Littérature scientifique sur le sujet « Folate pathway polymorphism »

Homocysteine and its modulating genes have strongly emerged as novel biomarkers for coronary artery disease (CAD). In the present study, we investigated whether polymorphisms in homocysteine pathway genes and the plasma levels of homocysteine, folate, and vitamin B12, independently or in combination, are associated with CAD risk. A total of 504 participants were recruited (cases, n = 254; controls, n = 250, respectively). Tetra primer allele refractory mutation system polymerase chain reaction (PCR) was used for resolving the genotypes of 5′10′ methylenetetrahydrofolate reductase ‘MTHFR’ polymorphisms (rs1801133, rs1801131), 5′ methyl tetrahydrofolate homocysteine methyltransferase ‘MTR’ polymorphism (rs1805087), paroxanse1 ‘PON1’ polymorphism (rs662), and cystathionine beta synthase ‘CBS’ polymorphism (rs5742905). Conventional PCR amplification was carried out for resolving angiotensin converting enzyme ‘ACE’ insertion/deletion (I/D) polymorphism (rs4646994). ANOVA analysis, adjusted for the covariates, revealed that rs1801133, rs1805087 polymorphisms and homocysteine levels were associated with CAD. Logistic regression analysis (adjusted) revealed similar findings. Logistic regression analysis after applying factorial design to the studied single nucleotide polymorphisms (SNPs) revealed that homocysteine levels and heterozygous and mutant alleles at rs1801133, rs1805087, along with mutant alleles at rs1801131, rs4646994, conferred higher risk for CAD. Our results provide insight into the multifactorial nature of coronary artery disease. We highlight that SNPs in folate pathway genes and homocysteine have role in disease causation and can be used in disease prediction strategies.

Summary Introduction: Osteoporosis is a chronic metabolic disease with multifactorial etiology. One of possible osteoporosis causes may be impairment of osteoclasts function which leads to increased bone resorption. This may be a result of many metabolic changes. It is believed that changes of folate-methionine metabolism in osteoporosis play an essential role in the etiology of this disease. Objective: The aim of this study was to examine how polymorphisms of SLC19A1 and FOLR3 genes may play the key role in folate-methionine pathway and influence on the etiology of osteoporosis. Results: The statistically overrepresentation of mutated GG genotype of FOLR3 (rs11235449) was observed in the control group compared to the osteopenia (34.9% in osteopenia vs. 37.8% in controls, p=0.025, OR=0.61). As to the SLC19A1 (rs3788200) polymorphism we have noted the statistically significant over-representation of wild-type GG genotype (35.8% vs. 26.2%, p=0.046, OR=1.57) and overrepresentation of wild-type G allele (56.9% vs. 50.2%, p=0.061, OR=1.31) in osteopenia group if compared to the controls. Conclusions: In our study we shown the protective role of mutated GG genotype of FOLR3 (rs11235449) polymorphism to osteopenia progress and possible role of wild-type GG genotype and wild-type G allele of SLC19A1 (rs3788200) polymorphism in osteopenia development.

Abstract Introduction. A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM. Methods. MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival. Results. Patients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03−0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10−8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05−0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03−0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15−52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64−19.66). Conclusions. MTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.

Abstract Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Results. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Conclusions. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTXrelated toxicity in children with NHL.

The risk of colorectal cancer (CRC) may be influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by impaired dietary folate intake as well as by polymorphic variants in one-carbon metabolism genes. A case–control study using seventy-one CRC patients and eighty unrelated healthy controls was carried out to assess the genetic association of fifteen SNP and one insertion in nine genes belonging to the folate pathway. Polymorphism selection was based on literature data, and included those which have a known or suspected functional impact on cancer and missense polymorphisms that are most likely to alter protein function. Genotyping was performed by real-time PCR and PCR followed by restriction analysis. The likelihood ratio statistic indicated that most of the polymorphisms were not associated with the risk of CRC. However, an increased risk of CRC was observed for two variant alleles of SNP mapping on the transcobalamin 2 gene (TCN2): C776G (rs1801198) and c.1026-394T>G (rs7286680). Considering the crucial biological function played by one-carbon metabolism genes, further investigations with larger cohorts of CRC patients are needed in order to confirm our preliminary results. These preliminary results indicate that TCN2 polymorphisms can be a susceptibility factor for CRC.

Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism.

Congenital heart defects (CHD) are the most common abnormalities occurring in 40% -60% of Down syndrome (DS) patients. The 5-methyltetrahydrofolate homocysteine methyl transferase reductase (MTRR) is one of the key regulatory enzymes involved in folate pathway. Disrupted folate pathway due to MTRR polymorphism could be a risk factor for CHD in DS. The aim of the study was to determine the association between polymorphism MTRR 66A> G and CHD in DS. Additionally, the impact of maternal endogenous factors on CHD was analyzed, intake of folate through diet, periconceptional folic acid supplementation, smoking and alcohol drinking. A total of 155 children with DS and 148 their mothers have been enrolled in this study. Genotyping was performed by PCR-RFLP. The frequency of alleles and genotypes of MTRR 66A> G polymorphisms was not significantly different between a group with CHD compared to a group without CHD among DS subjects as well as in their mothers. The mothers with mutated homozygous genotypes who have taken folic acid preparations from the fourth week before pregnancy to eight weeks of pregnancy were more likely to have DS-CHD+ child. The study results suggested that maternal MTRR 66A> G polymorphisms associated with their lifestyle habits such as folic acid intake could altered individual risk for CHD in DS child.

ObjectiveTo determine if functional polymorphisms of folate/homocysteine pathway enzymes are associated with homocysteine concentrations and/or coronary artery calcification (CAC) scores in patients with systemic lupus erythematosus (SLE) and controls.MethodsWe investigated 163 SLE patients and 160 controls. Functional polymorphisms in 6 genes in the folate/homocysteine pathway were genotyped: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, cystathionine β-synthase (CBS) 844ins68, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, thymidylate synthase (TYMS) 1494del6, and dihydrofolate reductase (DHFR) c.86+60_78.ResultsHomocysteine levels were higher in African American SLE patients than Caucasian patients and African American controls. Genotype distributions were significantly different in African American and Caucasian controls for 6 of the 7 polymorphisms. Genotype distributions for each polymorphism did not differ significantly between SLE patients and controls even after stratification by race. Glomerular filtration rate was strongly negatively correlated to homocysteine levels, and was therefore adjusted for as a covariate in the models of the effects of the polymorphisms on homocysteine levels. In SLE patients none of the 7 polymorphisms was associated with homocysteine concentrations. In Caucasian controls only MTHFR 677C>T and 1298A>C showed effects on homocysteine similar to what would be expected from the literature. There were no genotypic associations with median CAC scores in SLE patients or controls with and without stratification by race.ConclusionPolymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE.

Orofacial clefts are common congenital defects whose prevalence differs between geographical regions and ethnic groups. The inheritance is complex, involving the contribution of both genetic and environmental factors. The involvement of genes belonging to the folate pathway is still matter of debate, with strong evidences of association and conflicting results. After demonstrating the contribution, for a sample from the Italian population, of common mutations mapping on three genes of the folate pathway, our group tried to unravel their contribution in independent sample studies with different ethnicity. In the present investigation a set of 34 triads with oral cleft from Nassiriya, Iraq, has been genotyped for rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS polymorphisms. Association analysis evidenced a decreased risk of cleft for children carrying the 667G allele at TCN2 gene ( P = 0.02). This evidence further supported the relationship between polymorphisms of folate related genes and oral clefts, and outlined the relevance of studying populations having different ethnicity.

