-
1.
MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.
Visani, G, Loscocco, F, Ruzzo, A, Galimberti, S, Graziano, F, Voso, MT, Giacomini, E, Finelli, C, Ciabatti, E, Fabiani, E, et al
The pharmacogenomics journal. 2018;(3):444-449
Abstract
We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.
-
2.
Maternal MTHFR polymorphism (677 C-T) and risk of Down's syndrome child: meta-analysis.
Kaur, A, Kaur, A
Journal of genetics. 2016;(3):505-13
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is the most important gene that participates in folate metabolism. Presence of valine instead of alanine at position 677 and elevated levels of homocystein causes DNA hypomethylation which in turn favours nondisjunction. In this study, we conducted a meta-analysis to establish link between maternal single-nucleotide polymorphism (SNP) and birth of Down's syndrome (DS) child. A total of 37 case-control studies were selected for analysis including our own, in which we investigated 110 cases and 111 control mothers. Overall, the result of meta-analysis showed significant risk of DS affected by the presence of maternal SNP (MTHFR 677 C-T OR = 0.816, 95% CI = 0.741-0.900, P <0.0001). Heterogeneity of high magnitude was observed among the studies. The chi-square value suggested a highly significant association between homozygous mutant TT genotype and birth of DS child (χ² = 23.63, P = 0.000). Genetic models suggested that 'T' allele possesses high risk for DS whether present in dominant (OR = 1.23, 95% CI = 1.13-1.34); codominant (OR = 1.17, 95% CI = 1.10-1.25) or recessive (OR = 1.21, 95% CI = 1.05-1.38) form. The analysis from all 37 studies combined together suggested that MTHFR 677 C-T is a major risk factor for DS birth.
-
3.
Polymorphisms of the FTO and MTHFR genes and vascular, inflammatory and metabolic marker levels in postmenopausal women.
Chedraui, P, Pérez-López, FR, Escobar, GS, Espinoza-Caicedo, JA, Montt-Guevara, M, Genazzani, AR, Simoncini, T, ,
Journal of endocrinological investigation. 2016;(8):885-90
Abstract
OBJECTIVE To determine the prevalence of three single nucleotide polymorphisms (SNPs) in postmenopausal women with and without the metabolic syndrome (METS) and to explore levels of circulating biomarkers of inflammation, vascular and metabolic dysfunction according to SNP genotypes. METHODS DNA was extracted from the whole blood of 192 natural postmenopausal women (40 to 65 years) screened for the METS and tested for three gene SNPs related to obesity: the fat mass obesity (FTO: rs9939609) and the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C). Blood levels of angiopoietin, IL-8, sFASL, IL-6, TNF-α, sCD40L, PAI-1, u-PA, leptin, adiponectin, resistin, ghrelin, visfatin, adipsin and insulin were measured in a subgroup, with and without the METS, using multiplex technology (n = 100) and compared according to SNP genotypes. RESULTS Genotype frequency of the three studied SNPs did not differ in relation to the presence of the METS. However, genotypes CT+TT (C677T) and AT (rs9939609) were more prevalent in women with high triglyceride levels. Pooled sub-analysis (n = 100) found that median sCD40L and visfatin levels were higher in women with genotypes AT+TT (rs9939609) as compared to AA (1178 vs. 937.0 pg/mL and 0.93 vs. 0.43 ng/mL, respectively, p < 0.05). CONCLUSION Two SNP genotypes related to obesity were more prevalent in women with abnormal triglyceride levels and two vascular and inflammatory serum markers were higher in relation to the rs9939609 SNP.
-
4.
Cyclic supplementation of 5-MTHF is effective for the correction of hyperhomocysteinemia.
