Methylenetetrahydrofolate Reductase (MTHFR) Allele Frequencies in Amerindians

Neural tube defects (NTDs) have been associated with abnormalities of folate metabolism. Methylenetetrahydrofolate reductase (MTHFR) is the regulatory enzyme for the conversion of homocysteine to methionine. The C677T mutation in the MTHFR gene affects folate distribution, and homozygosity for the T allele may be associated with an increased risk of NTDs. A second mutation, an A1298C transversion in this same gene, is also associated with an increased risk for NTDs but only in conjunction with the 677T allele. A low incidence of NTDs has been observed in high‐altitude populations; however, these studies did not provide information about the allele distribution of genes involved in folate metabolism. This investigation compares allele frequencies of the C677T and A1298C polymorphisms between Quechua people living at 3200–4200 m in the Peruvian Central Andes and an Aché group living at low altitude. Allele frequencies at both loci were not significantly different between the two populations. The absence of the 677T/677T genotypes and of the 677T/1298C arrangement in both groups may indicate a genetic contribution to reduced risk for NTDs; however, factors other than altitude are likely responsible for the low variant allele frequencies in these populations.     

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism among Gaddi tribe of Indian state of Himachal Pradesh

Background: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been suggested to be positively associated with several disorders. Distribution of the mutant T-allele varies in ethnic and geographical populations of the world.

Aim: The aim of the present study was to investigate the distribution of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in a transhumant (Gaddi) tribal population of Himachal Pradesh dwelling at high and middle altitude and exposed to strong ultraviolet radiation.

Method and results: A total of 486 samples (141 males and 345 females) were randomly enrolled from the individuals aged 25–75 years who were unrelated up to first cousin. Among Gaddis, genotype frequencies of CC, CT and TT were 67.90%, 27.78% and 4.32%, respectively. Among males and females distribution of genotype frequencies also followed a similar trend. The studied population was in Hardy–Weinberg equilibrium (χ^2?=?2.213, df?=?1, p?=?0.136). Frequency of mutant T-allele in the Gaddi population was found to be 0.183, which might be due to European ancestry, endogamous nature and selection.     

Methylenetetrahydrofolate reductase deficiency in a patient with phenotypic findings of Angelman syndrome

Deficiency of methylenetetrahydrofolate reductase (MTHFR) is associated with a variable phenotype that includes mental retardation, gait abnormalities, and seizures. Many of the same clinical findings are also seen in patients with Angelman syndrome. We report on a patient with MTHFR deficiency who was initially diagnosed as having Angelman syndrome. This case illustrates that MTHFR deficiency can mimic the phenotype of Angelman syndrome and that MTHFR deficiency should be excluded in patients with manifestations of Angelman syndrome whose molecular studies of chromosome 15 are normal. Am. J. Med. Genet. 77:198–200, 1998. © 1998 Wiley-Liss, Inc.     

Methylenetetrahydrofolate reductase (MTHFR): The incidence of mutations C677T and A1298C in the Ashkenazi Jewish population

The polymorphic mutation C677T in the gene of MTHFR is considered a risk mutation for spina bifida and vascular disease. Another common mutation on the MTHFR gene, A1298C, has also been described as another risk mutation. We studied the frequencies of these two mutations on DNA samples from healthy Jewish individuals and compared them to the frequency of these mutations in DNA samples obtained from healthy individuals in South Texas. The presence of the C677T allele was determined by PCR and Hinf I digestion, and mutation A1298C by PCR and Mbo II digestion. A total of 310 alleles was examined for C677T in the Ashkenazi samples and 400 alleles in the non-Jewish samples. The rate of C677T among the Ashkenazi Jewish alleles was 47.7% as compared to 28.7% among the alleles from the non-Jewish population. The difference is statistically significant, P < 0.0005. Mutation A1298C was examined in 298 alleles of Jewish individuals and 374 alleles of non-Jewish counterparts from Texas. The rate of the A1298C mutation in the Jewish samples was 27.2% whereas in the non-Jewish was 35%. This was also statistically significant, P < 0.031. No individuals were homozygous for both mutations or were found to be homozygous for one mutation with heterozygosity of the other mutation, and that the C677T and the A1298C alleles did not occur in cis position. This study shows a unique distribution of C677T and the A1298C alleles among the Ashkenazi Jews. In spite of high frequency of C677T mutation, spina bifida is less common among Ashkenazi Jews. Further studies are needed to establish whether the C677T and the A1298C mutations have an impact on vascular disease in the Ashkenazi Jewish population. Am. J. Med. Genet. 86:380–384, 1999. © 1999 Wiley-Liss, Inc.     

