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.     

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.     

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 and spina bifida: evaluation of level of defect and maternal genotypic risk in Hispanics

The C677T and A1298C mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are each associated with reduced MTHFR activity. The C677T mutation in the heterozygous and homozygous state correlates with increased enzyme thermolability, with homozygous mutant genotypes showing significantly elevated plasma homocysteine levels and decreased plasma folate levels. The A1298C mutation results in decreased MTHFR activity, but changes in neither homocysteine nor folate levels are associated with A1298C variant genotypes. Our study determined the frequencies of the C677T and A1298C MTHFR mutations for spina bifida (SB) cases, mothers and fathers of SB cases, and controls in Hispanics of Mexican-American descent. In addition, our subject population was further categorized as to whether the spina bifida lesion occurred as an upper or lower level defect, according to the Van Allen "multi-site closure" model. Hispanic SB cases with upper level defects and their mothers were homozygous for the C677T variant allele at a higher rate than their respective controls (OR = 1.5 [95% CI 0.8-2.9], P = 0.30; OR = 2.3 [1.1-4.8], P = 0.04, respectively), with statistically significant results seen only for the maternal homozygous genotype. Homozygosity for the A1298C mutation was seen at a higher rate only in Hispanic mothers of both upper and lower level SB cases when compared to controls, but these results were not statistically significant. Our study provides evidence that the maternal C677T MTHFR homozygous mutant genotype is a risk factor for upper level spina bifida defects in Hispanics.     

Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with myocardial infarction in Tunisian young patients

Myocardial infarction (MI) is an important clinical problem because of its large contribution to mortality. The objective of this study is to assess whether two methylenetetrahydrofolate reductase (MTHFR) polymorphisms, C677T and A1298C, were associated with MI among Tunisian patients. One hundred young patients (<47 years old) with MI were recruited and compared with 200 control subjects with no history of MI. The most common MI risk factors were investigated. Fasting plasma homocysteine levels were measured. Genotypes of the MTHFR C677T and A1298 polymorphisms were studied by polymerase chain reaction. The mean plasma homocysteine level in the study group was raised when compared with the control group. Homozygous MTHFR C677T mutation was observed in 2 (2 %) patients and in 17 (8.5 %) control subjects, whereas heterozygous MTHFR C677T mutation was detected in 82 (82 %) patients versus only 79 (39.5 %) in control subjects. The mean total homocysteine concentrations were significantly higher in individuals with the 677TT and CT genotypes. Our results indicate that C677T and A1298C MTHFR mutations and hyperhomocysteinemia contributed to the risk factors for MI.     

Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians

We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11/72) of the individuals tested, and 47.2% (34/72) were heterozygous for this SNP. Homozygosity for the C677T MTHFR SNP was detected in 1.38%(1/72), and the frequency of the C677T heterozygotes was 18.1%(13/72). When we analyzed the combined frequency of the two SNPs, the frequency of double heterozygosity was19.6%, and the frequency of double homozygosity was completely absent among the study group. The 'C' allele frequency for MTHFR A1298C was 0.389, and the 'T' allele frequency for C677T mutation was 0.104. Out of the 72 individuals included in the study, 52 were acute myocardial infarction (AMI) patients and 20 were healthy individuals with no documented history of heart disease. The results of this study indicate that the MTHFR A1298C SNP is more prevalent among the Tamilians when compared to the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases.     

Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population

The gene MCOLN1 is mutated in Mucolipidosis type IV (MLIV), a neurodegenerative, recessive, lysosomal storage disorder. The disease is found in relatively high frequency among Ashkenazi Jews due to two founder mutations that comprise 95% of the MLIV alleles in this population [Bargal et al., 2000]. In this report we complete the mutation analysis of Jewish and non-Jewish MLIV patients whose DNA were available to us. Four novel mutations were identified in the MCOLN1 gene of severely affected patients: two missense, T232P and F465L; a nonsense, R322X; and an 11-bp insertion in exon 12. The nonsense mutation (R322X) was identified in two unrelated patients with different haplotypes in the MCOLN1 chromosomal region, indicating a mutation hotspot in this CpG site. An in-frame deletion (F408del) was identified in a patient with unusual mild psychomotor retardation. The frequency of MLIV in the general Jewish Ashkenazi population was estimated in a sample of 2,000 anonymous, unrelated individuals assayed for the two founder mutations. This analysis indicated a heterozygotes frequency of about 1/100. A preferred nucleotide numbering system for MCOLN1 mutations is presented and the issue of a screening program for the detection of high-risk families in the Jewish Ashkenazi population is discussed.     

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos

The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.     

