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Background The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function. Objective Choline supplements confer cognitive improvement for those diagnosed with fetal alcohol spectrum disorder (FASD), a common set of neurodevelopmental impairments; however, the effect sizes have been modest. In this retrospective analysis, we report that genetic polymorphisms affecting choline utilization are associated with cognitive improvement following choline intervention. Methods Fifty-two children from the upper midwestern United States and diagnosed with FASD, ages 2-5 y, were randomly assigned to receive choline (500 mg/d; n = 26) or placebo (n = 26) for 9 mo, and were genotyped for 384 choline-related single nucleotide polymorphisms (SNPs). Memory and cognition were assessed at enrollment, study terminus, and at 4-y follow-up for a subset. Results When stratified by intervention (choline vs. placebo), 14-16 SNPs within the cellular choline transporter gene solute carrier family 44 member 1 (SLC44A1) were significantly associated with performance in an elicited imitation sequential memory task, wherein the effect alleles were associated with the greatest pre-/postintervention improvement. Of these, rs3199966 is a structural variant (S644A) and rs2771040 is a single-nucleotide variant within the 3' untranslated region of the plasma membrane isoform. An additive genetic model best explained the genotype associations. Lesser associations were observed for cognitive outcome and polymorphisms in flavin monooxygenase-3 (FMO3), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1), fatty acid desaturase-2 (FADS2), and adiponectin receptor 1 (ADIPOR1). Conclusions These SLC44A1 variants were previously associated with greater vulnerability to choline deficiency. Our data potentially support the use of choline supplements to improve cognitive function in individuals diagnosed with FASD who carry these effect alleles. Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population. This trial was registered at www.clinicaltrials.gov as NCT01149538.

Background Nutrients and genetic polymorphisms participating in one-carbon metabolism may explain interindividual differences in inorganic arsenic (iAs) methylation capacity, which in turn may account for variations in susceptibility to iAs-induced diseases. Objectives 1) To evaluate the association between polymorphisms in five one-carbon metabolism genes (FOLH1 c.223 T > C, MTHFD1 c.1958 G > A, MTHFR c.665 C > T, MTR c.2756 A > G, and MTRR c.66 A > G) and iAs methylation capacity; 2) To assess if previously reported associations between nutrient intake and iAs methylation capacity are modified by those polymorphisms. Methods Women (n = 1027) exposed to iAs in Northern Mexico were interviewed. Blood and urine samples were collected. Nutrient dietary intake was estimated using a validated food frequency questionnaire. iAs methylation capacity was calculated from urinary iAs species (iAs, monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) measured by high performance liquid chromatography (HPLC-ICP-MS). One polymorphism in each of the five genes evaluated was genotyped by allelic discrimination. Multivariable linear regression models were used to evaluate if genetic polymorphisms modified the associations between iAs methylation capacity parameters and nutrient intake. Results The median (min-max) concentration of total arsenic (TAs) was 20.2 (1.3–2776.0) µg/g creatinine in the study population. Significant interactions for iAs metabolism were only found with FOLH1 c.223 T > C polymorphism and vitamin B12 intake, so that CT and CC genotype carriers had significantly lower %iAs, and higher DMA/iAs with an increased vitamin B12 intake, as compared to carriers of wild-type TT. Conclusion Differences in dietary nutrient intake and genetic variants in one-carbon metabolism may jointly influence iAs methylation capacity. Confirmation of these interactions in other populations is warranted.

Background Suboptimal folate intake, a risk factor for birth defects, is common even in areas with folate fortification. A polymorphism in methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), R653Q (MTHFD1 c.1958 G > A), has also been associated with increased birth defect risk, likely through reduced purine synthesis. Objective We aimed to determine if the interaction of MTHFD1 synthetase deficiency and low folate intake increases developmental abnormalities in a mouse model for MTHFD1 R653Q. Methods Female Mthfd1S+/+ and Mthfd1S+/- mice were fed control or low-folate diets (2 and 0.3 mg folic acid/kg diet, respectively) before mating and during pregnancy. Embryos and placentas were examined for anomalies at embryonic day 10.5. Maternal 1-carbon metabolites were measured in plasma and liver. Results Delays and defects doubled in litters of Mthfd1S+/- females fed low-folate diets compared to wild-type females fed either diet, or Mthfd1S+/- females fed control diets [P values (defects): diet 0.003, maternal genotype 0.012, diet × maternal genotype 0.014]. These adverse outcomes were associated with placental dysmorphology. Intrauterine growth restriction was increased by embryonic Mthfd1S+/- genotype, folate deficiency, and interaction of maternal Mthfd1S+/- genotype with folate deficiency (P values: embryonic genotype 0.045, diet 0.0081, diet × maternal genotype 0.0019). Despite a 50% increase in methylenetetrahydrofolate reductase expression in low-folate maternal liver (P diet = 0.0007), methyltetrahydrofolate concentration decreased 70% (P diet