Methylenetetrahydrofolate reductase (MTHFR): the incidence of mutations C677T and A1298C in the Ashkenazi Jewish population.

The polymorphic mutation C677T in the gene of MTHFR is considered a risk mutation for spina bifida and vascular disease. Another common mutation on the MTHFR gene, A1298C, has also been described as another risk mutation. We studied the frequencies of these two mutations on DNA samples from healthy Jewish individuals and compared them to the frequency of these mutations in DNA samples obtained from healthy individuals in South Texas. The presence of the C677T allele was determined by PCR and Hinf I digestion, and mutation A1298C by PCR and Mbo II digestion. A total of 310 alleles was examined for C677T in the Ashkenazi samples and 400 alleles in the non-Jewish samples. The rate of C677T among the Ashkenazi Jewish alleles was 47.7% as compared to 28.7% among the alleles from the non-Jewish population. The difference is statistically significant, P < 0.0005. Mutation A1298C was examined in 298 alleles of Jewish individuals and 374 alleles of non-Jewish counterparts from Texas. The rate of the A1298C mutation in the Jewish samples was 27.2% whereas in the non-Jewish was 35%. This was also statistically significant, P < 0.031. No individuals were homozygous for both mutations or were found to be homozygous for one mutation with heterozygosity of the other mutation, and that the C677T and the A1298C alleles did not occur in cis position. This study shows a unique distribution of C677T and the A1298C alleles among the Ashkenazi Jews. In spite of high frequency of C677T mutation, spina bifida is less common among Ashkenazi Jews. Further studies are needed to establish whether the C677T and the A1298C mutations have an impact on vascular disease in the Ashkenazi Jewish population.     

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis

Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case–control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and case–control studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies (P _Q < 0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03–1.64). However, the sensitivity analysis (exclusion of studies not in Hardy–Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR = 1.32 (1.10–1.58), P _Q = 0.27], and in type 2 diabetes [FE OR = 1.30 (1.06–1.60), P _Q = 0.38]. The additive model produced significant association in main analysis [RE OR = 1.65 (1.13–2.42), P _Q < 0.01] in Caucasians [FE OR = 1.48 (1.11–1.98), P _Q = 0.17] and in type 2 diabetes [RE OR = 1.65 (1.03–2.67), P _Q < 0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies.     

5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects

Persons with a thermolabile form of the enzyme 5,10 methylenetetrahydrofolate reductase (MTHFR) have reduced enzyme activity and increased plasma homocysteine which can be lowered by supplemental folic acid. Thermolability of the enzyme has recently been shown to be caused by a common mutation (677C^→T) in the MTHFR gene. We studied 41 fibroblast cultures from NTD-affected fetuses and compared their genotypes with those of 109 blood specimens from individuals in the general population. 677C^→T homozygosity was associated with a 7.2 fold increased risk for NTDs (95% confidence interval: 1.8–30.3; p value: 0.001). These preliminary data suggest that the 677C^→T polymorphism of the MTHFR gene is a risk factor for spina bifida and anencephaly that may provide a partial biologic explanation for why folic acid prevents these types of NTD.     

