presence of C instead of A allele provided protection against DS in mothers (odds ratios = 0.57, 95% confidence interval = 0.35-0.91, P = 0.01). Higher levels of homocysteine were independently associated with the risk of having DS child (P = 0.0001). Conclusion: Homocysteine acted as an independent risk factor in the present study and was not associated with folate metabolizing gene variants.

Different effects of maternal homocysteine concentration, MTHFR and MTRR genetic polymorphisms on the occurrence of fetal aneuploidy.

RESEARCH QUESTION: Do maternal homocysteine (Hcy) concentrations, MTHFR and MTRR genes have effects on the occurrence of fetal aneuploidy? DESIGN: A total of 619 aneuploidy mothers and 192 control mothers were recruited in this study. Differences in distributions of maternal MTHFR 677C>T, MTHFR 1298A>C and MTRR 66A>G genetic polymorphisms and maternal Hcy concentrations between aneuploidy mothers and control mothers were analysed. RESULTS: The maternal MTHFR 677C>T polymorphism was found to be a risk factor for the occurrence of many fetal non-mosaic aneuploidies studied here, including trisomies 13, 15, 16, 18, 21, 22, TRA and TS. The maternal MTHFR 1298A>C polymorphism was found to be a risk factor specifically associated with the occurrence of fetal trisomy 15 and fetal TS. The maternal MTRR 66A>G polymorphism was found to be a risk factor only specifically associated with the occurrence of fetal trisomy 21. The Hcy concentrations of mothers of trisomies 22, 21, 18, 16, 15 and TS fetuses were significantly higher than the Hcy concentrations of control mothers. CONCLUSIONS: Overall, data suggested an association between these maternal polymorphisms and the susceptibility of fetal non-mosaic trisomy and Turner syndrome. However, these three maternal polymorphisms had different associations with the susceptibility of different fetal aneuploidies, and the elevated maternal Hcy concentration appeared to be a likely risk factor for fetal Turner syndrome and fetal trisomies.

MTRR rs1532268 polymorphism and gastric cancer risk: evidence from a meta-analysis.

OBJECTIVE: The methionine synthase reductase (MTRR) gene encodes the MTRR enzyme involved in the metabolic pathway of homocysteine. Several studies investigated the effect of the MTRR rs1532268 gene polymorphism on the risk of gastric cancer (GC), but the results have been inconsistent. METHODS: We performed a comprehensive and systematic search of PubMed, Google Scholar, MEDLINE, Science Direct, Scopus, CNKI, and Web of Science. Five studies were included in this meta-analysis to determine whether MTRR rs1532268 polymorphism contributes to the risk of GC. RESULTS: Pooled data indicated that the MTRR rs1532268 polymorphism significantly increased GC risk under the allele comparison model (odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.01-1.29) and dominant model (OR = 1.14, 95% CI = 1.00-1.30). In the analysis stratified by ethnicity, no relationship was found in Whites or Asians. CONCLUSION: Our meta-analysis suggests a positive correlation between MTRR rs1532268 polymorphism and GC development.

Analysis of the frequency distribution of five single-nucleotide polymorphisms of the MTRRgene in a Chinese pediatric population with acute lymphoblastic leukemia.

STUDY OBJECTIVE: The objective of the present study was to examine the frequency distribution of five single-nucleotide polymorphisms (SNPs; rs1801394 A>G, rs1532268 C>T, rs162036 A>G, rs10380 C>T, and rs9332 C>T) of the methionine synthase reductase (MTRR) gene, their effects on methotrexate (MTX) concentration, and the risk of relapse in a Chinese pediatric population with acute lymphoblastic leukemia (ALL). DESIGN: This was a retrospective single-center study, and all analyses were exploratory. SETTING: Pediatric Department of Beijing Shijitan Hospital, Capital Medical University, Beijing, China. PATIENTS: One hundred and forty pediatric patients with ALL. INTERVENTION: All patients were treated according to the Chinese Children's Leukemia Group (CCLG)-ALL 2008 protocol. MEASUREMENTS AND MAIN RESULTS: Serum MTX concentrations were measured using fluorescence polarization immunoassay. Genotyping of five SNPs was performed using the Sequenom MassARRAY iPLEX platform. Chinese children with ALL had a significantly lower frequency of rs1801394 G than European (EUR) and South Asian (SAS) populations; significantly lower frequency of rs1532268 T than American (AMR), EUR, and SAS populations; and significantly lower frequencies of rs162036 G, rs10380 T, and rs9332 T than African and AMR populations (p < 0.01). Seven haplotypes were observed, with the ACACC being the most common haplotype (49.9%) in our study. The median dose-normalized concentrations of MTX in serum at 24 h in children with rs1532268 CT and TT genotypes were significantly higher than those with CC genotype (p = 0.04). Compared with children with AA-CC-AA-CC-CC diplotype, a significantly higher risk of relapse was observed in children with AG-CC-AA-CC-CC and AG-CC-AG-CC-CC diplotypes (p = 0.03 and 0.003, respectively). CONCLUSIONS: The present study confirmed the ethnic differences in the distribution of MTRR rs1801394, rs1532268, rs162036, rs10380, and rs9332 polymorphisms. The rs1532268 polymorphism had greater effects on MTX disposition. The AG-CC-AA-CC-CC and AG-CC-AG-CC-CC diplotypes were significantly associated with higher risk of relapse of ALL.

