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Biomedical subjects

R Rozen

Publications and source records attributed to R Rozen.

At least 37 records · Page 2Linked to original sources
PubMed2000

Methylenetetrahydrofolate reductase 677 C --> T polymorphism, plasma folate, vitamin B(12) concentrations, and risk of preeclampsia among black African women from Zimbabwe.

We conducted a case control study at Harare Maternity Hospital, Zimbabwe. We genotyped a total of 171 cases with preeclampsia or eclampsia and 185 normotensive control subjects for the methylenetetrahydrofolate reductase (MTHFR) 677 C --> T genotype. The wild-type allele frequency among cases and controls was 91.2 and 91.3%, respectively. Only one subject (0.3%) was homozygous for the 677 C --> T MTHFR genotype and this subject had preeclampsia. After adjustment for confounding factors, there was statistically no significant association between maternal MTHFR genotype and risk of preeclampsia (adjusted odds ratio = 1.0; 95% CI, 0.5-1.9). In addition, plasma homocyst(e)ine, vitamin B(12), and folate concentrations were not statistically different between normotensive control subjects with wild-type genotype as compared with normotensive subjects who were heterozygous for the mutant allele. Conversely, there was a strong graded association between maternal plasma folate concentration and risk of preeclampsia. Women with plasma folate concentrations less than 5.7 nmol/L experienced a 10. 4-fold increase in risk of preeclampsia. There was no clear pattern of preeclampsia risk and vitamin B(12) concentrations.

Adolescent↗
PubMed2000

Association between the methylenetetrahydrofolate reductase 677C-->T missense mutation and schizophrenia.

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better long-term outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome.

Adult↗
PubMed2000

Genetic modulation of homocysteinemia.

With the identification of hyperhomocysteinemia as a risk factor for cardiovascular disease, an understanding of the genetic determinants of plasma homocysteine is important for prevention and treatment. It has been known for some time that homocystinuria, a rare inborn error of metabolism, can be due to genetic mutations that severely disrupt homocysteine metabolism. A more recent development is the finding that milder, but more common, genetic mutations in the same enzymes might also contribute to an elevation in plasma homocysteine. The best example of this concept is a missense mutation (alanine to valine) at base pair (bp) 677 of methylenetetrahydrofolate reductase (MTHFR), the enzyme that provides the folate derivative for conversion of homocysteine to methionine. This mutation results in mild hyperhomocysteinemia, primarily when folate levels are low, providing a rationale (folate supplementation) for overcoming the genetic deficiency. Additional genetic variants in MTHFR and in other enzymes of homocysteine metabolism are being identified as the cDNAs/genes become isolated. These variants include a glutamate to alanine mutation (bp 1298) in MTHFR, an aspartate to glycine mutation (bp 2756) in methionine synthase, and an isoleucine to methionine mutation (bp 66) in methionine synthase reductase. These variants have been identified relatively recently; therefore additional investigations are required to determine their clinical significance with respect to mild hyperhomocysteinemia and vascular disease.

Amino Acid Substitution↗
PubMed2000

Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children.

BACKGROUND: Several studies have examined the association of the methylenetetrahydrofolate reductase (MTHFR) genotype with plasma homocysteine in adults, but few studies have been performed in children. OBJECTIVE: We measured the concentrations of plasma total homocysteine, folate, and vitamin B-12 in a group of healthy fasting children and related these to MTHFR genotype. DESIGN: After the subjects fasted, blood samples were collected into EDTA-containing tubes. Plasma, red blood cells, and the buffy coat were immediately stored at -80 degrees C for biochemical and molecular analyses. Plasma total homocysteine was determined by HPLC. Folate and vitamin B-12 were measured by a double-labeled radioimmunoassay, and the genotypic analysis was performed by polymerase chain reaction amplification of genomic DNA extracted from blood leukocytes. RESULTS: Plasma homocysteine concentrations correlated negatively with folate and vitamin B-12(,) but positively with age (P: < 0. 0001). Whereas folate and vitamin B-12 accounted for 27% and 19% of the variation in homocysteine, respectively, age accounted for 48% of the variation. When the cohort was divided into older (>10 y) and younger (</=10 y) individuals, folate was significantly lower in the older individuals who were homozygous for the mutation (T/T) than in those who were homozygous for the wild-type allele (C/C). Homocysteine was higher in the T/T group than in both the C/C and C/T subgroups aged >10 y. CONCLUSION: Our data show that in a healthy pediatric population, MTHFR genotype played a significant role in determining homocysteine concentrations in older (>10 y), nutritionally stressed children.