Epigenetics is a field of molecular biology that copes with the study of gene function regulation without variations in DNA structure or nucleotide sequences. Among the main epigenetic phenomema in eukaryotic cells there are DNA methylation and post-traslational mechanisms among which the major are histone methylation and acetylation. Epigenetic changes are potentially reversible phenomena that are controlled also by nutritional factors as the methyl-donors involved in the folate cycle. Plasma levels of B vitamins, among which “in primis” plasma folate concentrations, are implicated in epigenetic modulation so that it can be hypothesized that they may affect the modulation of gene expression through epigenetic mechanisms. Epigenetic modifications represent one of the earliest events in the genesis of some complex pathologies, therefore the study of the interaction between epigenetics and nutritional status is of great interest either to define the physiopathological mechanisms of development of some illnesses, and for possible personalized strategies of prevention. The present work has been articulated, at first, on the analysis of gene-nutritional interaction mechanisms within the folate cycle through the study of polymorphisms of enzymes involved in the metabolism of methyl-group donors; the aim was to study their possible role on the modulation of genomic DNA methylation in relationship to different plasma levels of idrosoluble B vitamins. In this regard, the most important functional polymorfisms known on the genes of one-carbon metabolism and their relationship with methylation status of polymorphonuclear cells DNA have been analyzed from a cohort of around 800 subjects within a clinical study, underlining the role of the key folate-related enzymes in the modulation of DNA methylation. Besides the function of genomic DNA methylation, the methylation status at specific sites has been also approached with the specific intent of considering a possible interrelationship between the role of promoter methylation and the co-presence of functional polymorphisms in the same genic site for a gene for which a precise functional effect is well-known. To address this issue the promoter region of coagulation factor VII gene was evaluated for both genetic and epigenetic modifications as a possible model of genetic-epigenetic interaction in the modulation of gene product regulation. The results showed the key importance of genetic-epigenetic interactions, so far unknowm, in modulating gene-expression at promoter gene sites. The role of other vitamins involved in one-carbon metabolism in major chronic diseases, and specifically the emerging role of B6 vitamin, have been also studied. Furthermore, a clinical study is now in progress to evaluate the function of gene-specific methylation in liver tissue where most of the folate cycle functions take place. The aim of this project is the evaluation of both genome-wide and gene-specific methylation status in the liver in comparison to that observed in peripheral blood mononuclear cells DNA to define whether methylation status of peripheral blood DNA may be regarded as a good systemic biomarker for this epigenetic feature of DNA in relation to B vitamins nutritional status in cancer disease. Results from this study may help to define possible functional markers of gene-nutrients interactions with effects on epigenetic modulation for future preventive or therapeutic strategies. With that purpose, a novel high-throughput array-based technique for the detection of gene-specific methylation at promoter sites has been optimized in our laboratory.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer accounting for 80% of childhood leukemia. The uncontrolled proliferation of lymphoid progenitors in the bone marrow and the accumulation of malignant lymphoblasts in peripheral blood characterize the disease. The molecular analysis of common genetic alterations in lymphoblastic cells has strongly contributed to the comprehension of ALL pathogenesis. Different gene polymorphisms (most of them SNPs) play an important role in the susceptibility to childhood ALL which probably derives from a combination and relation of genetic and environmental factors. Folic acid and the pool of folate of the one carbon-metabolic-pathway are key elements involved in several processes including DNA synthesis and methylation. Polymorphisms in genes coding for enzymes of the folate metabolic pathway can alter the intracellular folate status or distribution and sub-optimal/anomalous folate levels/distribution increase the risk of developing several neoplasias. The two main enzymes involved in cyclization of folate isoforms are DHFR and MTHFR. The first one is responsible for the conversion of dihydrofolate to tetrahydrofolate whilst the second one catalyzes the reduction of 5,10-methylene-THF to 5-methyl-THF. Studies have demonstrated that subjects with the homozygous DD-genotype have higher DHFR mRNA levels that may be responsible for storage of THF and other isoforms within the cell; reduced enzyme activity instead, has been associated to MTHFR 677TT homozygotes. This condition is responsible for an underutilization of methylene-THF in the cell with storage of folate reduced isoforms. Several studies have demonstrated that DHFR and MTHFR polymorphisms may be protective against hematological cancers such as ALL. It is to note that current treatment regimens achieve levels about 80% in overall survival (OS). Unfortunately, the side effects derived from the chemotherapeutic agents used can be severe, especially for high-risk patients. Therefore, the identification of additional markers which can improve risk stratification and individual tailored therapy regimens would be a great goal, in order to avoid over-treatment which can increase long-term adverse side effects. The aim of the present study was, therefore, to investigate whether common polymorphisms (i.e. MTHFR C677T and A1298C in addition to DHFR 19 bp INS/DEL and Bcl-2 -938 C>A) might influence the risk of childhood ALL. After a single analysis we can ascribe to MTHFR C677T gene polymorphism a protective significant role against childhood ALL (P=0.046), whilst Bcl-2 -938 C>A gene polymorphism seems to be a risk factor for the susceptibility to the disease (P=0.049). Then, considering parameters such as disease onset and therapy duration we can observe a significant higher mean age onset disease for homozygotes MTHFR 1298-CC (P=0.05). From the analysis of the therapy duration we found a significant association for MTHFR A1298C and Bcl-2 -938 C>A polymorphisms: MTHFR 1298CC homozygotes showed a slight higher mean therapy duration (P=0.05), as well as Bcl-2 -938AA homozygotes (P=0.03). Finally, in an exploratory way, to validate the proposed model we evaluated among healthy PBL cells harvested from subjects with opposite genotype condition considering DFHR and MTHFR genes (respectively, WW/CC and DD/TT), possible differences in base-line cellular viability and under MTX treatment. The pharmacological induced restriction in folate availability (MTX) yields to results in favor of WW/CC, whilst the base-line cell viability yields comparable results among genotypes. This is in line with the hypothesis that a higher MTX level could be present in DD/TT cells, prone to storage either natural folate isoforms (useful for the cell viability) or synthetic toxic analogue (MTX). This observation argues us into hypothesizing that also MTX being itself a synthetic folate analogue follows the same handling process. Now, inside the cell it should result in an elevated toxicity level, being responsible for an elevated death.