MTHFR (methylenetetrahydrofolate reductase) C677T polymorphism and psoriasis

The aim of the study was to evaluate possible association of MTHFR C677T gene polymorphism (NM_005957) with psoriasis. Genotypes of MTHFR C677T gene polymorphism were determined in a sample of 654 Caucasian (Czech) subjects. Case group (n = 410) included patients with psoriasis (plaque psoriasis diagnosed in 285 patients, other subtypes of psoriasis were observed in 125 patients). Control group (n = 244) consisted of healthy subjects without individual history of psoriasis, with similar age and gender characteristics. The MTHFR C677T polymorphism genotypes were determined by a polymerase chain reaction and a subsequent restriction analysis with HinfI. The genotypes of C(677)T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism were determined in a sample of 654 Caucasian (Czech) subjects. We proved a significant difference in genotype distribution (P _g = 0.03) and allelic frequency (P _a = 0.02) between psoriatic and control subjects (Table 3). The CC (the thermostabile) genotype was significantly more frequent in psoriatic patients compared to controls [OR = 1.55, 95% confidential interval (CI) = 1.12–2.15, P = 0.004814, P _corr = 0.01]. But, a significant increase of T allele in MTHFR gene was observed in patients with positive family history of diabetes (P _a = 0.02) and in those with a frequent tonsillitis/tonsillectomy (P _a = 0.04). No difference was observed between patients with and without positive family history of psoriasis (P _a = 0.251). But, when psoriatic patients were described for FHDM, FH-Ps, and PH-T simultaneously, The highest incidence of CT + TT genotypes was calculated for psoriasis patients with positive history of psoriasis and diabetes mellitus together with personal history of repeated tonsillitis/tonsillectomy compared to patients without all these three phenotypes (odds ratio = 3.17, 95% CI 1.33–7.56, P _corr = 0.04). In conclusion, MTHFR C677T polymorphism is marginally associated with psoriasis. The T allele (thermolabile) appears to be more frequent in psoriasis patients with positive history of psoriasis and diabetes mellitus together with personal history of repeated tonsillitis/tonsillectomy. This could reflect an inborn predisposition in complex regulation in one-carbon moieties transport in psoriatic patients and therefore, MTHFR genotype can be a part of genetic background of psoriasis.     

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site,G1793A

The importance of hyperhomocysteinemia, birth defects, and vascular diseases has been the subject of intense investigations. The polymorphic MTHFR mutations (C677T and A1298C) cause mild hyperhomocysteinemia, especially in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The subject of this report is the frequency of the polymorphic mutations in the MTHFR gene C677T, C1298A, and newly discovered mutation G1793A, as well as the association with MTRR polymorphic site A66G in different ethnic groups. Four ethnic groups were studied: African‐Americans, Caucasians, Hispanics, and Ashkenazi Jews. There are statistically significant differences in the frequency of these alleles in the different populations studied, which impacts compound heterozygosity for such alleles in these populations. DNA samples obtained from the blood of healthy individuals of African‐Americans, Hispanics, and Caucasians from south Texas were analyzed and compared to those obtained from Ashkenazi Jewish individuals. The polymorphic site, the G1793A allele, is least frequent among Ashkenazi individuals, 1.3%, compared to 6.9% among Caucasians (P = 0.001), 5.8% among Hispanics (P = 0.012), and 3.1% among African‐Americans. The MTRR polymorphic site shows the lowest allele frequency among Hispanics, 28.6%, compared to 34% among African‐Americans, 43.1% among Ashkenazi Jews (P = 0.002), and 54.4% among Caucasians (P < 0.0001). Statistically significant differences in allele frequencies of C677T and C1298A polymorphisms were also observed in these populations. Compound heterozygosity for multiple polymorphic alleles may play a role in birth defects and vascular diseases. © 2001 Wiley‐Liss, Inc.     

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and age of onset in schizophrenia: A combined analysis of independent samples

Methylenetetrahydrofolate reductase (MTHFR) is involved in the one‐carbon cycle, which is of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes two common polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) which both alter enzyme activity. The T‐allele of the C677T polymorphism has recently been associated with earlier age at onset of schizophrenia. In the present study we examined the association between the MTHFR C677T and A1298C polymorphisms and age at onset of schizophrenia in twelve samples consisting of 3,213 unrelated schizophrenia patients, including the original Scandinavian sample. There was no consistent relationship between MTHFR C677T, A1298C or combined 677T/1298C carriers and age of onset in schizophrenia when the results of each study were combined using meta‐analysis. The present results suggest that the investigated MTHFR polymorphisms do not influence age of onset in schizophrenia. © 2011 Wiley‐Liss, Inc.     

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A.

