Influence of the cystathionine beta-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine beta-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 micromol/l, P=0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P=0.034). These findings suggest that the CBS 844ins68 allele 'normalizes' homocysteine and folate levels in MTHFR 677TT individuals.     

Folate and the methylenetetrahydrofolate reductase 677C-->T mutation correlate with cognitive performance

Low folate status has been associated with cognitive decline. We investigated the association of folate status and the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism with performance on a battery of neuropsychological tests. Furthermore, we investigated whether the association of folate with cognitive performance was mediated by plasma homocysteine or risk of vascular disease. We used cross-sectional data from 818 individuals aged 50-70 years old. Low concentrations of erythrocyte folate but not serum folate were associated with poor performance on complex speed and memory tasks, independent of educational level and conventional risk factors of vascular disease. These associations were not mediated by homocysteine concentrations or carotid intima-media thickness. Subjects with the MTHFR 677TT genotype tended to perform better on cognitive tasks than CC/CT subjects, although this was significant for sensorimotor speed only (differences in Z-scores between MTHFR 677TT homozygotes and CC homozygotes -0.15, 95% CI: -0.30 to 0.00). Low concentrations of erythrocyte folate are associated with decreased cognitive performance, possibly through a homocysteine-independent mechanism such as DNA infidelity and mitochondrial decay.     

Association of RFC1 A80G and MTHFR C677T polymorphisms with Alzheimer's disease

We examined polymorphisms in reduced folate carrier gene (RFC1) and methylenetetrahydrofolate reductase gene (MTHFR) for association with sporadic AD (SAD) in Chinese population. Significant associations of RFC1 A80G G allele and GG genotype with SAD (p=0.008, OR=1.312, 95%CI=1.072-1.605, and p=0.042, OR=1.383, 95%CI=1.012-1.890) were found. Further stratification of total samples by APOE epsilon4 carrier status, age/age at onset and gender revealed that RFC1 A80G G allele was an APOE epsilon4-independent risk factor for late-onset AD, and it might increase the risk of AD in females. No significant associations of MTHFR C677T allele and genotype with AD were observed in total samples, but significant associations of T allele and TT genotype with AD (p=0.031, OR=1.586, 95%CI=1.042-2.414, and p=0.028, OR=2.250, 95%CI=1.074-4.712) were identified in APOE epsilon4 carrier subgroup, suggesting that MTHFR 677 T allele and APOE epsilon4 allele may synergistically act to increase AD risk. No significant effect of RFC1 G80A and MTHFR C677T polymorphisms on plasma folate and homocysteine levels was detected.     

Plasma total homocysteine levels and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene: a study in an Italian population with dementia

Hyperhomocysteinemia is a known risk factor for vascular disease and commonly occurs in the elderly. Several studies have shown an association between elevated plasma homocysteine levels and cognitive impairment, indicating that it may play a role in the pathophysiology of dementia. We studied plasma homocysteine, folate, vitamin B12 levels and the MTHFR C677T genotype in an Italian population of patients with dementia. We confirmed that elevated plasma tHcy (>14 micromol/l) is common in elderly subjects with dementia. Although we found a high prevalence of the MTHFR TT genotype (21.2%) the allele frequency is not over-represented relative to the control population. We also observed a high incidence of folate deficiency (38%) in subjects with dementia. Elevated homocysteine was associated with low plasma folate (<5.7 nmol/l) and the MTHFR TT genotype. Moderate to severe hyperhomocysteinemia (>26.1 nmol/l) was associated with a significantly lower MMSE score. Hyperhomocysteinemia may be neurotoxic by several different mechanisms affecting cognitive function. Further studies are needed to fully explore the potential of B vitamin supplementation to lower plasma homocysteine and improve cognitive function.     

Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: Low folate status alone may be the critical factor

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 μg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88–7.18; P < 0.001), and those with RCF less than 150 μg/L had eight times higher risk of NTD than subjects with levels over 400 μg/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs. Am. J. Med. Genet. 78:155–159, 1998. © 1998 Wiley-Liss, Inc.     

Homocysteinemia and its relationship with the methylentetrahydrofolate reductase polymorphism in various ethnic groups from western Venezuela

The prevalence of hyperhomocysteinemia and C677T MTHFR polymorphism was studied in various ethnic groups from Western Venezuela (60 Wayuu Indians, 42 italian immigrants and 77 Venezuelan mestizos) in relation with the prevalence of hyperhomocysteinemia and the C677T MTHFR polymorphism. Homocysteinemia was determined by polarized fluorescence immunoassay in an IMX system, serum folate was measured by radioimmunoanalysis and the MTHFR genotype was determined by PCR and restriction analysis. Hyperhomocysteinemia was defined as a value over 2 SD above the mean value for normal MTHFR (CC677) in each group. The prevalence of MTHFR variants (C677T and 677TT) was elevated in all ethnic groups (78% among the wayuu, 76% among Italians and 63% among mestizos) with a significant association between the concentrations of homocysteine and the levels of serum folate among the wayuu (p < 0.0001) and the mestizos (p < 0.001) only. Hyperhomocysteinemia was associated with MTHFR variants in 23% of the wayuu (OR: 6.17, CI 95: 0.74-51.36), 9.5% of the Italians (OR: 0.93, CI 95: 0.085-10.10) and 20.7 of the Venezuelans mestizos (OR: 5.2, CI 95: 1.08-24.90, p > 0.03). There was no relationship between hyperhomocysteinemia and folate deficiency in any of the groups studied. In conclusion, despite a high prevalence of C677T MTHFR variants in these ethnic groups of western Venezuela, the lack of no evidence of hyperhomocysteinemia combined with folate deficiency may imply that the nutritional status of these groups plays an important role in the control of hyperhomocysteinemia as a risk factor for cardiovascular disease.     

Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study.

Evidence for an involvement of aberrant homocysteine metabolism in the aetiology of schizophrenia is limited and controversial. A case-control study was performed to quantify the risk of schizophrenia in the presence of elevated homocysteine concentrations or homozygosity for the 677C --> T polymorphism (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene in subjects of Dutch ancestry. We determined the 677C --> T MTHFR genotype distribution in 254 well-defined patients and 414 healthy controls. Plasma homocysteine concentrations were measured in 62 patients with schizophrenia and 432 control subjects. When homocysteine concentrations were stratified into quartiles of the control distribution, we calculated an increased risk for schizophrenia in the fourth and third quartile versus the lowest quartile [odds ratio (OR) = 3.3; 95% confidence interval (CI): 1.2-9.2, and OR = 3.1; 95% CI: 1.2-8.0, respectively]. A significant dose-response relation of increasing homocysteine levels and increasing risk for schizophrenia was observed (P = 0.036). The 677TT genotype was associated with an OR of 1.6 [95% CI: 0.96-2.8] of having schizophrenia. Heterozygosity for the T allele compared to 677CC subjects accounted for an OR of 1.3 [95% CI: 0.91-1.8]. Elevated homocysteine levels and the MTHFR 677TT genotype are associated with an increased risk for schizophrenia. These observations support a causal relation between disturbed homocysteine metabolism and schizophrenia.     