Adolescent↗
PubMed2000

A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease.

BACKGROUND: Methionine synthase reductase (MTRR) catalyzes the regeneration of methylcobalamin, a cofactor of methionine synthase, an enzyme essential for maintaining adequate intracellular pools of methionine and tetrahydrofolate, as well as for maintaining homocysteine concentrations at nontoxic levels. We recently identified a common A-->G polymorphism at position 66 of the cDNA sequence of MTRR; this variant was associated with a greater than normal risk for spina bifida in the presence of low levels of cobalamin. OBJECTIVE: To investigate whether the polymorphism was associated with alterations in levels of homocysteine, folate, and vitamin B12, and with risk of developing premature coronary artery disease (CAD), in a population of individuals presenting for cardiac catheterization procedures. METHODS: We screened 180 individuals aged < 58 years with angiographically documented coronary-artery occlusions or occlusion-free major arteries for the presence of the 66A-->G MTRR polymorphism using a polymerase-chain-reaction-based assay. RESULTS: We identified a trend in risk of premature CAD across the genotype groups (P = 0.03) with a sex-adjusted relative risk of premature CAD equal to 1.49 (95% confidence interval 1.10-2.03) for the GG versus AA genotype groups. There was no difference in fasting levels of plasma total homocysteine, serum folate, and vitamin B12 among the three MTRR genotypes. CONCLUSIONS: Our findings suggest that the GG genotype of MTRR is a significant risk factor for the development of premature CAD, by a mechanism independent of the detrimental vascular effects of hyperhomocysteinemia. This association needs to be confirmed in other studies.

Age Factors↗
PubMed1999

Molecular cloning, expression and physical mapping of the human methionine synthase reductase gene.

Methionine synthase reductase (EC 2.1.1.135) is a flavoprotein essential for maintenance of methionine synthase in an active state. We characterized the human gene for methionine synthase reductase (MTRR). The gene is approximately 34kb and comprises 15 exons, varying in size from 43 to 1213bp, and 14 introns whose sizes vary from 108bp to 5kb. The positions of several junctions are conserved between the MTRR gene and the C. elegans ortholog, as well as with the rat cytochrome P450 reductase gene. A 1.3kb CpG island encompasses the 5'-flanking region and exon 1 and extends into intron 1. A short region including the transcription start site is sufficient to confer promoter activity, with a better outcome when accompanied by intron 1. The promoter region contains putative binding sites for Sp1, AP-1, AP-2 as well as CAAT motifs, but no consensus TATA box. Primer extension analysis revealed a single major transcription start site, located 137bp upstream of the previously reported initiator ATG. An alternative splicing event involving a portion of exon 1 predicts that translation can potentially be initiated at two different ATG codons. The gene was physically assigned to a narrow area between markers WI1755 and D5S1957.

Animals↗
PubMed1999

Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects.

Folic acid administration to women in the periconceptional period reduces the occurrence of neural tube defects (NTDs) in their offspring. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is the first genetic risk factor for NTDs in man identified at the molecular level. The gene encoding another folate-dependent enzyme, methionine synthase (MTR), has recently been cloned and a common variant, 2756A-->G, has been identified. We assessed genotypes and folate status in 56 patients with spina bifida, 62 mothers of patients, 97 children without NTDs (controls), and 90 mothers of controls, to determine the impact of these factors on NTD risk. Twenty percent of cases and 18% of case mothers were homozygous for the MTHFR polymorphism, compared to 11% of controls and 11% of control mothers, indicating that the mutant genotype conferred an increased risk for NTDs. The risk was further increased if both mother and child had this genotype. The MTR polymorphism was associated with a decreased O.R. (O.R.); none of the cases and only 10% of controls were homozygous for this variant. Red blood cell (RBC) folate was lower in cases and in case mothers, compared to their respective controls. Having a RBC folate in the lowest quartile of the control distribution was associated with an O.R. of 2.56 (95% CI 1.28-5.13) for being a case and of 3.05 (95% CI 1.54-6.03) for being a case mother. The combination of homozygous mutant MTHFR genotype and RBC folate in the lowest quartile conferred an O.R. for being a NTD case of 13.43 (CI 2.49-72.33) and an O.R. for having a child with NTD of 3.28 (CI 0.84-12.85). We propose that the genetic-nutrient interaction--MTHFR polymorphism and low folate status--is associated with a greater risk for NTDs than either variable alone.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1999

A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.