Background: Methylenetetrahydrofolate dehydrogenase (MTHFD1) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate (THF) in folate-dependent one-carbon metabolism. Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress. However, limited information is available on its relation to the development of atherothrombotic cardiovascular disease. Methods and results: We explored the association between a MTHFD1 polymorphism (rs1076991 C > T ) and acute myocardial infarction (AMI), and potential effect modifications by folic acid/B12 and/or vitamin B6 treatment in suspected stable angina pectoris patients (n Z 2381) participating in the randomized Western Norway B Vitamin Intervention Trial (WENBIT). During the median follow-up of 4.9 years 204 participants (8.6%) suffered an AMI. After adjusting for established CVD risk factors, the MTHFD1 polymorphism was significantly associated with AMI (HR: 1.49; 95% CI, 1.23e1.81). A similar association was observed among patients allocated to treatment with vitamin B6 alone (HR: 1.53; 95% CI, 1.01e2.31), and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 (HR: 2.35; 95% CI, 1.55 e3.57). However, no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo (HR: 1.29; 95% CI, 0.86e1.93) or folic acid/B12 (1.17; 95% CI, 0.83e1.65). Conclusion: A common and functional MTHFD1 polymorphism is associated with increased risk of AMI, although the risk seems to be dependent on specific B vitamin treatment. Further studies are warranted to elucidate the possible mechanisms, also in order to explore potential effect modifications by nutritional factors. publishedVersion

Objective The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. Methods A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42–67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. Results After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C > T (SNP 1137070), COMT c.472G > A (SNP 4680), MTHFR c.677C > T (SNP 1801133) and ESR1 454−351 A > G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT + TT (OR = 1.83; pcorr = 0.009 and OR = 1.85; pcorr = 0.003, resp.), and of the MTHFR c.677 TT and c.677 CT + TT (OR = 3.52; pcorr = 0.00009 and OR = 2.06; pcorr = 0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA + AA genotypes (OR = 2.23; pcorr = 0.03 and OR = 2.17; pcorr = 0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454−351 AG and 454−351 AG + GG genotypes were associated with lower risk of depression in postmenopausal women (OR = 0.48; pcorr = 0.012, and OR = 0.52; pcorr = 0.015, resp.). Conclusions Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women.

Acute Lymphoblastic Leukemia (ALL) is the most common childhood neoplasia. Studies have shown that susceptibility to ALL may be modulated by genetic variables. Our study investigated 21 genetic variants in the susceptibility of the population of the Brazilian Amazon region to B-cell ALL. The variants of the genes GGH, CEBPE, ARID5B, MTHFR and MTHFD1 were related to a protective effect against the development of ALL, whereas the variant of the gene ATIC was associated with a risk effect. The results suggest that genetic variants analyzed modulate of the risk of developing ALL in the studied population.

Resumen Introduccion y objetivos La medicina cardiovascular actual esta dirigida a la busqueda de marcadores de riesgo genetico con valor predictivo y/o pronostico. Entre las variantes de interes se encuentran los polimorfismos G894T en el gen oxido nitrico sintasa endotelial y G1958A en el gen metilentetrahidrofolato deshidrogenasa 1. El objetivo de este estudio fue determinar la posible asociacion entre estos polimorfismos y la cardiopatia isquemica (CI) en el sureste de Mexico (Yucatan). Metodos Estudio de casos y controles con pareamiento por edad, sexo y lugar de nacimiento. Se estudiaron 98 pacientes con CI y 101 controles. Todos los participantes fueron evaluados para los factores de riesgo tradicionales. Los polimorfismos se identificaron utilizando la reaccion en cadena de la polimerasa mediante analisis de la longitud de los fragmentos de restriccion. Se obtuvo el consentimiento informado de todos los participantes. Resultados Los polimorfismos G894T y G1958A no mostraron asociacion con la CI. Sin embargo, la estratificacion segun la manifestacion clinica mostro que el genotipo TT (G894T) se asocio con la angina (OR = 10,2; IC 95%, 1,51-68,8; p = 0,025). Se observo mayor frecuencia del genotipo GT en los pacientes con historia familiar de enfermedad coronaria. El analisis de regresion logistica identifico al tabaquismo (OR = 5,21; IC 95%, 2,1-12,9; p = 0,000), la hipertension arterial (OR = 3,54; IC 95%, 1,47-8,56; p = 0,005) y la obesidad (OR = 1,16; IC 95%, 1,1-1,27; p = 0,001) como factores predictores de CI. Conclusiones Los polimorfismos G894T y G1958A no mostraron asociacion con la CI. Sin embargo, la homocigosis del alelo 894T (NOS3) confiere riesgo para el desarrollo de angina en Yucatan.