Influence of combined methionine synthase (MTR 2756A > G) and methylenetetrahydrofolate reductase (MTHFR 677C > T) polymorphisms to plasma homocysteine levels in Korean patients with ischemic stroke

PURPOSE: Methionine synthase (MTR) and 5,10-methylenetetrahydrofolate reductase (MTHFR) are the main regulatory enzymes for homocysteine metabolism. The present case- control study was conducted to determine whether there is an association between the MTR 2756A > G or MTHFR 677C > T polymorphism and plasma homocysteine concentration in Korean subjects with ischemic stroke. MATERIALS AND METHODS: DNA samples of 237 patients who had an ischemic stroke and 223 age and sex-matched controls were studied. MTR 2756A > G and MTHFR 677C > T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Frequencies of mutant alleles for MTR and MTHFR polymorphisms were not significantly different between the controls and cases. The patient group, however, had significantly higher homocysteine concentrations of the MTR 2756AA and MTHFR 677TT genotypes than the control group (p=0.04 for MTR, p=0.01 for MTHFR). The combined MTR 2756AA and MTHFR 677TT genotype (p= 0.04) and the homocysteine concentrations of the patient group were also higher than those of the controls. In addition, the genotype distribution was significant in the MTHFR 677TT genotype (p=0.008) and combined MTR 2756AA and MTHFR 677TT genotype (p=0.03), which divided the groups into the top 20% and bottom 20% based on their homocysteine levels. CONCLUSION: The results of the present study demonstrate that the MTR 2756A > G and MTHFR 677C > T polymorphisms interact with elevated total homocysteine (tHcy) levels, leading to an increased risk of ischemic stroke.     

Interaction between common folate polymorphisms and B-vitamin nutritional status modulates homocysteine and risk for a thrombotic event

We have assessed the relationship between homocysteine, its thiol metabolites, specific folate coenzymes, and vitamin B12 according to the two main functionally relevant genotype-genotype categories that maintain the balance between homocysteine transsulphuration to cysteine, and homocysteine remethylation via folate dependent methionine biosynthesis, namely 2756A-->G-MS/66A-->G-MSR and 677C-->T-MTHFR/1298A-->C-MTHFR. We examined 152 individuals who were being treated for either thromboembolic (TE) or non-thromboembolic (non-TE) events. Chi2 test for linear trend in odds ratio provides reasonable evidence for an altered risk of thromboembolism within the range of compound MS/MSR genotypes encountered (wt/wt-->recessive/recessive) (p< or =0.05), but not within the same range of MTHFR/MTHFR genotypes. Logistic regression analysis of the risk for a TE event gave OR=0.49 (95% CI, 0.26-0.92; p=0.026) for 2756A-->G-MS, OR=1.08 (95% CI, 0.65-1.78) for 66A-->G-MSR, OR=1.19 (95% CI, 0.69-2.06) for 677C-->T-MTHFR and OR=0.98 (95% CI, 0.52-1.85) for 1298A-->C-MTHFR. When genotypes were examined individually, one-way ANOVA showed only 677C-->T-MTHFR (p=0.005 [TE]) and 2756A-->G-MS (p=0.005 [non-TE] and p=0.0006 [all subjects]) influence homocysteine. One-way ANOVA also showed that MTHFR/MTHFR compound genotype significantly influences TE homocysteine distribution (p=0.044), but no other variable. In MS/MSR, homocysteine distribution is not significantly affected in TE subjects, but approaches significance in non-TE individuals (p=0.062). However, the increased power obtained when all subjects are analysed demonstrates a significant influence of MS/MSR upon homocysteine distribution (p=0.008). Other significant influences of MS/MSR were on total cellular 5-methyl-H4folate in non-TE subjects (p=0.042) and vitamin B12 in TE subjects (p=0.018). Given the central role of vitamin B12 in MS/MSR activity, 5-methyl-H4folate and homocysteine were also looked at by vitamin B12 quartile, independent of genotype: Vitamin B12 quartile significantly affected homocysteine distribution in TE (p=0.013) but not non-TE individuals, with no effect on 5-methyl-H4folate distributions. Similarly, the prevalence of clinical phenotypes (p=0.013) and of 'high risk' 2756A-->G-MS wildtypes (p=0.039) was associated with the disposition of homocysteine/B12 in TE but not non-TE subjects. Overall, results indicate compound MS/MSR genotype is associated with risk for a TE event. This may be related to variation in activity of the functional enzymes coded for by polymorphic forms of compound MS/MSR, resulting in altered catalytic cycling of methylcobalamin/cob(I)alamin, which in turn influences Hcy (and total 5-methyl-H4folate). The effect on vitamin B12 is greater in TE than non-TE subjects. The compound MTHFR/MTHFR genotype also influences variation in Hcy in TE subjects, but seemingly without the same level of mediation by vitamin B12. These results are consistent with accepted paradigms and offer a plausible explanation for the effect and interaction of specific SNPs in the TE phenotype. The biological implications of the limited number of MTHFR/MTHFR mutant alleles that can coexist, usually no more than two, may be explained by the serious consequences to folate status that these genotype combinations precipitate. We show that lowering of all folate 1-C pools occurs in the rare ct/cc compound genotype, except for the 5,10-methenyl-H4folate pool, which expands. 5,10-methenyl-H4folate is the immediate product of 5,10-methylene-H4folate, which is likely diverted away from methionine biosynthesis via the aberrant MTHFR enzyme. Consequences for the methylation cycle may be severe, and in most cases lethal for the developing embryo, where methylation is required for dozens of critical processes, but particularly for maintaining DNA methylation patterns that are now known to regulate the expression of half the complement of human genes via CpG islands located in the 5' promotor region, or within the first few exons of the gene.     