The Ashkenazi Jewish Fanconi anemia mutation: Incidence among patients and carrier frequency in the at-risk population

Fanconi anemia (FA) is an autosomal recessive disease for which at least four complementation groups exist. Recently the gene that corrects the defect in Fanconi anemia complementation group C cells (FACC) has been cloned. We have previously identified a common mutation in the FACC gene, which accounts for a majority of FA cases in Ashkenazi Jewish individuals. We here describe the use of allele-specific oligonucleotide (ASO) hybridization to determine the frequency of this mutation among additional Jewish FA patients and to determine the carrier frequency in the Jewish population. The common IVS4 + 4A → T allele was found on 19/23 (83%) Jewish FA chromosomes, indicating that it is indeed responsible for most cases of FA among Ashkenazi Jews. The carrier frequency was 2/314 for Jewish individuals and the mutant allele was not detected in 130 non-Jewish controls. © 1994 Wiley-Liss, Inc.     

The C677T mutation of the 5,10-methylenetetrahydrofolate reductase gene is a moderate risk factor for spina bifida in Italy.

OBJECTIVE: To estimate the risk for spina bifida associated with the common mutation C677T of the MTHFR gene in a country with a relatively low prevalence of NTDs. DESIGN: Case-control study. SUBJECTS: Cases: 203 living patients affected with spina bifida (173 myelomeningocele and 30 lipomeningocele); controls: 583 subjects (306 young adults and 277 unselected newborns) from northern and central-southern Italy. SETTING: Cases: three spina bifida centres; young adult controls: DNA banks; newborn controls: regional neonatal screening centres. MAIN OUTCOME MEASURES: Prevalence of the C677T genotypes in cases and controls by place of birth; odds ratios for spina bifida and estimated attributable fraction. RESULTS: The prevalence of T/T, T/C, and C/C genotype was 16.6%, 53.7%, and 29.7% in controls and 25.6%, 43.8%, and 30.6% in cases, respectively. We found no differences between type of defect or place of birth. The odds ratio for spina bifida associated with the T/T genotype v C/C plus T/C was 1.73 (95% CI 1.15, 2.59) and the corresponding attributable fraction was 10.8%. No increased risk was found for heterozygous patients (OR=0.79, 95% CI 0.53-1.18). CONCLUSION: This study, as well as the meta-analysis we updated, shows that homozygosity for the MTHFR C677T mutation is a moderate risk factor in Europe, and even in Italy where there is a relatively low prevalence of spina bifida. The estimated attributable fraction associated with this risk factor explains only a small proportion of cases preventable by periconceptional folic acid supplementation. Thus, other genes involved in folate-homocysteine metabolism, their interaction, and the interaction between genetic and environmental factors should be investigated further.     

Genotype and haplotype distributions of MTHFR677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis

Common single nucleotide polymorphisms (SNPs; 677C>T and 1298A>C) in the methylenetetrahydrofolate reductase gene ( MTHFR) decrease the activity of the enzyme, leading to hyperhomocysteinemia, particularly in folate-deficient states. We calculate herein the haplotype frequencies of the MTHFR 677 and 1298 polymorphisms in pooled general populations derived from published data. We selected 16 articles that provided reliable data on combined MTHFR genotypes in general populations ( n = 5389). The combined data comprised the following totals for each genotype at nucleotide positions 677 and 1298: 838 CC/AA (i.e., 677CC/1298AA), 1225 CC/AC, 489 CC/CC, 1120 CT/AA, 1093 CT/AC, 8 CT/CC, 606 TT/AA, 10 TT/AC, and 0 TT/CC. The estimated haplotype frequencies, and the fractional contribution of each, were 677C/1298A, 0.37; 677C/1298C, 0.31; 677T/1298A, 0.32; and 677T/1298C, 0.0023 to 0.0034. Thus, a vast majority of 677T alleles and 1298C alleles are associated with 1298A alleles and 677C alleles, respectively. There may be an increased frequency of the very rare cis 677T/1298C haplotype in some parts of the United Kingdom and Canada, possibly due to a founder effect. Further studies on both SNPs are needed to determine their exact role in various clinical settings.     

Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss

BACKGROUND Polymorphisms C677T and A1298C of the MTHFR gene have been implicated in fetal viability. In this study, we determined the allele and genotype frequencies of these polymorphisms in different populations, including spontaneous abortion (SA) fetal tissues, with the objective of evaluating their impact on fetal viability. METHODS 342 samples of fetal tissues, selected from SA occurring during the 1980s, 230 samples from subjects born in the 1980s and a third set of samples from 204 subjects born in the 1950s, were genotyped by using TaqMan probes. RESULTS The wild CC genotype of the C677T polymorphism showed a strong protective effect against abortion (0.03 in SA versus 0.47 in 1950s and 0.43 in 1980s) (P < 0.0001). Genotypes of three mutations in the combinations of polymorphisms for C677T and A1298C showed a very low frequency in the living population; however, the three mutations genotypes were over expressed in the SA group (0.02 in 1950s; 0.03 in 1980s and 0.17 in SA) (P < 0.0001). Samples with four mutations (n = 2) were found only in the SA group. CONCLUSIONS There is no linkage disequilibrium between C667T and A1298C polymorphisms. Fetal viability is directly related to the CC genotype as a protector while the three and four mutation MTHFR genotypes appear to be a determinant on fetal non-viability and SA.     

Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population

Canavan disease is a severe progressive autosomal recessive disorder, which is characterised by spongy degeneration of the brain. The disease is caused by mutations in the aspartoacylase gene. Two different mutations were reported on 98% of the alleles of Ashkenazi Jewish patients, in which population the disease is highly prevalent. In non-Jewish patients of European origin, one mutation (914C > A) is found in 50% of the alleles, the other alleles representing all kinds of different mutations. We here describe the results of the mutation analysis in 17 European, non-Jewish patients. Ten different mutations were found, of which four had not been described before (H21P, A57T, R168H, P181T). A deletion of exon4, which until now had only been described once, was revealed in all five alleles of Turkish origin tested, indicating that this is a founder effect in the Turkish population.     

MTHFR C677T polymorphisms among the Ahirs and Jats of Haryana (India).

Methylenetetrahydrofolate reductase (MTHFR) is a vital enzyme catalyzing the nicotinamide adenine dinucleotide phosphate (NADPH) linked reduction of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which serves as cofactor in methylation of homocysteine to methionine. Three clinically important mutations of the MTHFR gene namely C677T, A1298C, and T1317C are reported to be associated with various pathological conditions. The present study deals with the screening of C677T mutation among two endogamous groups viz. Ahirs and Jats of Haryana (India). The mutation is reported to be significantly associated with thrombosis, hypertension, stroke and myocardial infraction, neural tube defects (NTDs), and recurrent pregnancy loss. The T allele among Jats is found to be more frequent (0.06) than Ahirs (0.03). Moreover, the Jats population shows a significant deviation from Hardy-Weinberg equilibrium with respect to C677T mutation. This could probably be due to some selection pressure operating in the population.     

A novel mutation in the HEXA gene specific to Tay-Sachs disease carriers of Jewish Iraqi origin

An increased frequency of carriers of 1:140, as defined by reduced hexosaminidase A (HexA) activity, was observed among Iraqi Jews participating in the Tay-Sachs disease (TSD) carrier detection program. Prior to this finding, TSD among Jews had been restricted to those of Eastern European (Ashkenazi) and Moroccan descent with carrier frequencies of 1:29 and 1:110 for Jews of Ashkenazi and Moroccan extraction, respectively. A general, pan-ethnic frequency of approximately 1:280 has been observed among other Jewish Israeli populations. Analysis of 48 DNA samples from Iraqi Jews suspected, by enzymatic assay, to be carriers revealed a total of five mutations, one of which was novel. In nine carriers (19%), a known mutation typical to either Ashkenazi or Moroccan Jews was identified. DeltaF304/ 305 was detected in four individuals, and + 1278TATC in three. G269S and R170Q each appeared in a single person. The new mutation, G749T, resulting in a substitution of glycine to valine at position 250 has been found in 19 of the DNA samples (40%). This mutation was not detected among 100 non-carrier, Iraqi Jews and 65 Ashkenazi enzymatically determined carriers. Aside from Ashkenazi and Moroccan Jews, a specific mutation in the HEXA gene has now also been identified in Jews of Iraqi descent.     

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations

The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ∼2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ∼5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750–1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ∼650 years ago, and into the Iraqi–Jewish community ∼450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.     

A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A-->C mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A-->C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD.     

Linkage disequilibrium of common Gaucher disease mutations with a polymorphic site in the pyruvate kinase (PKLR) gene

Gaucher disease (GD), caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GBA), is the most common human glycolipid storage disease. The incidence of the disease is particularly high in the Ashkenazi Jewish population, with a carrier frequency of 0.068. The 1226A→G and 84GG mutations are the two predominant disease-causing alleles. We investigated the association of various mutations in the GBA gene with different alleles of a highly polymorphic site in the adjacent pyruvate kinase (PKLR) gene. Ninety-seven unrelated type I GD patients of various genotypes were studied to determine their genotype for the PKLR gene trinucleotide repeat polymorphism. One hundred out of 104 (96%) alleles carrying the 1226G mutation also carried the A1 allele of the PKLR gene, which is present in only 6.7% of the control population. The calculated linkage disequilibrium between 1226G and the A1 allele of the PKLR gene is 0.957. Mutation 84GG was found to be uniquely associated with the PKLR A6 allele, with a linkage disequilibrium of 1.00. The association of several less frequent GD mutations with PKLR alleles was also studied. These results support the hypothesis that the 1226G and 84GG mutations in the Ashkenazi Jewish population each originated in a single founder. Further studies of the association of the 1226G and 84GG mutations with PKLR alleles in European non-Jewish GD patients could help in the study of the chronological order of these mutations and may shed light on the history of the Ashkenazi Jews in the past two millennia. Am. J. Med. Genet. 78:233–236, 1998. © 1998 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.     

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.