MTRR 66A Research Articles

Association of maternal genetic polymorphisms with fetal growth restriction syndrome in Russian pregnant women from Rostov region

BackgroundFetal growth restriction (FGR) is one of the main syndromes causing fetal morbidity and mortality. It was known to be associated with different factors including maternal, fetal, and environmental. However, the effect of genetic factors in FGR is not totally understood. Recently, researchers have focused on investigating genetic variants as possible markers of FGR. This especially concerns maternal genetic polymorphisms since they could serve as prenatal prognostic biomarkers. Accordingly, we aimed to study the association of several polymorphisms affecting vital processes of pregnancy with FGR in pregnant women. Targeted polymorphisms include methylenetetrahydrofolate reductase (MTHFR) 677C > T; methionine synthase reductase (MTRR) 66A > G; methionine synthase (MTR) 2756A > G; angiotensinogen (AGT) 704 T > C; and vascular endothelial growth factor A (VEGFA) 634C > G. In addition, this study examined SNP–SNP interactions, linkage disequilibrium (LD), and haplotypes association for these polymorphisms in the studied population.ResultsAccording to our data, MTRR 66(GG) carriers had increased FGR risk (OR = 3.18, 95% CI 1.31–7.72) while (AG) genotype was associated with lower FGR risk (OR = 0.37, 95% CI 0.17–0.84). AGT 704T > C also showed significant association with FGR with allele (T) as a risk factor. SNP–SNP interactions analysis revealed antagonistic relationship between these two polymorphisms and haplotypes association confirmed this finding. High LD possibility was shown between MTHFR 677C > T and MTR 2756A > G (D′ = 0.999) located on chromosome 1.ConclusionWe suggest MTRR 66A > G and AGT 704T > C as associated with FGR susceptibility with antagonistic interaction. Result will help to expand our understanding of FGR as a multifactorial syndrome and improve prenatal prognosis using maternal genetic biomarkers, but further studies in different populations are needed to confirm findings.

Polymorphisms in Maternal Selected Folate Metabolism-Related Genes in Neural Tube Defect-Affected Pregnancy.

Neural tube defects (NTDs) are abnormalities of the brain and spinal cord, which occur as a result of failure in neural tube closure during embryogenesis. Causes of NTDs are complex and multiple, with hereditary, lifestyle, and environmental factors appearing to play a role. In spite of their impact on public health, the role genetics play on NTDs in Ethiopia is lacking. In this study, the role of polymorphisms in MTHFR 677C > T (rs1801133), MTHFR 1298A > C (rs1801131), MTRR 66A > G (rs1801394), RFC1 80A > G (rs1051266), and TCN2 776C > G (rs1801198) on the risk of having NTD-affected pregnancy was investigated. One hundred women with NTD-affected pregnancy and 100 women with normal pregnancy were included in the study. DNA was extracted from saliva and genotyping for five polymorphisms in four genes was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The departure of the genotype's distribution from Hardy-Weinberg equilibrium (HWE) was evaluated using the x2 goodness-of-fit test. Frequencies of genotypes and alleles in case and control mothers were determined and differences between relative frequencies were evaluated by the x2 or the Fisher's exact test. The statistically significant difference was absent in the genotype and allele frequencies for all the analyzed polymorphisms between cases and controls (P > 0.05). MTHFR 677C > T, MTHFR 1298A > C, MTRR 66A > G, RFC1 80A > G, and TCN2 776C > G polymorphisms lack association with the risk of having a pregnancy affected by NTD. The role of other genes or environmental factors in NTD etiology needs to be investigated.

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

Research questionDo maternal homocysteine (Hcy) concentrations, MTHFR and MTRR genes have effects on the occurrence of fetal aneuploidy? DesignA 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. ResultsThe 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. ConclusionsOverall, 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.