Objectives Neural tube defect (NTD) is a common disease among neonates with multiplex symptom and complex origins, and the exact mechanism of NTD has not been definitely elucidated. Nevertheless, it is hypothesized that NTD risk can be prevented by periconceptional folic acid in folate metabolism. The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene has been proved to play an important role in folate metabolism, which was strongly associated with the high risk for NTD. We focused on three folate metabolism-related single-nucleotide polymorphisms (SNPs) on the MTHFD1 gene to evaluate the associations between MTHFD1 polymorphisms and NTD susceptibility. Methods We genotyped blood samples from 222 specimens (including 122 NTD-affected infants and 100 healthy controls) in a case–control study. We investigated the association between NTD and three selected tag-SNPs on MTHFD1 gene: 401A > G (rs1950902), 2305C > T (rs17857382) and 1958G > A (rs2236225) by the SNapShot method. These SNPs were identified by Haploview 4.2 software with HapMap databases, and then these associations were evaluated by the Mann–Whitney test, one-way analysis of variance (ANOVA) and chi-square test. Furthermore, a meta-analysis of the association between MTHFD1 1958G > A and NTD risk was also performed. Results In our study, an increased risk of NTD was observed for 1958G > A of MTHFD1 (AA vs. GG: OR = 2.63, 95% CI = 2.61–5.70; AA vs. GG + GA: OR = 2.10, 95% CI = 1.07–4.14; A vs. G: OR = 1.62, 95% CI = 1.11–2.36). However, the other two SNPs (401A > G and 2305C > T) displayed no statistically significant association with NTD risk. The overall result of the meta-analysis indicated that the 1958G > A variant might not be a genetic susceptible factor for the Caucasian population. Conclusions Our analysis implicated that MTHFD1 1958G > A was significantly associated with the susceptibility of NTD in a Chinese population. In addition, the AA homozygote carriers were more likely to suffer NTD, compared with the others with GA or GG genotypes. Validation of the risk effect and functional impact of this polymorphism is needed in future investigations.

Folate-mediated one-carbon metabolism is a metabolic network of interconnected pathways that is required for the de novo synthesis of three of the four DNA bases and the remethylation of homocysteine to methionine. Previous studies have indicated that the thymidylate synthesis and homocysteine remethylation pathways compete for a limiting pool of methylenetetrahydrofolate cofactors and that thymidylate biosynthesis is preserved in folate deficiency at the expense of homocysteine remethylation, but the mechanisms are unknown. Recently, it was shown that thymidylate synthesis occurs in the nucleus, whereas homocysteine remethylation occurs in the cytosol. In this study we demonstrate that methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), an enzyme that generates methylenetetrahydrofolate from formate, ATP, and NADPH, functions in the nucleus to support de novo thymidylate biosynthesis. MTHFD1 translocates to the nucleus in S-phase MCF-7 and HeLa cells. During folate deficiency mouse liver MTHFD1 levels are enriched in the nucleus >2-fold at the expense of levels in the cytosol. Furthermore, nuclear folate levels are resistant to folate depletion when total cellular folate levels are reduced by >50% in mouse liver. The enrichment of folate cofactors and MTHFD1 protein in the nucleus during folate deficiency in mouse liver and human cell lines accounts for previous metabolic studies that indicated 5,10-methylenetetrahydrofolate is preferentially directed toward de novo thymidylate biosynthesis at the expense of homocysteine remethylation during folate deficiency.

Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G , MTHFD1 G1958A , CBS 844ins68 , TC2 C776G and A67G , SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ⩾49 years ( P P = 0.03), tobacco habit ( P MTHFR 1298AC/CC ( P = 0.028), MTR 2756AG/GG ( P = 0.010) and RFC1 80AG/GG ( P = 0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 ( P = 0.005); age ⩾49 years and MTR 2756 AG/GG ( P = 0.004) and RFC1 80AG/GG ( P = 0.006) genotypes; male gender and MTHFR 1298 AC/CC ( P = 0.030), MTR 2756 AG/GG ( P = 0.006) and RFC1 80 AG/GG ( P = 0.009); tobacco non-habit and MTHFD1 1958GA/AA ( P = 0.040); tobacco and MTHFR 1298 AC/CC ( P = 0.054) and MTR 2756 AG/GG ( P = 0.010); alcohol non-consume and RFC1 80 AG/GG ( P = 0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours ( P = 0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

PurposeThe purpose of the study was to determine the frequency of occurrence of polymorphisms of genes MTHFR (C677T), MTR (A2756G), and MTHFD1 (G1958A), as well as to analyze the concentration of homocysteine (Hcy), methionine (Met), asymmetric dimethylarginine (ADMA), and arginine (Arg) in epileptics treatment with antiepileptic drugs (AEDs), and controls.MethodThe study included 65 epileptic patients treated with variable AEDs and 61 controls. The levels of Hcy and Met were determined by HPLC/EC, ADMA and Arg by HPLC with fluorescence detection. Polymorphisms of the studied genes were determined by PCR-RFLP.ResultsThe study demonstrates that AEDs treatment in epileptics leads to increase in Hcy (p

Objective Endometriosis has been considered an epigenetic disease. Single nucleotide polymorphisms (SNPs) located in genes encoding enzymes of the folate and choline metabolism may affect DNA methyltransferase activity. Study design We studied 16 SNPs in 12 folate and choline metabolism genes, including BHMT (rs7356530 and rs3733890), BHMT2 (rs625879), CBS (844ins68), CHDH (rs893363 and rs2289205), CHKA (rs7928739), MTHFD1 (rs2236225), MTHFR (rs1801133), MTR (rs1805087), MTRR (rs1801394), PCYT1A (rs712012 and rs7639752), PEMT (rs4244593 and rs4646406) and TCN (rs1801198) in one hundred and sixty-three infertile women with minimal endometriosis and one hundred and fifty fertile women. Results There were no significant differences between genotype and allele frequencies of these gene variants in infertile women with endometriosis ( n =163) and controls ( n =150). The lowest, but not statistically significant, p values of the trend test were observed for the CBS 844ins68 and MTR rs1805087 ( p trend =0.0527 and p trend =0.0771, respectively) polymorphisms. However, the exhaustive multifactor dimensionality reduction analysis revealed an epistatic interaction between rs1801133 of MTHFR and rs4244593 of PEMT in endometriosis-associated infertility ( p =0.0240). Conclusions Our results showed moderate evidence for the contribution of SNPs located in genes encoding folate and choline metabolism enzymes to infertility in women with endometriosis.

As it becomes evident that single nucleotide polymorphisms (SNPs) in humans can create metabolic inefficiencies, it is reasonable to ask if such SNPs influence dietary requirements. Epidemiologic studies that examine SNPs relative to risks for diseases are common, but there are few examples of clinically sized nutrition studies that examine how SNPs influence metabolism. Studies on how SNPs influence the dietary requirement for choline provide a model for how we might begin examining the effects of SNPs on nutritional phenotypes using clinically sized studies (clinical nutrigenomics). Most men and postmenopausal women develop liver or muscle dysfunction when deprived of dietary choline. More than one-half of premenopausal women may be resistant to choline deficiency-induced organ dysfunction, because estrogen induces the gene [phosphatidylethanolamine-N-methyltransferase (PEMT)] that catalyzes endogenous synthesis of phosphatidylcholine, which can subsequently yield choline. Those premenopausal women that do require a dietary source of choline have a SNP in PEMT, making them unresponsive to estrogen induction of PEMT. It is important to recognize differences in dietary requirements for choline in women, because during pregnancy, maternal dietary choline modulates fetal brain development in rodent models. Because choline metabolism and folate metabolism intersect at the methylation of homocysteine, manipulations that limit folate availability also increase the use of choline as a methyl donor. People with a SNPs in MTHFD1 (a gene of folate metabolism that controls the use of folate as a methyl donor) are more likely to develop organ dysfunction when deprived of choline; their dietary requirement is increased because of increased need for choline as a methyl donor.