Distribution of Methionine Synthase Reductase (MTRR) Gene A66G Polymorphism in Indian Population.

Methionine synthase reductase (MTRR) is an important enzyme of the folate/homocysteine pathway. It is responsible for regulation of methionine enzyme by reductive methylation. A common variant A66G is reported in the FMN-binding domain of the MTRR gene, which leads to substitution of isoleucine by methionine (I22M) in MTRR enzyme with reduced activity. Reduced catalytic activity of enzyme leads to high homocysteine concentration in blood and increases risk for numerous diseases. The frequency of A66G polymorphism varies in different ethnic groups. The present study has been designed to evaluate the frequency of MTRR A66G gene polymorphism in the Eastern UP population by PCR-RFLP method. Along with this we also performed a meta-analysis to evaluate the global prevalence of this polymorphism. Databases were screened to identified the eligible studies. The prevalence of the G allele and GG genotype was determined by the use of prevalence proportion with 95% CI. Open meta-analyst software was used for the meta-analysis. Total 1000 blood samples were analyzed, the frequencies of A and G alleles were 0.35 and 0.65 respectively. Meta-analysis results revealed that the prevalence of G allele and GG genotype were 49.4% (95% CI 40.6-58.1, p ≤ 0.001) and 24.3% (95% CI 17.8-30.9, p ≤ 0.001) respectively. In sub-group meta-analysis, the lowest frequency of G allele was found in South America (32.7%; 95% CI 14.1-51.3, p ≤ 0.001), and highest in Asia (56.4%; 95% CI 39.5-73.3, p ≤ 0.001). The results of the meta-analysis showed that the Asian population has the highest frequency of G allele and highest frequency of the GG genotype was found in the European population.

Variants of Genes Involved in Metabolism of Folate Among Patients with Breast Cancer: Association of TYMS 3R Allele with Susceptibility to Breast Cancer and Metastasis.

BACKGROUND & OBJECTIVE: Breast cancer (BC) is known to be the most prevalent cancer among women. One-carbon metabolism disturbance might play an important role in the etiology of BC. The present study aimed to investigate the thymidylate synthase (TYMS), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and methionine synthase reductase (MTRR) variants as good candidates for studying the role of genetic variants of folate metabolizing enzymes in the risk of BC. METHODS: The present case-control study includes 100 BC patients and 141 healthy females. The TYMS 2R/3R (rs34743033), MTR c.2756A>G (rs1805087), and MTRR c.66A>G (rs1801394) variants were detected by polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (RFLP), and a designed amplification-refractory mutation system (ARMS) method, respectively. RESULTS: The 3R allele of TYMS enhanced the risk of BC by 2.84-fold (P<0.001). In the presence of TYMS 3R/3R, compared to TYMS 2R/3R, there was a trend toward enhancing the risk of metastasis by 4.15-fold (95% CI: 0.96-17.85, P=0.055). The frequencies of MTR c.2756A>G and MTRR c.66A>G variants were not significantly different among patients and controls. CONCLUSION: We observed that the TYMS 3R is a risk allele for susceptibility to BC and this allele may increase the risk of metastasis in BC patients. .