A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia

5-methyltetrahydrofolate is the predominant form of folate in plasma. It may be the preferred substrate for transport via the reduced-folate carrier (RFC). We isolated a cDNA for the reduced folate carrier (RFC-1) from human skin fibroblasts. A common polymorphism at position 80 in exon 2 of RFC-1 was identified. This polymorphism changes a guanine (G) to an adenine (A), abolishing a CfoI restriction site. Using genomic DNA samples from 169 healthy subjects, we identified 27.1% GG homozygotes, 21.9% AA homozygotes, and 50.9% GA heterozygotes. We explored the impact of this polymorphism, separately and in combination with the 677C->T polymorphism in the methylenetetrahydrofolate reductase gene, on folate status and total homocysteine levels. We found a moderate, but significant, increase in total homocysteine levels in doubly homozygous 80GG/677TT subjects as compared to 80GG/677CC (P = 0.01) or 80GG/677CT (P = 0.04) subjects. In addition, individuals who were 80AA/677CT had higher plasma folate levels than those who were 80GG/677CT (P = 0.02).     

A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: relationships with C677T polymorphism and homocysteine/folate metabolism

5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine/methionine metabolism. The most-studied C677T polymorphism in the MTHFR gene results in a thermolabile variant with reduced activity, and is associated with increased levels of total plasma homocysteine, a risk factor for coronary artery disease. A new mutation in the MTHFR gene (A1298C) has also been reported to lower enzyme activity. Whether A1298C is a risk factor for coronary artery disease, separately or in combination with C677T, and/or relative to total plasma homocysteine and folate status, is unclear to date. We evaluated this hypothesis in 470 angiographically characterized subjects, 302 with coronary artery disease, and 168 with normal coronary arteries. The frequency of the 1298C allele was 0.33 and that of combined heterozygosity 0.315. No difference was found in the frequency of the genotypes or when analyzed for combined heterozygosity between patients with coronary artery disease and normals. Independent of folate status, the 1298C allele was not associated with increased total plasma homocysteine. No additional effect of A1298C on total plasma homocysteine was observed in 148 combined heterozygotes compared with 98 heterozygotes for the C677T alone. These findings do not support a major role for the A1298C mutation in homocysteine metabolism and emphasize the hypothesis that MTHFR genotypes may interfere with coronary artery disease risk only when an unbalanced nutritional status leads to raised total plasma homocysteine levels.     

Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women

Maternal impairments in folate metabolism and elevated homocysteinemia are known risk factors for having a child with Down syndrome (DS) at a young age. The 80G>A polymorphism of the reduced folate carrier gene (RFC-1) has been recently demonstrated to affect plasma folate and homocysteine levels, alone or in combination with the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. We performed the present study on 80 Italian mothers of DS individuals, aged less than 35 at conception, and 111 Italian control mothers, to study the role of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C genotypes to the risk of a DS offspring at a young maternal age. When polymorphisms were considered alone, both allele and genotype frequencies did not significantly differ between DS mothers and control mothers. However, the combined MTHFR677TT/RFC-1 80GG genotype was borderline associated with an increased risk (OR 6 (CI 95%: 1.0-35.9), P = 0.05), and to be MTHF1298AA/RFC-1 80(GA or AA) was inversely associated with the risk (OR 0.36 (CI 95%: 0.14-0.96), P = 0.04). Present results seem to indicate that none of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C polymorphisms is an independent risk factor for a DS offspring at a young maternal age; however, a role for the combined MTHFR/RFC-1 genotypes in the risk of DS pregnancies among young Italian women cannot be excluded.     

A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk.

Epigenetic mechanisms such as methylation of DNA, could lead to abnormal neurodevelopment and may be important in the etiology of schizophrenia. Maternal dietary folate intake may play a role in determining methylation levels. The MTHFR gene C677T polymorphism influences folate metabolism and intracellular availability of folate metabolites for methylation. We carried out a meta-analysis of MTHFR C677T genotype and schizophrenia risk, and found that TT homozygotes had a significantly increased risk, OR 1.48 (1.18-1.86). This supports the hypothesis that folate status is a determinant of schizophrenia risk. Larger studies of this issue are required, together with studies of maternal genotype which could identify whether maternal folate status during pregnancy is important.     

Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring.

PURPOSE: We present a case-control study of seven polymorphisms of six genes involved in homocysteine/folate pathway as risk factors for Down syndrome. Gene-gene/allele-allele interactions, haplotype analysis and the association with age at conception were also evaluated. METHODS: We investigated 94 Down syndrome-mothers and 264 control-women from Campania, Italy. RESULTS: Increased risk of Down syndrome was associated with the methylenetetrahydrofolate reductase (MTHFR) 1298C allele (OR 1.46; 95% CI 1.02-2.10), the MTHFR 1298CC genotype (OR 2.29; 95% CI 1.06-4.96), the reduced-folate-carrier1 (RFC1) 80G allele (1.48; 95% CI 1.05-2.10) and the RFC1 80 GG genotype (OR 2.05; 95% CI 1.03-4.07). Significant associations were found between maternal age at conception > or = 34 years and either the MTHFR 1298C or the RFC 180G alleles. Positive interactions were found for the following genotype-pairs: MTHFR 677TT and 1298CC/CA, 1298CC/CA and RFC1 80 GG/GA, RFC1 80 GG and methylenetetrahydrofolate-dehydrogenase 1958 AA. The 677-1298 T-C haplotype at the MTHFR locus was also a risk factor for Down syndrome (P = 0.0022). The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase 844ins68 polymorphisms were not associated with increased risk of Down syndrome. CONCLUSION: These results point to a role of maternal polymorphisms of homocysteine/folate pathway as risk factors for Down syndrome.     

Folate levels determine effect of antioxidant supplementation on micronuclei in subjects with cardiovascular risk