The importance of hyperhomocysteinemia, birth defects, and vascular diseases has been the subject of intense investigations. The polymorphic MTHFR mutations (C677T and A1298C) cause mild hyperhomocysteinemia, especially in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The subject of this report is the frequency of the polymorphic mutations in the MTHFR gene C677T, C1298A, and newly discovered mutation G1793A, as well as the association with MTRR polymorphic site A66G in different ethnic groups. Four ethnic groups were studied: African-Americans, Caucasians, Hispanics, and Ashkenazi Jews. There are statistically significant differences in the frequency of these alleles in the different populations studied, which impacts compound heterozygosity for such alleles in these populations. DNA samples obtained from the blood of healthy individuals of African-Americans, Hispanics, and Caucasians from south Texas were analyzed and compared to those obtained from Ashkenazi Jewish individuals. The polymorphic site, the G1793A allele, is least frequent among Ashkenazi individuals, 1.3%, compared to 6.9% among Caucasians (P = 0.001), 5.8% among Hispanics (P = 0.012), and 3.1% among African-Americans. The MTRR polymorphic site shows the lowest allele frequency among Hispanics, 28.6%, compared to 34% among African-Americans, 43.1% among Ashkenazi Jews (P = 0.002), and 54.4% among Caucasians (P < 0.0001). Statistically significant differences in allele frequencies of C677T and C1298A polymorphisms were also observed in these populations. Compound heterozygosity for multiple polymorphic alleles may play a role in birth defects and vascular diseases.     

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy in IDDM patients

A missense mutation in the methylenetetrahydrofolate reductase gene (MTHFR), C677T, results in a thermolabile variant with reduced activity. Elevated levels of homocysteine have been recognized as a risk factor for vascular disease. Insulin-dependent diabetes mellitus (IDDM) is characterized by a higher prevalence of vascular complications. We analyzed the frequency of C677T MTHFR in IDDM and control groups. The genotype distribution did not differ between control subjects (n = 297) and IDDM patients (n = 392) (chi(2) = 5.413, df = 2, P > 0.05). The MTHFR T677T genotype was found significantly more frequently in IDDM patients with diabetic nephropathy (0.216) compared with the IDDM patients without nephropathy (0.056); the odds ratio was 2.635 (95% CI 1.768-3.927). Thus, we suggest that the T677T genotype of the MTHFR gene is an independent risk factor for diabetic nephropathy in IDDM.     

Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical, biochemical, and molecular study of the family

A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was made in four sibs at different ages. The first three, including a pair of twins, had retarded psychomotor development, poor social contact, and seizures. Biologically, hyperhomocysteinemia and hypomethioninemia were found associated with low folate levels in serum and red cells, especially undetectable methyltetrahydrofolate in red cells. In the fourth child, prenatal diagnosis was not conclusive because of moderate decrease of enzymatic activity in chorionic villi and trophoblast. The girl was also affected, as shown by hyperhomocysteinemia and low folate levels found several days after birth. A 677C-->T (Ala-->Val) mutation was found in a homozygous state in the four children and in the father. Additionally, a second homozygous mutation, 1081C-->T, changing an arginine to cysteine also was identified in all of the children, whereas the distantly consanguineous parents were heterozygous. This amino acid substitution affecting an arginine residue in a sequence located at the end of catalytic domain seems critical for the function of the enzyme. The difficulty of prenatal diagnosis is discussed given the variability found in enzymatic activity and in the clinical phenotypes.     

Methylenetetrahydrofolate reductase gene polymorphisms and lung cancer: a meta-analysis

So far, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and lung cancer provide controversial or inconclusive results. To clarify the effect of MTHFR polymorphisms on the risk of lung cancer, a meta-analysis of all case-control observational studies was performed. The studies provided 5,111/6,415 cases/controls for C677T and 5,087/6,232 cases/controls for A1298C. The heterogeneity (P = 0.0001, I ² = 76.6%) for C677T among the eight studies was extreme. Cluster analyses based on the frequencies of the C677T genotype of the control group in each study revealed that the studies could not cluster together according to their ethnicity. The random effects (RE) model showed that the 677T allele was not associated with the risk of lung cancer compared with the C allele [OR = 1.12, 95% confidence interval (CI) (0.97–1.28), P = 0.12]. The contrast of homozygotes, recessive model, dominant model produced the same pattern of results as the allele contrast. In regard to the A1298C polymorphism, there was no heterogeneity among the seven studies comparing the C versus the A allele (P = 0.24, I ² = 24.4%), but no significant association was detected by the RE model or the fixed effects model [FE odds ratio (OR) = 0.99 (0.93–1.05) and RE OR = 1.00 (0.92–1.08)]. The effect of MTHFR polymorphisms (C677T, A1298C) on the risk of lung cancer was undetectable, even though analyzed on a relatively good number of subjects (totally 11,526 subjects) by meta-analysis (statistical power = 93.9%). Although MTHFR polymorphisms were associated with the risk of colorectal cancer, leukemia, and gastric cancer supported by other meta-analysis, our pooled data suggest no evidence for a major role of these two variants in carcinogenesis of lung cancer. The results implied that different tumors evolve by different pathological pathways and the roles of MTHFR in cancer is determined by its target genes.     