Distribution of gene polymorphism in folate metabolism pathway and its effect on serumhomocysteine concentration / 中国临床药理学与治疗学

AIM: To study the polymorphism distribution of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes and their influence on serum homocysteine (Hcy) concentration. METHODS: A total of 148 patients diagnosed with ischemic stroke from November 2020 to February 2021 in Yijishan Hospital of Wanan Medical College were selected for the study, and patients were typed for MTHFR 677C/T and MTRR 66A/G genes using fluorescent staining in situ hybridization technique. Serum Hcy concentrations were measured in 21 patients using a circulating enzyme assay. The distribution of MTHFR 677C/T and MTRR 66A/G gene polymorphisms were analyzed, and the differences in serum Hcy concentrations between patients with different genotypes were compared. RESULTS: The mutation rates of MTHFR 677C/T and MTRR 66A/G genes were 42.57% and 26.01%, respectively, and no significant differences in gene distribution frequencies were observed between men and women (P>0.05). The mean Hcy serum concentration was (16.04±4.34) μmol/L in 21 patients, including 8 patients (38.10%) with 0.05). CONCLUSION: MTHFR gene polymorphisms can affect serum Hcy concentrations. The MTHFR genotyping can be considered for individualized folic acid supplement. This conclusion should be further verified by expanding the clinical sample size.

Variants c.677 C>T, c.1298 A>C in MTHFR, and c.66 A>G in MTRR Affect the Occurrence of Recurrent Pregnancy Loss in Chinese Women.

Objective: Although genetic variants of key enzymes in the folic acid-methionine metabolic circulation, including methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) were thought to be related to the risk of recurrent pregnancy loss (RPL), the results of recent studies have been inconsistent. Therefore, the present retrospective case-control study was designed to explore whether the variants c.66A>G in MTRR and c.677C>T and c.1298A>C in MTHFR are associated with the susceptibility of RPL in Southeast Chinese women. Materials and Methods: In total, samples from 237 RPL patients and 618 healthy controls were collected and genotyped by fluorescent quantitative polymerase chain reaction. The frequencies of the variants were calculated and compared between the two groups. The relative risk of the various genotypes was further determined by calculating the odds ratio (OR) at a 95% confidence interval (CI). Results: A significant positive correlation was observed between the variants MTHFR c.677C>T, MTHFR c.1298A>C, MTRR c.66A>G, and RPL susceptibility (MTHFR c.677C>T, OR = 0.74, 95% CI = 0.58-0.95, p = 0.02; MTHFR c.1298A>C, OR = 1.39, 95% CI = 1.09-1.77, p = 0.008; MTRR c.66A>G, OR = 1.38, 95% CI = 1.10-1.73, p = 0.006). Further analysis of the genotypic distributions of the three variants between the two groups showed that the MTHFR c.677C>T heterozygote was associated with lower RPL risk, while the MTHFR c.1298A>C variant and MTRR c.66A>G heterozygote were correlated with higher RPL risk (dominant model, MTHFR c.677C>T, OR = 0.70, 95% CI = 0.52-0.95, p = 0.02; MTHFR c.1298A>C, OR = 1.39, 95% CI = 1.03-1.88, p = 0.032; MTRR c.66A>G, OR = 1.62, 95% CI = 1.20-2.19, p = 0.002). Conclusion: MTHFR c.677C>T and c.1298A>C and MTRR c.66A>G were associated with RPL in Southeast Chinese women.

Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice.

Nonalcoholic fatty liver disease (NAFLD) is associated with dietary folate deficiency and mutations in genes required for one­carbon metabolism. However, the mechanism through which this occurs is unclear. To improve our understanding of this link, we investigated liver morphology, metabolism and fuel storage in adult mice with a hypomorphic mutation in the gene methionine synthase reductase (Mtrr gt ). MTRR enzyme is a key regulator of the methionine and folate cycles. The Mtrr gt mutation in mice was previously shown to disrupt one­carbon metabolism and cause a wide-spectrum of developmental phenotypes and late adult-onset macrocytic anaemia. Here, we showed that livers of Mtrr gt/gt female mice were enlarged compared to control C57Bl/6J livers. Histological analysis of these livers revealed eosinophilic hepatocytes with decreased glycogen content, which was associated with down-regulation of genes involved in glycogen synthesis (e.g., Ugp2 and Gsk3a genes). While female Mtrr gt/gt livers showed evidence of reduced ß-oxidation of fatty acids, there were no other associated changes in the lipidome in female or male Mtrr gt/gt livers compared with controls. Defects in glycogen storage and lipid metabolism often associate with disruption of mitochondrial electron transfer system activity. However, defects in mitochondrial function were not detected in Mtrr gt/gt livers as determined by high-resolution respirometry analysis. Overall, we demonstrated that adult Mtrr gt/gt female mice showed abnormal liver morphology that differed from the NAFLD phenotype and that was accompanied by subtle changes in their hepatic metabolism and fuel storage.