Ambrosino, P, Lupoli, R, Di Minno, A, Nardo, A, Marrone, E, Lupoli, V, Scaravilli, A, Mitidieri, E, Tufano, A, Di Minno, MN
Nutrition research (New York, N.Y.). 2015;(6):489-95
Abstract
Folic acid supplementation is the mainstay treatment of hyperhomocysteinemia (HHcy). However, no recommendations are currently available in regard to the optimal replacement therapy. Therefore, this prospective study hypothesized that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-methyltetrahydrofolate (5-MTHF) would reduce plasma levels of fasting total homocysteine (tHcy) in patients with mild/moderate HHcy. Patients with a new diagnosis of mild/moderate HHcy were evaluated for the methylenetetrahydrofolate reductase genotype and the presence of major features of metabolic syndrome. All enrolled subjects received a cyclic 5-MTHF oral supplementation and were reevaluated after each treatment cycle for a total of 2 years. In the 246 enrolled subjects, a significant reduction of tHcy levels occurred after the first cycle of treatment (from 31.6 ± 13.6 to 14.4 ± 5.77 μmol/L, P < .001) and during the whole 2-year follow-up (from 31.6 ± 13.6 to 12.18 ± 3.03 μmol/L, P < .001). The values of tHcy returned to reference range in 117 subjects (51.3%) after the first cycle and in 198 (86.8%) during the follow-up. The risk of failure in tHcy level normalization was increased in patients with metabolic syndrome (hazard ratio [HR], 3.49; 95% confidence interval [CI], 1.46-8.36), higher baseline tHcy levels (HR, 1.045; 95% CI, 1.018-1.073), or methylenetetrahydrofolate reductase homozygous mutation (HR, 6.59; 95% CI, 2.64-16.4). This study clearly shows that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-MTHF supplementation is able to significantly reduce tHcy levels in patients with mild/moderate HHcy.
-
5.
Maternal methylenetetrahydrofolate reductase C677T polymorphism and down syndrome risk: a meta-analysis from 34 studies.
Rai, V, Yadav, U, Kumar, P, Yadav, SK, Mishra, OP
PloS one. 2014;(9):e108552
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis. AIM: A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome. METHODS PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment. RESULTS Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR = 1.26, 95% CI = 1.09-1.46, p = 0.001; for TT vs. CC, OR = 1.49, 95% CI = 1.13-1.97, p = 0.008; for CT vs. CC, OR = 1.29, 95% CI = 1.10-1.51, p = 0.001; for TT+CT vs. CC, OR = 1.35, 95% CI = 1.13-1.60, p = 0.0008; for TT vs. CT+CC, OR = 0.76, 95% CI = 0.60-0.94, p = 0.01). CONCLUSION The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy.
-
6.
[The significance of folate metabolism in complications of pregnant women].
Seremak-Mrozikiewicz, A
Ginekologia polska. 2013;(5):377-84
Abstract
Proper metabolism of folates has a crucial role for body homeostasis. Folate metabolism regulates changing of amino acids (homocysteine and methionine), purine and pyrimidine synthesis and DNA methylation. These whole biochemical processes have significant influence on hematopoietic, cardiovascular and nervous system functions. The disturbances of folate cycle could result in chronic hypertension, coronary artery disease, higher risk of heart infarction, could promote cancers development, and psychic and neurodegenerative diseases. No less important is the connection with complications appearing in pregnant woman (recurrent miscarriages, preeclampsia, fetus hypotrophy intrauterine death, preterm placenta ablation, preterm delivery) and fetus defects (Down syndrome, spina bifida, encephalomeningocele, myelomeningocele). The complex process of folate metabolism requires adequate activity of many enzymes and presence of co-enzymes. A key enzyme in folate metabolism is methylenetetrahydrofolate reductase (MTHFR - methylenetetrahydrofolate reductase), and 677C>T polymorphism of MTHFR gene is connected with lower enzymatic activity In several researches it was indicated that 677C>T MTHFR polymorphism is an independent factor influencing homocysteine concentration in serum, and also folate concentration in serum and red blood cells. Nevertheless, it was also observed the correlation of 677C>T MTHFR polymorphism with Down syndrome, and neural tube defects appearance in fetus. In European populations frequency of mutated 677TT genotype ranges from a few to several percent. Women carriers of 677TT or 677CT MTHFR genotypes are exposed on folate metabolism disturbances and on the consequences of incorrect folate process during pregnancy Nowadays in this group of women folic acid supplementation is widely recommended. In the light of modern knowledge the attention was also focused on the importance of metafolin administration that omitted pathways of folic acid transformation after administration, and in pregnant women certainly is valuable complement of supplementation in this respect.