Immune deficiency presenting as mycobacterial infection

All the discrete genetic defects identified to date that seem to specifically predispose to infection with NTM or BCG have occurred in the pathways involving the generation of or response to IFN-gamma (Fig. 3). This natural genetic survey therefore suggests that one of the most critical cytokines in the control of NTM and BCG is IFN-gamma. Unfortunately, this recognition does not give us a clear sense of the critical mechanism(s) involved and still leaves us at a phenomenological level of understanding. Therefore, even though IFN-gamma appears to be the most critical cytokine in the control of mycobacteria by the "experiments of nature" cited earlier, it is likely that other cytokines are involved in the more proximal events of killing of intracellular parasites and viral control. These cytokines or chemokines may perform better therapeutically than [figure: see text] does IFN-gamma if they are better able to evoke the critical antimycobacterial mechanism(s). Dissection of these pathways, identification of the most proximal factors, and exploitation of these findings for the treatment of mycobacterial and other intracellular infections is the critical charge for the future.     

Methylenetetrahydrofolate reductase enzyme polymorphisms as maternal risk for Down syndrome among Turkish women

Advanced maternal age is the only fully accepted risk factor for trisomy 21, while most children with Down syndrome (DS) are born to younger mothers (<35 years). The relationship between chromosomal nondisjunction leading to aneuploidy and folate metabolism has drawn attention in the recent years. In this study, we examined the two polymorphisms in genes encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR), namely, 677C > T and 1298A > C. The prevalence of these variant genotypes in mothers of DS children (case mothers) (n = 152) was compared with controls (n = 91). Frequencies of MTHFR 677C > T genotypes (CC, CT, and TT) and also combination of heterozygous and homozygous variant genotypes (CT or TT) (P = 0.28) demonstrated no difference between the case and control groups. Genotype frequencies of MTHFR 1298A > C (AA, AC, and CC) were similar among the case and control mothers. Variant genotypes of MTHFR 1298A > C (AC or CC) were also insignificant when compared between the two groups. This is yet the largest case-control study conducted for MTHFR 677C > T and also the first to investigate a possible relation with MTHFR 1298A > C. The data presented in this study fail to support the relationship between MTHFR 677C > T and 1298A > C polymorphisms and risk of having a child with DS.     

Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis

To clarify the influence of MTHFR C677T and A1298C polymorphisms on gastric cancer (GC), a meta-analysis of eight case-control studies (1,584/2,785 cases/controls) was carried out. Overall, there was moderate heterogeneity among studies, and the C677T allele T was associated with a 27% increased risk of GC compared with C allele: the random effects (RE) OR (95% confidence interval in parenthesis) was significant [OR=1.27 (1.13–1.44)]. In East Asians, the association was significant: RE OR=1.28 (1.14–1.44), whereas, in Caucasians it was not significant. Regarding gastric cancer adenocarcinoma (GCA), an association for the allele contrast in East Asians was detected: fixed effects (FE) OR=1.36 (1.18–1.56). The recessive model for allele T produced significant results overall and in East Asians for GC [FE OR=1.47 (1.26–1.72) and FE OR=1.61 (1.32–1.96), respectively] and for GCA [RE OR=1.53 (1.13–2.05) and FE OR=1.70 (1.36–2.12)]. The A1298C polymorphism was associated with GCA in East Asians: the FE OR for the allele contrast (C vs. A) was 1.38 (1.18–1.62), and under a recessive model for allele C, OR=1.62 (1.28–2.06). There were no sources of bias in the selected studies; the differential magnitude of effect in large versus small studies was not significant. In conclusion, there is evidence of association between MTHFR polymorphisms and GC, mainly in East Asians.