The Role of Vitamin B12 in Fasting Hyperhomocysteinemia and Its Interaction with the Homozygous C677T Mutation of the Methylenetetrahydrofolate Reductase (MTHFR) Gene

2000 ◽  
Vol 83 (04) ◽  
pp. 563-570 ◽  
Author(s):  
Antonio Coppola ◽  
Pasquale Madonna ◽  
Isabella Fermo ◽  
Anna Pagano ◽  
Giuseppina Mazzola ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Phenotypic Expression ◽  
Mthfr Gene ◽  
Response To Treatment ◽  
First Episode ◽  
Mthfr Genotype ◽  
C677t Mutation ◽  
Folate And Vitamin B12 ◽  
Ms Gene

SummaryTotal fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 ± 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 ± 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 µM in men and >15 µM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78–5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42; 0.84–2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61–14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = −0.42 and −0.25) than with the 677CC or CT MTHFR genotype (r = −0.37 and −0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 ± 206 vs. 408 ± 185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p ≤0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p ≤0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B12 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.

C677T Methylenetetrahydrofolate Reductase and Plasma Homocysteine Levels among Thai Vegans and Omnivores

2013 ◽  
Vol 83 (2) ◽  
pp. 86-91 ◽  
Author(s):  
Saowanee Kajanachumpol ◽  
Kalayanee Atamasirikul ◽  
Phieuvit Tantibhedhyangkul
Keyword(s):  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Vitamin B12 Deficiency ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Serum Folate ◽  
Geometric Means ◽  
C677t Mutation ◽  
B12 Deficiency ◽  
Mthfr Mutation

Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia.

Methylenetetrahydrofolate reductase polymorphisms as risk factors for retinal venous occlusive disease: A literature review

2021 ◽  
pp. 112067212110006
Author(s):  
Manuel Marques ◽  
Francisco Alves ◽  
Miguel Leitão ◽  
Catarina Rodrigues ◽  
Joana Tavares Ferreira
Keyword(s):  
Risk Factors ◽  
Literature Review ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Mthfr Polymorphisms ◽  
Vein Occlusion ◽  
C677t Mutation ◽  
Retinal Vascular Disease

The role of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene in retinal vein occlusion (RVO) is a theme of discussion since the first reports of RVO in patients with MTHFR C677T mutation and without classic acquired risk factors for retinal vascular disease. The association between MTHFR polymorphisms and RVO has been studied over the last 20 years producing conflicting results. This review aims to summarize the literature concerning the role MTHFR polymorphisms as risk factors for RVO.

Association of homocysteine (but not of MTHFR 677 C>T, MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily

2006 ◽  
Vol 96 (08) ◽  
pp. 154-159 ◽  
Author(s):  
Rosa-Maria Guéant-Rodriguez ◽  
Guido Anello ◽  
Rosario Spada ◽  
Antonino Romano ◽  
Adrian Fajardo ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Methionine Synthase ◽  
Italian Population ◽  
Significant Independent Predictor ◽  
Methionine Synthase Reductase ◽  
Ischaemic Cerebrovascular Disease ◽  
Folate And Vitamin B12 ◽  
Neutral Effect

SummaryAssociation between methylenetetrahydrofolate reductase polymorphism (MTHFR 677 C>T), a determinant of homocysteine plasma level (t-Hcys), with ischaemc cerebrovascular disease (iCVD) seems to be neutral in North Europe and North America. The association of 2756 A>G of methionine synthase (MTR), 66 A>G of methionine synthase reductase (MTRR) and 776 C>G of transcobalamin (TCN2) needs to be evaluated further. It was the objective of this study to evaluate the association of these polymorphisms, t-Hcys, vitamin B12 and folate levels with iCVD, in an Italian population from Sicily. We investigated the association of these polymorphisms, t-Hcys, vitamin B12 and folate with iCVD in 252 subjects, including 131 cases and 121 sexand agematched healthy controls. t-Hcys was higher in the iCVD group than in controls [15.3 (11.5–17.9) vs. 11.6 (9.4–14.5) µM; P=0. 0007] and also in subjects withTCN2 776CG genotype, compared to homozygous genotypes [13.5 (9.9± 16.9) vs. 11.7 (9.6 ± 14.4) µM; P=0. 0327]. The folate level in cases and controls was consistent with an adequate dietary intake [12.7 (9.0–15.3) vs. 12.5 (9.6–16.9) nM; P=0. 7203]. In multivariate analysis, t-Hcys was a significant independent predictor of iCVD with an odds ratio of 1.14 (95% C.I. : 1.06–1.24; P=0. 0006). No association was found between MTHFR, MTR, MTRR and TCN2 polymorphisms and iCVD risk. We have found an influence of t-Hcys and a neutral effect of MTHFR, MTR, MTRR and TCN2 on iCVD risk in Sicily. The neutral influence of these polymorphisms may be explained by adequate status in folate and vitamin B12. Other factors underlying the increased t-Hcys need further investigations.