MTHFD1 1958G>A, a polymorphism in folate metabolism, increases risk of pregnancy complications. A mouse model exhibited developmental defects, increased weight and decreased leukocyte counts. To examine the latter associations, we genotyped 651 women from a premature birth cohort. Prematurity and 1958G>A were not associated. Increases in the inflammatory marker CRP (logistic regression, p = 0.055) and BMI (chi-square, p = 0.0113) were associated with AA genotype in women with low folate. MTHFD1 1958G>A may influence immune function and obesity.

Choline is a required nutrient with roles in liver and brain function, lipid metabolism, and fetal development. Recent data suggest that choline requirements may be altered by polymorphisms in the phosphatidylethanolamine N -methyltransferase (PEMT) gene (ie, 5465G→A; rs7946 and −744G→C; rs12325817) and in the methylenetetrahydrofolate dehydrogenase (MTHFD1) gene (ie, 1958G→A; rs2236225). This controlled feeding study, conducted in 2000-2001, examined the effects of the PEMT and MTHFD1 genetic variants on biomarkers of choline metabolism in premenopausal Mexican-American women (N=43) after a 7-week period of folate restriction (135 μg as dietary folate equivalents) and after a 7-week period of folate treatment (400 and 800 μg dietary folate equivalents/day combined). Throughout the 14-week study choline intake remained constant at 349 mg/day. The genotype frequencies of the women were 3GG, 19GA, and 21AA for PEMT G5465A; 9GG, 17GC and 17CC for PEMT G-744C; and 9GG, 21GA and 13AA for MTHFD1 G1958A. During folate restriction, homocysteine was adversely influenced by PEMT 5465AA ( P =0.001 relative to the G allele) and by MTHFD1 1958AA ( P =0.085 relative to 1958GG); whereas the decline in phosphatidylcholine was attenuated by PEMT −744CC ( P =0.017 relative to −744GG). During folate treatment, no effects of the genotypes on the response of the measured variables were detected. These data suggest that polymorphisms in genes relevant to choline metabolism modulate parameters of choline status when folate intake is restricted. Additional studies with larger samples sizes are needed to examine the relationship between these genetic variants and varied choline intake in populations with increased demands for choline (eg, pregnant women).

There is growing evidence that folate metabolism is involved in migraine pathophysiology, mainly in migraine with aura. Even though folate metabolism is regulated by a number of enzymes, only two functional polymorphisms have been tested in association studies with migraine. Here, we have explored the possible role in migraine of other folate-metabolizing enzymes which are in close interdependency with 5′,10′-methylenetetrahydrofolate reductase analyzing functional polymorphisms of these enzymes in a case-control study. Individually, thymidylate synthase (TS), methenyltetrahydrofolate cyclohydrolase formyltetrahydrofolate synthase (MTHFD1), or methionine synthase (MS) polymorphisms did not modify the general risk for suffering migraine. Nevertheless, we observed a strong interaction between TS and MTHFR mutated genotypes, which increased over 8-fold the risk for experiencing aura among migraineurs; MTHFD1 and MTHFR mutated genotypes also increased together the risk for migraine in general (OR = 3.08; 95% CI = 1.3–7.4). We conclude that the pathogenetic role of the MTHFR T677 allele in migraine is modulated by functional polymorphisms of TS and MTHFD1.

Objective To investigate the association between one-carbon metabolism and recurrent pregnancy loss (RPL). One-carbon metabolism is important for maintaining pregnancy, and the enzymes codified by these genes are relevant to this metabolic pathway. Design Case-control study. Setting An urban university-based hospital in South Korea. Patient(s) A cohort of 353 RPL patients (3.09 ± 1.65 pregnancy losses) and 226 control subjects. Intervention(s) None. Main Outcome Measure(s) Genotyping was assessed by polymerase chain reaction–restriction fragment length polymorphism assay. We examined polymorphisms in four genes: methionine synthase ( MTR ); methionine synthase reductase ( MTRR ); methylenetetrahydrofolate dehydrogenase 1 ( MTHFD1 ); and thymidylate synthase ( TS ). Result(s) The MTR 2756AA polymorphism was associated with RPL. Gene-gene interaction analysis revealed that the frequency of the MTR 2756A– TS 6-bp allele combination was significantly higher in RPL. Conclusion(s) Based on these results, we propose that the MTR 2756AA genotype and MTR 2756A– TS 6-bp allele combination are possible predisposing factors for RPL development in Korean women.