Associations between folate metabolism enzyme polymorphisms and breast cancer: A meta-analysis.

We performed this meta-analysis to explore associations between folate metabolism enzyme polymorphisms and breast cancer (BC) in a larger pooled population. Systematic literature research was performed to identify eligible studies for pooled analyses. Totally 92 genetic association studies were included for analyses. The pooled analyses revealed significant findings for MTRR rs1801394 polymorphism in South Asians, for MTR rs1805087 polymorphism in Caucasians and East Asians, and for MTHFR rs1801133 polymorphism in East Asians. In conclusion, the present meta-analysis indicated that MTRR rs1801394, MTR rs1805087, and MTHFR rs1801133 polymorphisms could be used to identify individuals at high risk of developing BC.

The MTHFR 677C>T polymorphism is associated with unmetabolized folic acid in breast milk in a cohort of Canadian women.

BACKGROUND: Maternal nutrition and genetics are determinants of breast-milk nutrient composition and, as such, are determinants of the nutritional exposure of breastfed infants. OBJECTIVES: The aim of this study was to determine whether common maternal single nucleotide polymorphisms (SNPs) in folate-dependent enzymes are associated with breast-milk folate content in a cohort of mothers enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. METHODS: The MIREC study is a Canadian prospective pregnancy cohort study that recruited 2001 participants between 2008 and 2011. Five folate-related SNPs-MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTHFR 1793G>A (rs2274976), MTR 2756A>G (rs1805087), and MTRR 66A>G (rs1801394)-were genotyped. Breast milk was sampled ∼1 mo postpartum, and tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF, 5,10-methenyl-THF, and unmetabolized folic acid (UMFA) were measured using liquid chromatography-tandem mass spectrometry in a subset of participants (n = 551). Associations were assessed using Wald's test. Associations were considered significant if P ≤ 0.01 (Bonferroni correction for multiple testing). RESULTS: None of the SNPs were associated with total breast-milk folate. However, the MTHFR 677C>T SNP was associated with breast-milk UMFA (R2 = 0.01; unadjusted P = 0.004), explaining a small portion of total variance; this association remained significant when adjusted for other covariates, including supplemental folic acid consumption. The MTHFR 1793G>A and MTRR 66A>G SNPs tended to be associated with 5-methyl-THF (R2 = 0.008, P = 0.04) and reduced folates (THF + 5-methyl-THF + 5-formyl-THF + 5,10-methenyl-THF; R2 = 0.01, P = 0.02), respectively. CONCLUSIONS: We found that total breast-milk folate content was not associated with any of the folate-related SNPs examined. The association between the MTHFR 677C>T SNP and breast-milk UMFA, albeit modest, highlights the need to better understand the determinants of breast-milk folate and the impact they might have on milk folate bioavailability.

Research Progress of Folate Metabolic Gene Polymorphism / 医药导报

Through summarizing and analyzing a large number of documents and reports of large academic conferences in China, the current situation and the prospect of individualized drug delivery model were analyzed based on folate metabolic gene in pharmaceutical care. Folate metabolic genemethylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G were related with development of multiple diseases. Its polymorphism guidesindividualized drug administrationto increase the efficacy of drugs or decrease adverse effects.

The roles of MTRR and MTHFR gene polymorphisms in congenital heart diseases: a meta-analysis.

Background: We performed the present study to better elucidate the correlations of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms with the risk of congenital heart diseases (CHD).Methods: Eligible articles were searched in PubMed, Medline, Embase and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations of MTHFR and MTRR gene polymorphisms with CHD.Results: A total of 47 eligible studies were finally included in our meta-analysis. Our overall analyses suggested that MTRR rs1801394, MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms were all significantly associated with the risk of CHD in certain genetic models. Further subgroup analyses according to ethnicity of study participants demonstrated that the MTRR rs1801394 polymorphism was significantly correlated with the risk of CHD only in Asians, whereas MTRR rs1532268, MTHFR rs1801133 and MTHFR rs1801131 polymorphisms were significantly correlated with the risk of CHD in both Asians and Caucasians.Conclusions: Our findings indicated that MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may affect the risk of CHD in Asians and Caucasians, while the MTRR rs1801394 polymorphism may only affect in risk of CHD in Asians.