Ethnic Differences in the Frequency of the C677T Mutation in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Healthy Israeli Populations

2000 ◽  
Vol 4 (3) ◽  
pp. 309-311 ◽  
Author(s):  
Rivka Dresner Pollak ◽  
Yechiel Friedlander ◽  
Arthur Pollak ◽  
Maria Idelson ◽  
Idit Bejarano-Achache ◽  
...  
Keyword(s):  
Ethnic Differences ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
C677t Mutation

Hyperhomocysteinaemia, low folate concentrations and MTHFR C677T mutation in abdominal aortic aneurysm

VASA ◽  
2014 ◽  
Vol 43 (3) ◽  
pp. 181-188 ◽  
Author(s):  
Hui Cao ◽  
Xinhua Hu ◽  
Qiang Zhang ◽  
Jun Li ◽  
Bing Liu ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Folic Acid ◽  
Aortic Aneurysm ◽  
Vitamin B12 ◽  
Gene Mutation ◽  
Plasma Levels ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Abdominal Aortic ◽  
C677t Mutation

Background: Homocysteine (Hcy) has been implicated in abdominal aortic aneurysm (AAA). However, the association of Hcy, vitamin B12, and folate in patients with AAA has not been studied in China. This study was conducted with the aim to evaluate the relationship of vitamin B12, folic acid, and Hcy levels in AAA. Patients and methods: 463 patients who had AAA were included in this study. 463 control subjects were age- and sex-matched with the patients. In all of the subjects, we evaluated total plasma levels Hcy, vitamin B12, folic acid and the distribution of the C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation. Results: The mean plasma Hcy levels were significantly higher in patients with AAA compared with controls (18.37 ± 6.97 vs. 12.89 ± 4.08 μmol/L, P < 0.001). The frequency of homozygous (TT) genotype in MTHFR C677T mutation was significantly higher in patients with AAA than that in control subjects (19.4 % vs. 11.9 %, P = 0.002). The fasting Hcy correlated negatively with folate (A r = - 0.311, P < 0.01; Control: r = - 0.348, P < 0.01). The aneurysm size was significantly greater (P < 0.001) in patients with hyperhomocysteinemia than that in patients with normal Hcy plasma levels. The size of the AAA had a linear correlation with the plasma Hcy level (r = 0.286; P< 0.001). Conclusions: Serum folate deficiency and hyperhomocysteinemia were associated with an increased risk of AAA in Northeast China. The homozygous (TT) genotype of MTHFR gene mutation may be a crucial hereditary risk factor in AAA.

Homocysteine, folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects

2002 ◽  
Vol 102 (6) ◽  
pp. 631-637 ◽  
Author(s):  
Joey M. KAYE ◽  
Kim G. STANTON ◽  
Vincent J. MCCANN ◽  
Samuel D. VASIKARAN ◽  
Valerie BURKE ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Serum Folate ◽  
Type I ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Mthfr Genotype ◽  
Erythrocyte Folate

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n = 354; Type II, n = 392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P<0.01), remaining significant when additionally adjusted for serum folate (P = 0.043 and P = 0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P<0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.

scholarly journals Influence of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Homocysteine Concentrations after Nitrous Oxide Anesthesia

2008 ◽  
Vol 109 (1) ◽  
pp. 36-43 ◽  
Author(s):  
Peter Nagele ◽  
Barbara Zeugswetter ◽  
Caspar Wiener ◽  
Hansjörg Burger ◽  
Michael Hüpfl ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Elective Surgery ◽  
Plasma Concentrations ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Outcome Variable ◽  
Wild Type ◽  
Oxide Anesthesia

Background Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (677C&gt;T, 1298A&gt;C) cause elevated plasma homocysteine concentrations and have been linked to fatal outcomes after nitrous oxide anesthesia. This study tested the hypothesis that patients with common MTHFR 677C&gt;T or 1298A&gt;C mutations develop higher plasma homocysteine concentrations after nitrous oxide anesthesia than wild-type patients. Methods In this prospective, observational cohort study with blinded, mendelian randomization, the authors included 140 healthy patients undergoing elective surgery. All patients received 66% nitrous oxide for at least 2 h. The main outcome variable, plasma total homocysteine, and folate, vitamin B12, and holotranscobalamin II were measured before, during, and after surgery. After completion of the study, all patients were tested for their MTHFR 677C&gt;T or 1298A&gt;C genotype. Results Patients with a homozygous MTHFR 677C&gt;T or 1298A&gt;C mutation (n = 25) developed higher plasma homocysteine concentrations (median [interquartile range], 14.9 [10.0-26.4] microm) than wild-type or heterozygous patients (9.3 [7.5-15.5] microm; n = 115). The change in homocysteine after nitrous oxide anesthesia was tripled in homozygous patients compared with wild-type (5.6 microm [+60%] vs. 1.8 microm [+22%]). Only homozygous patients reached average homocysteine levels considered abnormal (&gt; 15 microm). Plasma 5-methyl-tetrahydrofolate concentrations increased uniformly by 20% after nitrous oxide anesthesia, indicating the inactivation of methionine synthase and subsequent folate trapping. Holotranscobalamin II concentrations remained unchanged, indicating no effect of nitrous oxide on vitamin B12 plasma concentrations. Conclusions This study shows that patients with a homozygous MTHFR 677C&gt;T or 1298A&gt;C mutation are at a higher risk of developing abnormal plasma homocysteine concentrations after nitrous oxide anesthesia.

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