The interaction of folate cycle enzyme genes and the risk of extrapyramidal side effects of antipsychotics

Personalized medicine means the selection of therapy for patients, taking into account the assessment of genetic risk factors for side effects. A number of studies show that folate metabolism disorders, including single nucleotide polymorphisms (SNPs) in the genes of folate-metabolizing enzymes, are more frequently detected in schizophrenic patients than in the general population. The role of SNPs of the key folate cycle enzymes in developing the extrapyramidal side effects of antipsychotics has not yet been studied, although there is evidence of their association with other movement disorders.Objective: to analyze the association between the carriage of SNP alleles of MTHFR 677C>T, MTR 2756A>G, and MTRR 66A>G and the severity of extrapyramidal side effects of antipsychotics in patients with schizophrenia.Patients and methods. The investigation included 61 patients with schizophrenia (according to the criteria for ICD-10 Code F20). All the patients took antipsychotics for at least 7 hospital days were examined using real-time polymerase chain reaction (PCR) with allele-specific primers, followed by detection for the carriage of SNP alleles of MTHFR 677C>T, MTR 2756A>G, and MTRR 66A>G. The standardized Simpson–Angus scale (SAS) was used to evaluate the severity of extrapyramidal symptoms; the PCR test results were unknown during their examination.Results and discussion. In the patients carrying a low-functional 677 T allele in the gene of the key folate cycle enzyme MTHFR, the severity of extrapyramidal side effects of antipsychotics was statistically significantly higher than in the carriers of the wild-type genotype: 13.27±5.10 versus 9.84±6.03 SAS scores, respectively (t=-2.40; p=0.020). In addition, the carriage of the wild allele A of SNP in the MTRR 66A>G gene (F=3.83; p=0.0283; pcorr.=0.043) is associated with the severity of extrapyramidal symptoms. There was a direct moderate correlation of the number of risk alleles at two loci with the total SAS score (r=0.51; p=0.00017).Conclusion. The polymorphic allele of MTHFR 677T and the wild allele of MTRR 66A can be regarded as risk alleles for the development of extrapyramidal side effects of antipsychotics.

Polymorphisms of genes required for methionine synthesis and DNA methylation influence mitochondrial DNA methylation.

Aim: Impaired methylation of the mitochondrial DNA and particularly in the regulatory displacement loop (D-loop) region, is increasingly observed in patients with neurodegenerative disorders. The present study aims to investigate if common polymorphisms of genes required for one-carbon metabolism (MTHFR, MTRR, MTR and RFC-1) and DNA methylation reactions (DNMT1, DNMT3A and DNMT3B) influence D-loop methylation levels. Materials & methods: D-loop methylation data were available from 133 late-onset Alzheimer's disease patients and 130 matched controls. Genotyping was performed with PCR-RFLP or high resolution melting techniques. Results: Both MTRR 66A > G and DNMT3A -448A > G polymorphisms were significantly associated with D-loop methylation levels. Conclusion: This exploratory study suggests that MTRR and DNMT3A polymorphisms influence mitochondrial DNA methylation; further research is required to better address this issue.

Effects of methionine synthase and methionine synthase reductase polymorphisms on hypertension susceptibility.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are strongly associated with hypertension incidence, although such association is inconsistent among ethnicities studied. However, effects of polymorphisms of other genes related to folate metabolism besides MTHFR on hypertension susceptibility are not well known yet. The aim of this study was to elucidate whether methionine synthase (MTR) 2756A>G and methionine synthase reductase (MTRR) 66A>G polymorphisms might be associated with risks of hypertension susceptibility in the Korean population. Genotyping of these two polymorphisms was performed for 232 hypertensive patients and 247 unrelated healthy controls using polymerase chain reaction-restriction fragment length polymorphism technique. In the present study, mutations of MTR 2756A>G and MTRR 66A>G polymorphisms were associated with increased and decreased susceptibility to hypertension, respectively. Allele combinations from these two polymorphisms were also related to hypertension prevalence. When polymorphism data were stratified according to clinical components of hypertension, The G allele of MTR 2756A>G polymorphism was significantly associated with an increased risk of hypertension in subjects with BMI < 26.1kg/m2 (P = 0.004), WC < 87.2 in. (P = 0.021), FBG < 95.5mg/dL (P = 0.011), triglyceride < 133.5mg/dL (P = 0.034), and HDL-cholesterol < 52.2mg/dL (P = 0.036). The G allele of MTRR 66A>G polymorphism was significantly associated with a decreased risk of hypertension in subjects with WC ≥ 87.2 in. (P = 0.029), FBG ≥ 95.5mg/dL (P = 0.032) and triglyceride ≥ 133.5mg/dL (P = 0.027). MTR 2756A>G and MTRR 66A>G polymorphisms related to folate metabolism might be genetic markers for risk of hypertension in the Korean population.

