MTHFD1 G1958A Research Articles

Association analysis of CβS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer’s disease in Chinese

Folate deficiency and elevated plasma homocysteine play important roles in pathogenesis of Alzheimer's disease (AD). The aim of this study was to test the association of folate metabolism-related genes, cystathionine beta-synthase gene (CbetaS) and 5, 10-methylenetetrahydrofolate dehydrogenase gene (MTHFD1), with sporadic AD. The CbetaS 844ins68 polymorphism was determined by PCR and the MTHFD1 G1958A single nucleotide polymorphism (rs2236225) by PCR-RFLP. No significant difference of allele and genotype contributions of the CbetaS polymorphism between AD cases and controls was detected, before and after stratification by APOE epsilon4-carrying status, age/age at onset and genders. No significant difference of allele and genotype contributions of the MTHFD1 polymorphism between AD cases and controls was detected in total samples. When stratified by age/at onset age, we found that A allele and AA genotype frequencies in cases were higher than in controls and the differences were close to significant [A vs. G, P = 0.032, Odds ratio (OR) 1.642, 95% CI 1.040-2.591; AA + GA vs. GG, P = 0.068, OR 1.665, 95% CI 0.961-2.885; AA vs. GG, P = 0.059, OR 3.458, 95% CI 0.894-13.369] in <65 years groups, which suggested that the MTHFD1 G1958A A allele might be a weak risk factor for early onset AD although it needs further confirmation.

Genetic Variants in Phosphatidylethanolamine N-methyltransferase and Methylenetetrahydrofolate Dehydrogenase Influence Biomarkers of Choline Metabolism When Folate Intake Is Restricted

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).

P57 Rheumatoid arthritis: phenomenology, personality profile, stress and their inter-relationship

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 < 0.001), male gender (P = 0.03), tobacco habit (P < 0.001), 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.

Candidate molecular markers associated with endocrine resistance in breast carcinoma

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 < 0.001), male gender (P = 0.03), tobacco habit (P < 0.001), 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.

MTHFR C677T Polymorphism Modulates Red Cell TPMT Activity

Background: Thiopurine methyl transferase (TPMT) irreversibly transfers a methyl group from S-adenosylmethione (SAM) to 6-mercaptopurine (6-MP) producing 6-Methyl MP and S-adenosylhomocysteine (SAH). The adenosyl moiety of SAH is subsequently cleaved and homocysteine can be remethylated to methionine. The methyl donor for this folate-dependent remethylation cycle is 5-methyltetrahydrofolic acid, which is formed in a reaction catalysed by 5,10-methylenetetrahydrofolate reductase (MTHFR). Polymorphisms in enzymes catalysing SAH recycling may thus indirectly impact on TPMT activity and the capacity to methylate thiopurine drug metabolites. Intracellular SAM and SAH levels are known to be influenced by two common polymorphisms in the MTHFR gene C677T and A1298C. A further polymorphism, R653Q, in the MTHFD1 gene is also associated with significant disturbance in folate-dependant methylation. Aims: The aim of this study was to determine whether polymorphisms in the MTHFR gene might influence TPMT activity. Methods: Blood specimens were selected from consecutive samples referred to the Purine Research Unit for TPMT enzyme assay. The study populations were restricted to Caucasians throughout the UK. Three groups were identified comprising 83 patients with normal TPMT activity in the 12.0–14.0 Unit range and 138 patients with a carrier TPMT phenotype 4.0–7.5 U subdivided 68 patients who were heterozygous for TPMT, TPMT*3C, *3A, or *2 and 70 patients with carrier TPMT phenotype but wild-type TPMT genotype. All patients were genotyped for the MTHFR C677T and A1298C and MTHFD1 G1958A variants. Results: In the carrier range, 51.4% of patients had a wild-type TPMT genotype. The MTHFR 677TT genotype frequency of 0.08 was significantly lower in the normal group compared to a frequency of 0.228 found in the TPMT carrier group with a wild-type TPMT genotype (OR = 3.22, P = .0216). No significant differences in the frequencies of the MTHFR A1298C homozygous or MTHFD1 G1958A homozygous genotypes were found when the 2 carrier groups were compared with the normal TPMT activity group. Variant MTHFR and MTHFD1 genotypes did not have an additive effect on TPMT phenotype. Discussion: These results suggest that the MTHFR 677TT genotype significantly modulates the red cell TPMT activity. This finding is particularly important within the context of TPMT testing prior to the start of AZA therapy and explains some lack of concordance between TPMT genotype and phenotype.

Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections

Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account known factors influencing plasma homocysteine levels. Ninety-five patients with past sCAD were compared with 95 age- and sex-matched healthy individuals. Homocysteine, vitamin B6, B12, folate, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), cystathionine beta-synthase (CBS 844ins68bp) and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 G1958A) were assessed and any associations were analysed using multivariate statistics. The occurrence of sCAD was associated with elevated homocysteine levels with an odds ratio of 1.327 per 20 % percentile. Homocysteine levels were influenced by gender, smoking status, occurrence of hypertension, vitamin B12 and folate levels, and by the MTHFR TT genotype. MTHFR, CBS 844ins68bp, and MTHFD1 G1958A genotype were not independently associated with the occurrence of sCAD. These data suggest that elevated homocysteine is associated with the occurrence of sCAD. The MTHFR C677T polymorphism is associated with the homocysteine level.

Methylenetetrahydrofolate-dehydrogenase 1958G→A polymorphism is a genetic determinant of NTD risk for Italian mothers

Neural Tube Defects (NTDs) have a well-established genetic basis, although specific genetic predisposing factors had not been identified until now. Genetic variants of enzymes involved with folate pathway might be expected to have impact on NTD risk. Given its key role in folate metabolism, the methylenetetra-hydrofolate dehydrogenase (MTHFD1) could represent an attractive candidate in NTD etiology. MTHFD1 is a trifunctional protein and mediates the interconversion of 5,10-MTHF; 5,10-methenylTHF; and 10-formylTHF. 10-formyl THF and 5,10methenylTHF are the donor cofactors for de novo purine and pyrimidine biosynthesis and, thus, the biosynthesis of DNA. Recently, a polymorphism, G1958A, in the MTHFD1 gene was suggested as maternal genetic risk factor for NTD in the Irish population. In this study, we examined the impact of the MTHFD1 G1958A polymorphism on NTD risk in the Italian population by a casecontrol study and family-based studies. The study population consisted of 95 unrelated Italian NTD children, 42 mothers and 40 fathers who were recruited from the Spina Bifida Center of the Gaslini Hospital, Genoa. A total of 145 healthy individuals were recruited from a blood donors accessible bank and used as control group. The presence of the MTHFD1 1958G→A, MTHFR (methylenetetrahydrofolate reductase) 1298A→C and RFC-1 (reduced folate carrier 1) 80A→G polymorphisms was investigated by PCR-RFLP methods. We found no increased risk for MTHFD1 mutant genotypes of the children and fathers. On the contrary, significant risk estimates resulted for the homozygous 1958AA genotype of the mothers (OR = 3.05; P = 0.046). This maternal effect was confirmed by transmission disequilibrium test (TDT) that showed no preferential transmission of 1958A allele to the affected children from informative parents. Since our previous study has shown that the MTHFR A1298C and RFC-1 A80G polymorphisms are genetic determinant of NTD risk for Italian mothers, potential gene-gene interactions were examined. We found a significant interaction between the MTHFD1 G1958A polimorphism and both MTHFR A1298C (4.46-fold increased risk) and RFC-1 A80G (9.14-fold increased risk) mutant alleles in the mothers. We conclude that a common genetic variant of MTHFD1 gene, the G1958A, is a maternal genetic risk factor for NTD. These findings highlight the importance of further considering maternal genotype when evaluating NTD susceptibility loci. from 48th Annual Meeting of the Society for Research into Hydrocephalus and Spina Bifida Dublin, Ireland, 23–26 June 2004 Published: 23 December 2004