The relationship between gene polymorphism of MTRR A66G and lower extremity deep venous thrombosis.

OBJECTIVE: To investigate the relationship between gene polymorphism of MTRR A66G and lower extremity deep venous thrombosis (DVT). METHODS: Two hundred and two patients with DVT as experimental group and 240 normal adults (control group) were enrolled in this study and white blood cells were collected, respectively. Polymorphism of the 66 loci in MTRR gene was detected by polymerase chain reaction-sequence-specific primers (PCR-SSP) in two groups. The frequency of genotype and allele distribution of each group was compared. RESULTS: The frequency of AA, AG and GG genotypes in 66 sites of MTRR gene were 26.76%, 4 3.66% and 29.58% in DVT group and 43.57%, 44.28% and 12.14% in control group, respectively. There was no significant difference in the distribution frequency between two groups (χ = 3.2, P > .5). CONCLUSIONS: The gene polymorphism of MTRR A66G may not be an independent genetic risk factor in DVT in China.

Are polymorphisms in MTRR A66G and MTHFR C677T genes associated with congenital heart diseases in Iranian population?

BACKGROUND: The 5, 10-methyleneterahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are two essential enzymes involved in folate metabolism. The relationship between genetic polymorphisms and congenital heart defects (CHDs) is inconsistent. Our aim was to investigate the association between two well-known polymorphisms of MTHFR and MTRR genes, C677T and A66G, respectively, and CHDs in Iranian patients. METHODS: We enrolled 74 patients with ventricular septal defect (VSD) and 79 with tetralogy of fallot (TOF) along with 147 healthy controls. C677T and A66G polymorphisms were detected using tetra-primer ARMS (amplification refractory mutation system) PCR. RESULTS: Individuals carrying homozygote mutant (TT) genotype of C677T polymorphism represented the highest risk for CHDs (OR=7.3, 95% CI: 0.8-61, P=0.06). Also, significantly increased risk of VSD was observed in individuals with TT genotype (OR=10, 95% CI: 1-92.2, P=0.04). However, the frequency for variant allele (T) of C677T polymorphism was not statistically different between cases and controls (16.3% and 20.9%, respectively). For A66G polymorphism, we found that AG and GG genotypes had higher frequencies in the patients (48.4% and 21.6% respectively) than controls (42.9% and 15.6%, respectively). In line with this, combined AG+GG genotype represented with significantly elevated risk of CHDs (OR=1.6; 95% CI: 1-2.6, P=0.03). AG+GG combination was also identified as a risk factor for TOF (OR=1.8, 95% CI: 1-3.3, P=0.04). CONCLUSION: We demonstrated that C677T polymorphism of MTHFR gene was significantly associated with VSD in our patients. Our study also suggested that A66G polymorphism of MTRR gene may contribute to the development of TOF in Iranians.

Association of Three Single Nucleotide Polymorphisms in MTR and MTRR Genes with Lung Cancer in a Turkish Population.

AIMS: Folate metabolism plays a critical role in DNA methylation and synthesis. Polymorphisms in folate metabolism may affect enzyme activities and thereby affect the cancer risk. Methionine synthase (MTR) and methionine synthase reductase (MTRR) are critical enzymes for the folate cycle. In this study, possible associations between genetic variabilities in MTR and MTRR and susceptibility to lung cancer (LC) were investigated in a Turkish population. METHODS: A case-control study with 193 LC cases and 199 noncancerous controls was conducted. DNA was extracted from leukocytes using the high pure polymerase chain reaction (PCR) template preparation kit. The MTR 2756 A>G (rs1805087), MTRR 524 C > T (rs1532268), and MTRR 66 A>G (rs1801394) genotypes were determined using PCR-restriction fragment length polymorphism (PCR-RFLP) assays. The genotype and haplotype analyses of these polymorphisms were performed using SPSS 21 and Haploview 4.2, respectively. RESULTS: An association between the MTRR A66G polymorphism and LC (p = 0.042) was found. In addition, this allele was observed more frequently in smokers compared to nonsmokers (p = 0.030). In contrast, the distribution of the MTR 2756 A>G and the MTRR 524 C > T allele frequencies were similar in the subject cases and controls. CONCLUSIONS: In conclusion, the present study suggests an association between the MTRR 66 A>G gene polymorphisms and LC risk in a Turkish population.