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels.

DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of DNA methylation patterns during cell division. Several human diseases are characterized by impaired DNMT1 gene methylation, but less is known about the factors that regulate DNMT1 promoter methylation levels. Dietary folates and related B-vitamins are essential micronutrients for DNA methylation processes, and we performed the present study to investigate the contribution of circulating folate, vitamin B12, homocysteine, and common polymorphisms in folate pathway genes to the DNMT1 gene methylation levels. We investigated DNMT1 gene methylation levels in peripheral blood DNA samples from 215 healthy individuals. All the DNA samples were genotyped for MTHFR 677C > T (rs1801133) and 1298A > C (rs1801131), MTRR 66A > G (rs1801394), MTR 2756A > G (rs1805087), SLC19A1 (RFC1) 80G > A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp insertion/deletion (indel) (rs34489327), DNMT3A -448A > G (rs1550117), and DNMT3B -149C > T (rs2424913) polymorphisms. Circulating homocysteine, folate, and vitamin B12 levels were available from 158 of the recruited individuals. We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels. Furthermore, both MTR rs1805087 and TYMS rs34743033 polymorphisms showed a statistically significant effect on DNMT1 methylation levels. The present study revealed several correlations between the folate metabolic pathway and DNMT1 promoter methylation that could be of relevance for those disorders characterized by altered DNA methylation.

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

Maternal nutrition and genetics are determinants of breast-milk nutrient composition and, as such, are determinants of the nutritional exposure of breastfed infants. 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. 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). 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. 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.

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels.

Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation.

Polymorphism of Folate metabolism genes and risk of lung cancer

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality worldwide. Folate metabolism plays an important role in carcinogenesis through its involvement in the process of dNamethylation and repair.The aim of our studywas to evaluate the relationship between MTHFR С677Т (rs1801133), MTR A2756G (rs1805087), MTRR А66G (rs1801394) gene polymorphisms and lung cancer risk.Material and methods.Asystematic literature search was conducted in the electronic databases pubmed, elibrary.ru in the time period between 2003 and 2018.Results.The MTHFR C677Tand MTRR А66G gene polymorphisms were found to be significantly associated with lung cancer. No significant association between the MTR A2756Gpolymorphism and lung cancer risk was found. the variant alleles of MTR 2756A &gt; Gand MTRR 66A &gt; Gpolymorphisms may have a joint effect on lung cancer risk. anumber of factors, such as nationality, smoking, gender, and an accurate diagnosis can influence the results of studies on the role of genes involved in folate cycle in patients with lung cancer.Conclusion.Future studies are needed to consider gene-gene and gene-environment interactions in lung cancer. Further investigations on MTHFR С677Т (rs1801133), MTR A2756G (rs1805087), MTRR А66G (rs1801394) polymorphisms and lung cancer susceptibility may provide a theoretical basis for lung cancer prevention.

Genetic Polymorphisms of TYMS, MTHFR, ATIC, MTR, and MTRR Are Related to the Outcome of Methotrexate Therapy for Rheumatoid Arthritis in a Chinese Population.

Objective: Analysis of the relationship between single nucleotide polymorphisms (SNPs) and outcomes of methotrexate (MTX) therapy for rheumatoid arthritis (RA) in China.Materials and Methods: TYMS 28 bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) enzyme proteins may be related to the outcomes of MTX therapy, according to our previous meta-analysis. A total of 162 patients with RA were included in our study. SNPs were evaluated using polymerase chain reaction (PCR). Disease Activity Score 28 (DAS28) was used to evaluate the clinical response, and adverse drug reactions (ADRs) were collected after physical examinations of the patients.Results: The MTHFR 677C>T gene showed a relationship with the ADRs of MTX in the Recessive model [TT vs. (CC+CT)] (p = 0.04, OR = 2.20, 95% CI: 1.01, 4.77). In the Codominant model [CT vs. (CC+TT)], the MTHFR 677C>T gene also showed a trend of association with ADRs (p = 0.08, OR = 0.52, 95% CI: 0.25, 1.08). No significant difference was found between TYMS, MTHFR, ATIC, MTR, and MTRR gene polymorphisms and the RA response or ADRs related to MTX in our study.Conclusion: Our results showed that the MTHFR [677C>T (rs1801133)] TT genotype is associated with ADRs to MTX in Chinese RA patients. Other SNPs, including TYMS 28bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) gene polymorphisms, were not associated with MTX treatment outcomes. Further studies are required to validate these findings.