We have investigated the effect of modest supplementation with alpha-tocopherol (100 mg/day), beta-carotene (6 mg/day), vitamin C (100 mg/day) and selenium (50 microg/day) on oxidative stress and chromosomal damage, and the influence of methylenetetrahydrofolate reductase (MTHFR) genotype on these end-points. Subjects were two groups of middle-aged men differing in cardiovascular risk; 46 survivors of myocardial infarction before age 50 and 60 healthy controls. They were randomly divided into equal groups to receive antioxidants or placebo for 12 weeks. Twenty-eight patients and 58 controls completed the intervention. Micronucleus levels in peripheral lymphocytes and changes seen after intervention were studied in relation to the MTHFR C677T genotype, basal homocysteine and plasma folate levels. Ferric reducing ability of plasma and concentration of malondialdehyde were measured to assess the antioxidant effect of supplementation. There was no association of micronuclei with folate, homocysteine or malondialdehyde levels before supplementation. Micronucleus frequencies and plasma folate levels did not vary significantly with MTHFR genotype. Homocysteine levels in subjects with the TT variant genotype were significantly higher compared with CT or CC (P = 0.001), especially in subjects with low folate (P = 0.012). In the placebo control group an increase in micronuclei (P = 0.04) was detected at the end of the intervention period. This effect was not seen in the supplemented group. In antioxidant-supplemented myocardial infarction survivors we found an increase in the ferric reducing ability of plasma (P < 0.001) and a decrease in malondialdehyde (P = 0.001). Micronucleus frequency showed a decrease, strongest in subjects with normal folate levels (P = 0.015). In subjects with low folate levels, a high correlation was found between micronuclei after supplementation and homocysteine, both before (r = 0.979, P = 0.002) and after supplementation (r = 0.922, P = 0.009). Thus, folate deficiency may amplify the effect of other risk factors such as elevated homocysteine levels or variant MTHFR genotype, as well as influencing the ability of antioxidant supplementation to protect against genetic damage.     

MTHFR Gene polymorphisms, B-vitamins and hyperhomocystinemia in young and middle-aged acute myocardial infarction patients

We have examined the prevalence of the C677T and A1298C single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in healthy Tamilians and in patients with acute myocardial infarction and related this polymorphism to plasma homocysteine concentrations, serum folate, serum cobalamin and riboflavin status. The SNPs in the MTHFR gene were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Plasma homocysteine, serum folate and serum cobalamin concentrations were analyzed using an automated chemiluminescence method and riboflavin status was assessed by measuring the erythrocyte glutathione reductase activity using spectrophotometric method. Out of the 200 young and middle-aged (<48 years) individuals included in the study, 100 were acute myocardial infarction (AMI) patients and 100 were healthy individuals with no documented history of heart diseases. There was a significant increase in homocysteine levels among the AMI patients as compared to the healthy controls (p<0.001). The results of this study indicate that hyperhomocystinemia is more prevalent in Tamilian AMI patients and that the MTHFR C677T and A1298C SNPs are not associated with hyperhomocystinemia. Folate status was found to be within normal range in all the study subjects. There was no correlation between homocysteine and different biochemical variables including cobalamin, folate and riboflavin. However, serum cobalamin was found to be significantly decreased in AMI patients when compared to controls (p<0.001). The simultaneous presence of decreased serum cobalamin status, hyperhomocystinemia and mutant genotype for both the SNPs might lead to an increased risk for the occurrence of AMI. Further intervention trials including the supplementation of cobalamin may prove whether homocysteine level decrease in response to the supplementation of cobalamin in individuals with hyperhomocystinemia and mutant genotype for both the above mentioned SNPs.     

MTRR and MTHFR polymorphism: link to Down syndrome?

Polymorphisms in genes encoding the folate metabolizing enzymes methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase reductase (MTRR A66G) have been linked to the etiology of Down syndrome. We examined the prevalence of these variant genotypes in mothers who had given birth to a child with Down syndrome (n = 48) and in control mothers (n = 192), and investigated the biochemical factors influenced by the presence of MTRR A66G and MTHFR C677T. The frequency of the MTRR variant genotypes (AG, GG) was significantly higher in mothers of children with Down syndrome compared to controls (P = 0.0028). MTHFR C677T genotype frequencies were not significantly altered in mothers of children with Down syndrome (P = 0.74). However, mothers who had a MTHFR CT or TT genotype and a MTRR GG genotype had a 2.98-fold increased risk of having a child with Down syndrome (P = 0.02). The MTRR polymorphism did not increase plasma homocysteine. Higher homocysteine was found with the presence of the MTHFR T allele. In conclusion, MTRR A66G is significantly more common in mothers of children with Down syndrome but does not appear to increase the risk for Down syndrome by changing homocysteine metabolism. Women who have both the MTRR and MTHFR variant genotypes are also at increased risk of producing offspring with Down syndrome.     

Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy

Previous studies have shown conflicting findings in linking polymorphic variation in folate-related genes to the risk of neural tube defect pregnancy. Recent evidence points to maternal genotype being important in determining NTD risk. A case-control study was undertaken in 97 mothers of NTD cases from the northern region of the UK. Pregnant controls (n = 190) from a regional DNA bank and non-pregnant controls (n = 100) from the same geographical area were recruited. MTHFR 677C >T, MTHFR 1298A >C, MTRR 66A >G, SHMT 1420C >T, CbetaS 844ins68, and RFC-1 80G >A allele and genotype frequencies were determined and odds ratios (OR) calculated. Erythrocyte folate levels for cases and controls were also measured and a comparison made of median erythrocyte folate levels stratified according to genotype. The MTHFR 677C >T variant was not shown to be an independent NTD risk factor in mothers of NTD-affected pregnancy. A second polymorphism in MTHFR, 1298A >C, was less frequently observed in mothers of NTD cases (OR [95% CI]=0.57 [0.33, 0.97]). Possession of compound 1298A >C and 677C >T variants elevated risk of NTD pregnancy considerably (TT/AC+TT/CC vs CC/AA OR [95% CI]=6.56 [1.10, 39.33]). Erythrocyte folate levels were persistently lower in NTD mothers (p = 0.001) despite assays being conducted many years after the index pregnancy (17.6+/-12.6 years). Erythrocyte folate levels were depressed in the presence of the MTHFR 677C >T variant.     

叶酸代谢相关基因多态性及血浆同型半胱氨酸与唐氏综合征关系研究

目的研究叶酸代谢相关的亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTH-FR)基因多态性与唐氏综合征(Down syndrome,DS)发生的关系。方法选择100例生育过DS患儿的汉族母亲及100名相匹配的正常对照组母亲,PCR-限制性片段长度多态性方法检测MTHFR677C/T的基因型,化学发光法检测血浆中同型半胱氨酸(homocysteine,HCY)的水平。结果病例组MTHFR677T等位基因的频率较对照组增高,差异有统计学意义(P=0.002);杂合基因型CT的比值比为2.12(95%CI:1.14～3.94);而纯合基因型TT的比值比为3.43(95%CI:1.41～8.36)。平均血浆HCY浓度在病例组[(9.04±3.85)μmol/L]较对照组[(6.53±2.06)μmol/L]增高,差异有统计学意义(P<0.01)。MTHFR677位点一个和(或)两个等位基因C→T的变异,不论在病例组还是对照组均可引起HCY水平的显著增加(P<0.01)。同为MTHFR677CC基因型,病例组中的血浆HCY浓度仍较对照组增高(P<0.01),这种增加不依赖于MTHFR的基因型。结论血浆HCY和叶酸代谢相关基因的遗传多态性是汉族妇女生育DS患儿的危险因素。     

No association of the C677T methylenetetrahydrofolate reductase polymorphism with schizophrenia

Some serological and genetic studies have suggested that alterations in folate metabolism are associated with increased vulnerability to schizophrenia. In particular, these findings are most striking for the role of a putatively functional variant (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To test the hypothesis that the T allele and the TT genotype are risk factors for psychosis, we genotyped the C677T polymorphism in 206 participants with schizophrenia or schizoaffective disorder and 359 participants from a population control sample. Neither the T allele nor the TT genotype was associated with increased risk for schizophrenia. These results do not support a role for the C677T MTHFR variant in schizophrenia.