Introduction : Les déterminants génétiques du statut en folate (MTHFR, MTR, NOS3, SHMT1 et 2, MTHFD1 et 2, MTHFS, SLC19A1, ABCB1, FOLR2 et FOLH1) sont variablement associés au risque primaire de fentes chez les sujets hispaniques, irlandais, norvégiens et polonais. Ce risque est associé aux déterminants génétiques de la vitamine B12 (TCN2) en Italie et au métabolisme de la choline (BHMT, BHMT2 et PCYT1A) en Pologne. Des polymorphismes génétiques du gène CBS, une enzyme majeure de la voie de la transulfuration, y sont associés en Italie. But de l'étude : Nous avons étudié les déterminants génétiques des fentes labio-maxillo-palatines en France en lien avec le métabolisme des monocarbones par SNP Array. Méthodes : Notre étude cas-témoins porte sur 250 enfants, leurs mères (200), et 521 contrôles appareillés. Une analyse multiplex de 384 SNPs (77 gènes sélectionnés dans la base NCBI et à partir d'études in silico), a été réalisée par technologie Golden Gate Illumina (BeadExpress Reader, San Diego, California). Toutes les analyses ont été réalisées en modèles additifs, dominants et récessifs. Résultats : En analyse univariée chez les mères en modèle additif, rs2124459 CBS, rs35789560 FPGS, rs234709 CBS, rs4816 PCMT1, rs737865 COMT, rs4820889 TCN2, rs13043752 AHCY, rs2168781 SHMT1 et rs1801229 CUBN sont associés au risque primaire de fentes. Après correction de Bonferroni, seul CBS rs2124459 1552+1199A-->G atteint la significativité dans le modèle additif avec P= 0,009 (OR (Dd) versus (dd) = 0,46 (0,26 to 0,81) et (DD) versus (Dd) = 0,51 (0,26 to 0,97)). En modèle dominant le P= 0,09 (OR (DD, Dd) versus (dd) = 0,40 (0,23 to 0,69). Chez les enfants, CBS rs2124459 est associé au risque de fentes dans les modèles additif et dominant, avec des P=0.026 et P=0.011respectivement. Discussion et conclusion: CBS est très fortement associée au risque primaire de fentes chez les mères et les enfants. Ces résultats montrent une mise en jeu prépondérante de la voie de la transulfuration dans l'étiologie des fentes en France
Background : Monocarbons determinants are involved in the etiology of cleft lip with or without cleft palate, based on ethnical background and periconceptional mother's diet. Genetic polymorphisms of actors of folate and monocarbon availability (MTHFR, MTR, NOS3, SHMT1 and 2, MTHFD1 and 2, MTHFS, SLC19A1, ABCB1, FOLR2 and FOLH1) are in association with the primary risk of oro-facial cleft in contrasting ways in Hispanic, non-Hispanic-white, Irish, Norwegian or Polish subjects. The actors of B12 availability like TCN2 are only involved in Italian subjects. Cholin metabolism (BHMT, BHMT2 and PCYT1A) is reported in Polan. CBS, actor of transulfuration pathway?s, is in association with cleft risk in Italian studies. Aim : This study is built to determine the primary risk of cleft (OCF) in association with single nucleotid polymorphisms of the actors of folate, B12 and choline availability, monocarbons metabolism and transulfuration pathway?s in France. Methods : We performed a case-control study of 250 children and their mothers (200), and 521 matches controls. A multiplex analysis of 384 SNPs (77 genes), selected by NCBI databases research's and in silico studies was performed, using GoldenGate Illumina technology (BeadExpress Reader, San Diego, California) with appropriate genotyping controls. Genotypes with call rate under 0.95 and SNPs with Hardy-Weinberg disequilibrium linkage were excluded. SNP association analyses were performed applying additive, dominant and recessive models to the data. Results :In univariate analysis of mothers versus controls for additive model 9 SNPs were found in association with primary risk of cleft, concerning rs2124459 CBS ; rs35789560 FPGS ; rs234709 CBS ; rs4816 PCMT1 ; rs737865 COMT ; rs4820889 TCN2 ;rs13043752 AHCY ; rs2168781 SHMT1 ; rs1801229 CUBN. After multiple testing correction, only CBS rs2124459 1552+1199A-->G reached statistical significance in additive models, with P= 0.009 in the additive model (OR (Dd) versus (dd) = 0.46 (0.26 to 0.81) and (DD) versus (Dd) = 0.51(0.26 to 0.97)). P= 0.09 in the dominant model (OR (DD, Dd) versus (dd) = 0.40 (0.23 to 0.69), respectively. In patients, CBS rs2124459 was significantly associated with a reduced risk of OFC in both additive and dominant models, with respectively P=0.026 and P=0.011. Discussion and conclusion : This study reported an intronic SNP from CBS not previously described, with a strong association with primary risk of cleft in mothers and child. These results argues to the predominant way of transulfuration in etiology of oro-facial cleft in France