ИНФАРКТ МИОКАРДА В ПОСТПАРТАЛЬНОМ ПЕРИОДЕ У МОЛОДОЙ ЖЕНЩИНЫ С ДЕФИЦИТОМ ПРОТЕИНА С

Women of childbearing age without cardiovascular risk factors have low risk of acute myocardial infarction. Pregnancy has been shown to increase the risk of myocardial infarction compared to the risk in non-pregnant women of similar age. Acute myocardial infarction during pregnancy or postpartum period as a rule develops due to coronary spasm or non-atherogenic thrombosis or spontaneous coronary dissection. Thrombosis is most likely related to hypercoagulable state of pregnancy and postpartum period. It is worth considering the importance of defects of coagulation, such as Leiden factor, protein C, protein S, antithrombin III and mutations of propter genes. There is also the significant role of antiphospholipid antibodies in young women. We present the clinical case of acute ST-elevation myocardial infarction in 34-years old woman without traditional cardiovascular risk factors, which was developed after childbirth due to non-atherogenic left anterior coronary artery thrombosis. Her coagulation profile showed normal results for antithrombin III, protein S, prothrombin gene mutation, factor V Leiden and antiphospholipid antibody syndrome. At the same time the protein C activity decreased to 43 % as well as trombophilia genetic markers MTHFRC677T, MTRR 66A>G, ITGA2:807 C>T and ITGB:1565 T>C genetic polymorphisms were revealed.

One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation.

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation.The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.

Nonassociation of homocysteine gene polymorphisms with treatment outcome in South Indian Tamil Rheumatoid Arthritis patients.

The aim of the study was to look for any association of MTR 2756A>G and MTRR 66A>G gene polymorphisms with clinical phenotype, methotrexate (MTX) treatment response, and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). A total of 335 patients with RA were investigated. MTR 2756A>G gene polymorphism was analyzed by PCR-RFLP, and MTRR 66A>G SNP was analyzed by TaqMan 5' nuclease assay. The allele frequencies were compared with HapMap groups. MTR 2756G allele was found to be associated with risk of developing RA. The allele frequencies of MTR 2756A>G and MTRR 66A>G SNPs in controls differed significantly when compared with HapMap groups. Neither of the SNPs influenced the MTX treatment outcome and adverse effects. Neither of the SNPs seems to be associated with MTX treatment outcome and adverse events in South Indian Tamil patients with RA.

Genetic Variants Involved in One-Carbon Metabolism: Polymorphism Frequencies and Differences in Homocysteine Concentrations in the Folic Acid Fortification Era.

Folate and other B vitamins are essential co-factors of one-carbon metabolism, and genetic variants, such as polymorphisms, can alter the metabolism. Furthermore, the adoption of food fortification with folic acid showed a decrease of homocysteine concentration. The aim of this study was to investigate the frequencies of the polymorphisms of enzymes and carrier proteins involved in one-carbon metabolism, and to evaluate homocysteine concentrations in the presence of these genetic variants in a population exposed to mandatory food fortification with folic acid. Using data from a population-based cross-sectional study in São Paulo, Brazil, the study population comprised 750 participants above 12 years of age of both genders. A linear regression model was used to evaluate the homocysteine concentrations according to genetic variants and folate level. The results showed that the minor allelic frequencies were 0.33 for MTHFR (rs1801133), 0.24 for MTHFR (rs1801131), 0.19 for MTR (rs1805087), 0.42 for MTRR (rs1801394), 0.46 for RFC1 (rs1051266), and 0.47 for DHFR (19-bp deletion). The genetic variants of MTHFR 677C>T, MTRR 66A>G and RFC-1 80G>A were different according to race. The homocysteine concentrations increased in the CT and TT compared to CC genotypes of polymorphism MTHFR 677C>T in all populations, and differences between the homocysteine concentrations according to the genotypes of MTHFR 677C>T were observed regardless of folate level.

Major Polymorphisms of Genes Involved in Homocysteine Metabolism in Malaria Patients in Ouagadougou, Burkina Faso.

