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Summarymethylenetetrahydrofolate reductase polymorphism (MTHFR C677T) is an established determinant of homocysteine plasma level (t-Hcys) while its association with coronary artery disease (CAD) seems to be more limited. In contrast, the association of the substitutions A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR) and C776G of transcobalamin (TCN) to both t-Hcys and CAD needs to be evaluated further. The objective was to evaluate the association of these polymorphisms with t-Hcys and CAD in a French population. We investigated the individual and combined effects of these polymorphisms and of vitamin B12 and folates with t-Hcys in 530 CAD patients and 248 matched healthy controls. t-Hcys was higher in the CAD group than in controls (11.8 vs 10.4 μM, P median and MTRR AA genotype were two significant independent predictors of CAD with respective odds ratios of 3.1 (95 % CI: 1.8-5.1, P

Transcobalamin (TC) is the plasma transporter that delivers vitamin B12 to cells. We have already reported that HT-29 and Caco-2 cells secrete different TC variants. HT-29 secretes 2 TC isoproteins (codon 259-Pro/Arg [259-P/R]), exhibiting unequal concentrations (TC 259-P > TC 259-R), and Caco-2 cells only secrete the phenotype 259-R. We investigated the relation between phenotypic and genetic TC polymorphism in HT-29 cells transfected with Caco-2 TC complementary DNA and in 159 healthy Caucasians. We found that codon 259-R is buried and, thus, the genetic polymorphism provides no explanation why the TCs from HT-29 and Caco-2 cells have different isoelectric points in nondenaturing isoelectric focusing (IEF). The newly translated TC in HT-29 cells from the Caco-2 complementary DNA recombinant plasmid had the same isoelectric point as the TC constitutively expressed in HT-29 cells, suggesting that TC phenotypic variability involves a specific cell folding of the protein. The codon 259 polymorphism was found to have a biallelic distribution: homozygotes P = 34.6%, heterozygotes R/P = 47.8%, and homozygotes R = 17.6%. In heterozygous samples, the IEF showed that the TC 259-P/TC 259-R ratio = 1.6. The blood apo-TC concentration of 259-P homozygous Caucasians was significantly higher than that of homozygous 259-R (P

The vitamin B 12 status of 20 subjects who were on home parenteral nutrition after surgical or functional small bowelresection and were given 1000 μ g cyanocobalamin every 3 mo was studied by comparing their plasma vitamin B 12 , homocysteine (HS), and methylmalonic acid (MMA) concentrations. The plasma vitamin B 12 concentration (median 145 pmol/L, 95% confidence interval: 123–217) was subnormal in four cases and borderline in four others. In the “low B 12 ” group, the concentrations of the markers of vitamin B 12 deficiency were in the normal range: HS 10.7 μ mol/L (8.0–12.3); and MMA, 0.15 μ mol/L (0.09–0.19). References values were HS, 10.0 μ mol/L (9.4–12.6); and MMA, 0.16 μ mol/L (0.10–0.19). Thus, there were no metabolic signs of vitamin B 12 deficiency in these subjects on parenteral nutrition, despite the fact that their plasma vitamin B 12 levels were low. Analysis of individual data showed that the four patients with low circulating B 12 had markers of intracellular vitamin B 12 deficiency in the normal range.

The concentrations of vitamin B12, its analogs, and the haptocorrin and transcobalamin carriers in 21 patients suffering from Crohn's disease and a group of controls (20 adults) were measured. There were no significant differences in the mean values for vitamin B12, total corrinoids (vitamin B12 + analogs), or vitamin B12 or total corrinoids bound to haptocorrin or transcobalamin of the Crohn's and control patients. There was a significant increase in the binding capacity of transcobalamin in the Crohn's patients compared to the controls (P

Moderate hyperhomocysteinemia is a risk for neural tube defect and neurodegenerative and vascular diseases and has nutritional, metabolic, and genetic determinants. Its prevalence in sub-Saharan Africa remains unknown.Our goal was to evaluate the prevalence of hyperhomocysteinemia and the influence of nutritional, metabolic, and genetic determinants in savanna and coastal regions of Togo and Benin.Volunteers were recruited from coastal (C groups; n = 208) and savanna (S group; n = 68) regions. Vitamin B-12, folate, total homocysteine (tHcy), cystatin C (a marker of glomerular filtration), and inflammatory and nutritional protein markers were measured in plasma, and the methylenetetrahydrofolate reductase (MTHFR) 677C--T and 1298A--C polymorphisms and the methionine synthase 2756A--G polymorphism were examined in genomic DNA.Moderate hyperhomocysteinemia (tHcy15 micromol/L) was recorded in 62.3% and 29.4% of the subjects from the coast and savanna, respectively (P0.0001). A histogram distribution of tHcy in the coastal groups showed a distinct group, C2 (15% of the total group), with tHcy28 micro mol/L. Folate6.75 nmol/L (lower quartile) and MTHFRCT/TT genotype were the 2 main risk factors for moderate hyperhomocysteinemia in the whole population [odds ratios: 5.3 (95% CI: 2.5, 11.2; P0.0001) and 4.9 (1.6, 14.8; P = 0.0048), respectively] and in the C2 group [odds ratios: 15.9 (4.5, 56.8; P0.0001) and 9.0 (2.3, -35.2; P = 0.0017), respectively]. Cystatin C was another potent risk factor in the C2 group.A high prevalence of hyperhomocysteinemia in coastal West Africa, related to folate concentrations and the MTHFR 677 T allele, suggests the need to evaluate the influence of hyperhomocysteinemia on disease in this area.

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region.

Glomerular filtration is one of the major determinants of plasma total homocysteine (tHcy). To evaluate the respective roles of residual glomerular filtration (by measuring a specific protein marker, cystatin C), genetic polymorphisms and nutritional status in tHcy blood levels in end-stage renal disease patients (ESRD) under hemodialysis and supplemented with folate, we measured tHcy, folate, vitamin B 12 (B 12 ), creatinine, cystatin C, albumin and C-reactive protein and determined the polymorphism of methylenetetrahydrofolate reductase (MTHFR) (C677T and A1289C) and of methionine synthase (MS) (A2756G) in 114 ESRD patients before hemodialysis and 76 control subjects. All patients received a folate supplementation of 700 μg/day. Hyperhomocysteinemia was observed in all patients and exceeded the upper normal limit by 2-fold in 52.4% of the patients. Serum folate was significantly increased and the B 12 level was not different from controls. Folate, Cystatin C and creatinine were significantly correlated to tHcy, while no correlation was found between tHcy, albumin and C-reactive protein. No difference in genotype frequency between ESRD patients and controls was found for MTHFR A1289C and MS A2756G. The MTHFR 677TT genotype was less frequent and was associated with a significantly higher tHcy level in patients. Folate and residual glomerular filtration estimated by cystatin C and creatinine levels were two independent determinants of tHcy in ESRD patients. These data suggest that hyperhomocysteinemia is a consequence as well as a complicating factor of renal failure.