碩士
國立臺灣大學
藥學研究所
96
Background Folate is one of vitamin B complex. Epidemiological studies reveal the incidence of pregnancy complications and newborn neural tube defect in folate-insufficient pregnant women. Thereby, it is recommended to boost higher dose of folic acid during the first trimester of pregnancy for the prevention from unwilling complications. Combining the knowledge of metabolomics and pharmacogenomics, we tried to study the effect of folate intake in pregnant women and genetic impact from the view point of folate metabolites. Methods Healthy and pregnant women in outpatient service of Eugene Clinic were enrolled in our study. We collected blood samples during their routine blood drawn for LC/MS-MS and HPLC detection of folate metabolites. The use of folate supplement, basic demographic data and dietary preference were surveyed by a questionary. Genotypes of the selected genes including MTHFR, MTR, MTRR, MTHFD1, ALDH1L1, AMT, FOLH1and BHMT were determined using SNPstream system. Results The 89 participants include 7 healthy non-pregnant women, 26 pregnant women without folate supplement and 56 pregnant women with regular folate intake. We successfully detected FA, 5MeTHF, 5FoTHF, 5,10CHTHF, and plasma homocysteine concentration. In pregnant women receiving daily folate supplement, erythrocyte 5MeTHF concentration increases with the gestation age. Although plasma and erythrocyte folate concentration decrease with time in pregnant women without folate supplement, it is not statistically significant (p> 0.05). Folate supplement did not make difference in plasma homocysteine levels of pregnant women. However there’s an inverse relation between plasma folate metabolites and homocysteine. Among18 successfully determined genes, genotypes of MTHFR, MTR, MTRR, ALDH1L1, AMT, FOLH1, BHMT genes were correlated to the concentrations of folate metabolites. The 5FoTHF/5,10CHTHF ratio is correlated to the distribution of genotypes of MTHFR, MTRR, and ALDH1L1. Conclusion Folate supplement importantly changed 5MeTHF concentration compared to the other folate metabolites and elevated plasma 5MeTHF immediately. In the pregnant women with regular folate supplement, erythrocyte 5MeTHF level increases with gestational age. It might be due to the increase during pregnancy in folate uptake capacity via altered hormone regulation. In pregnant women without folate supplement, levels of folate metabolites varied, which was associated with genotypes of MTHFR, MTR, MTRR, ALDH1L1, and AMT. The 5FoTHF/5,10CHTHF ratio is relatively low in pregnant women carrying heterozygotic SNPs of MTHFR, MTRR, ALDH1L1 genes. It may be as a maker for evaluating genetic effects on folate maintenance.