This study analyzed the four main polymorphisms of the genes in homocysteine metabolism in malaria patients. Forty-two randomly selected subjects, diagnosed positive for Plasmodium falciparum, were included. The four genotypes were detected by real-time PCR using the MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, and MTRR 66A>G detection kit (Sacace Biotechnologies REF: T01002-96-S). The results revealed frequencies of 90% 677CC, 10% 677CT, and 00% 677TT for MTHFR C677T; 78.6% 1298AA, 19% 1298AC, and 2.4% 1298CC for MTHFR A1298C; 61.9% 2756AA, 33.3% 2756AG, and 4.8% 2756GG for MTR A2756G; and 50% of 66AA, 45% of 66AG, and 5% of 66GG for MTRR A66G. Correlations were found between A2756G MTR genotypes and parasitaemia (P = 0.02), MTRR A66G and hemoglobin genotypes (P = 0.009), and MTHFR A1298C and sex (P = 0.01). This study demonstrated for the first time an association between the A2756G MTR alleles and Plasmodium falciparum malaria in Burkina Faso and gave an overview of the genotypic distribution of the major SNPs influencing the metabolism of homocysteine.

Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis

Methotrexate (MTX) is widely used and considered a first-line disease modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX effectiveness in RA patients, although inconsistent results have been reported. A systematic review and meta-analysis were performed to identify genetic variants associated with MTX efficacy. A total of 30 publications that included 34 genes and 125 SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the systematic review (SR), and 21 studies were included in 9 meta-analyses. Associations between MTX response in RA patients in MTHFR 1298A > C (rs1801131), ATIC 347C > G (rs2372536), RFC-1 80G > A (rs1051266), SLC19A1 A > G (rs2838956) and SLC19A1 G > A (rs7499) genetic polymorphisms were found, but not observed between the MTHFR 677C > T (rs1801133), TYMS 28 bp VNTR (rs34743033), MTRR 66A > G (rs1801394), and ABCB1 3435C > T (rs1045642). However, for the polymorphisms not being associated following meta-analysis could still be associated if larger cohorts were used, and studies of other polymorphisms are necessary in large cohorts and a rigorous way, which may provide more accurate results for the effect of the gene polymorphisms on the MTX response.

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.

The RFC1 80G>A, among Common One-Carbon Polymorphisms, Relates to Survival Rate According to DNA Global Methylation in Primary Liver Cancers.

Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low (≤5.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (p<0.0001) with a higher Hazard Ratio (HR = 6.62, p = 0.001). The subjects carrying the AA genotype in association with high mCyt did not show a significant difference in survival rate as compared with the G allele carriers (p = 0.919). The RFC1 80G>A polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers.

The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects.

Almost 15 years ago it was hypothesized that polymorphisms of genes encoding enzymes involved in folate metabolism could lead to aberrant methylation of peri-centromeric regions of chromosome 21, favoring its abnormal segregation during maternal meiosis. Subsequently, more than 50 small case-control studies investigated whether or not maternal polymorphisms of folate pathway genes could be risk factors for the birth of a child with Down syndrome (DS), yielding conflicting and inconclusive results. However, recent meta-analyses of those studies suggest that at least three of those polymorphisms, namely MTHFR 677C>T, MTRR 66A>G, and RFC1 80G>A, are likely to act as maternal risk factors for the birth of a child with trisomy 21, revealing also complex gene-nutrient interactions. A large-cohort study also revealed that lack of maternal folic acid supplementation at peri-conception resulted in increased risk for a DS birth due to errors occurred at maternal meiosis II in the aging oocyte, and it was shown that the methylation status of chromosome 21 peri-centromeric regions could favor recombination errors during meiosis leading to its malsegregation. In this regard, two recent case-control studies revealed association of maternal polymorphisms or haplotypes of the DNMT3B gene, coding for an enzyme required for the regulation of DNA methylation at centromeric and peri-centromeric regions of human chromosomes, with risk of having a birth with DS. Furthermore, congenital heart defects (CHD) are found in almost a half of DS births, and increasing evidence points to a possible contribution of lack of folic acid supplementation at peri-conception, maternal polymorphisms of folate pathway genes, and resulting epigenetic modifications of several genes, at the basis of their occurrence. This review summarizes available case-control studies and literature meta-analyses in order to provide a critical and up to date overview of what we currently know in this field.