-
7.
Maternal gene polymorphisms involved in folate metabolism and the risk of having a Down syndrome offspring: a meta-analysis.
Yang, M, Gong, T, Lin, X, Qi, L, Guo, Y, Cao, Z, Shen, M, Du, Y
Mutagenesis. 2013;(6):661-71
Abstract
Down syndrome (DS) is the most common chromosomal abnormality. Many studies have assessed the association between maternal gene polymorphisms involved in folate metabolism and the risk of having a DS offspring, but data are conflicting. Our study aimed to arrive at a more accurate estimation. Therefore, we carried out a meta-analysis of 26, 17, 9, 15, 9 and 6 case-control studies on the relationship between maternal methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, methionine synthase reductase (MTRR) A66G, reduced folate carrier 1 A80G and cystathionine β-synthase 844ins68 polymorphisms and the risk of having a DS offspring. The allele contrast and model-free approach were used. Results showed marginal significant associations for MTHFR C677T, overall [odds ratio (OR) = 1.28 (1.22, 1.46) and generalised odds ratio (ORG) = 1.35 (1.16, 1.57)] and in Caucasian [OR = 1.15 (1.03, 1.29) and ORG = 1.20 (1.04, 1.38)], Asian [OR = 1.68 (1.08, 2.63) and ORG = 1.74 (1.08, 2.80)] and Brazilian [OR = 1.22 (1.04, 1.43) and ORG = 1.28 (1.06, 1.55)] populations; for MTRR A66G, overall [OR = 1.22 (1.02, 1.46) and ORG = 1.31 (1.06, 1.62)]; and for RFC1 A80G, overall [OR = 1.16 (1.02, 1.31) and ORG = 1.18 (1.01, 1.37)]. MTHFR A1298C, MTR 12756G and CBS 844ins68 polymorphisms produced non-significant results. Since potential confounders could not be ruled out completely in this meta-analysis, further studies are needed to confirm these results.
-
8.
Association of methylenetetrahydrofolate reductase gene 677C > T polymorphism and Down syndrome.
Costa-Lima, MA, Amorim, MR, Orioli, IM
Molecular biology reports. 2013;(3):2115-25
Abstract
The association between Down syndrome (DS) and maternal polymorphisms in genes encoding folic acid metabolizing enzymes remains a controversial issue. A meta-analysis was performed to evaluate the association of maternal MTHFR 677C > T polymorphism and the risk of having a child with DS. Case-control studies were screened from major literature databases. Twenty articles from 13 countries worldwide, with a total of 2,101 DS and 2,702 control mothers, attended the inclusion criteria. We found a 50 % increase for the association of maternal homozygous TT genotype and DS in both fixed (OR = 1.51; 95 % CI 1.22-1.87) and random effects models (OR 1.54; 95 % 1.15-2.05). Similarly, a significant pooled OR was found for the heterozygote CT, with an OR 1.26; 95 % CI 1.10-1.43 (fixed effects model) and OR 1.28; 95 % 1.08-1.51 (random effects model). As ultra-violet B solar radiation highly depends on latitude, and can promote, in less pigmented skin, intravascular folate photolysis, we stratified the analysis by latitude region, defining as Tropical (between 23.5(°) S and 23.5(°) N), Sub-Tropical (between 23.5(°) and 40(°) N and S), and Northern (≥ 40(o) N). Significant association was only found for Sub-Tropical area, both using fixed and random effect models. In conclusion, MTHFR 677C > T polymorphism is a moderate risk factor for DS for some populations, and populations located in Sub-Tropical region seem to be at greater risk. Latitude, ethnicity, skin pigmentation, and red blood cell folate are important variables to be considered in future studies.