Impairment of folate and cobalamin (vitamin B(12)) metabolism has been observed in families with neural tube defects (NTDs). Genetic variants of enzymes in the homocysteine remethylation pathway might act as predisposing factors contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C-->T mutation in methylenetetrahydrofolate reductase (MTHFR). We now report a polymorphism in methionine synthase reductase (MTRR), the enzyme that activates cobalamin-dependent methionine synthase. This polymorphorism, 66A-->G (I22M), has an allele frequency of 0.51 and increases NTD risk when cobalamin status is low or when the MTHFR mutant genotype is present. Genotypes and cobalamin status were assessed in 56 patients with spina bifida, 58 mothers of patients, 97 control children, and 89 mothers of controls. Cases and case mothers were almost twice as likely to possess the homozygous mutant genotype when compared to controls, but this difference was not statistically significant. However, when combined with low levels of cobalamin, the risk for mothers increased nearly five times (odds ratio (OR) = 4.8, 95% CI 1.5-15.8); the OR for children with this combination was 2.5 (95% CI 0.63-9.7). In the presence of combined MTHFR and MTRR homozygous mutant genotypes, children and mothers had a fourfold and threefold increase in risk, respectively (OR = 4.1, 95% CI 1.0-16.4; and OR = 2.9, 95% CI 0.58-14.8). This study provides the first genetic link between vitamin B(12) deficiency and NTDs and supports the multifactorial origins of these common birth defects. Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1999

Cerebral vascular complication and hyperhomocysteinemia in a cystinotic uremic child.

We report a 13-year-old girl with nephropathic cystinosis on chronic peritoneal dialysis who presented with two episodes of stroke. Laboratory evaluation showed severe hyperhomocysteinemia (108 mumol/l). Further testing revealed that she was homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) gene. Treatment with folic acid and vitamin B12 lowered plasma homocysteine to less than 20 mumol/l. No further episodes of stroke occurred over a follow-up of 12 months. Homocysteine levels should be measured in patients with chronic renal failure, since simple and safe treatment with folic acid and vitamin B12 is effective in lowering the plasma homocysteine level in patients with the thermolabile MTHFR allele.

Adolescent↗
PubMed1999

The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia.

Elevated plasma homocysteine levels are associated with increased risk for cardiovascular disease and neural tube defects in humans. Folate treatment decreases homocysteine levels and dramatically reduces the incidence of neural tube defects. The flavoprotein methylenetetrahydrofolate reductase (MTHFR) is a likely target for these actions of folate. The most common genetic cause of mildly elevated plasma homocysteine in humans is the MTHFR polymorphism A222V (base change C677-->T). The X-ray analysis of E. coli MTHFR, reported here, provides a model for the catalytic domain that is shared by all MTHFRs. This domain is a beta8alpha8 barrel that binds FAD in a novel fashion. Ala 177, corresponding to Ala 222 in human MTHFR, is near the bottom of the barrel and distant from the FAD. The mutation A177V does not affect Km or k(cat) but instead increases the propensity for bacterial MTHFR to lose its essential flavin cofactor. Folate derivatives protect wild-type and mutant E. coli enzymes against flavin loss, and protect human MTHFR and the A222V mutant against thermal inactivation, suggesting a mechanism by which folate treatment reduces homocysteine levels.

Amino Acid Sequence↗
PubMed1999

A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk.

We previously reported (J. Chen et al., Cancer Res., 56: 4862-4864, 1996; J. Ma et al., Cancer Res., 57: 1098-1102, 1997) that a 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism (677C-->T, ala-->val) was associated with lower risk of colorectal cancer. In this study, we examined the relationship of a polymorphism (2756A-->G, asp-->gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls. The frequency of the homozygous variant genotype (gly/gly) was slightly lower among cases (3%) than controls (5%). The odds ratio for the gly/gly genotype was 0.59 [95% confidence interval (CI), 0.27-1.27] compared with those with the homozygous wild type (asp/asp). There were no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR polymorphism. However, similar to the interaction observed for the MTHFR polymorphism among men who consumed less than 1 alcoholic drink/day, those with the gly/gly genotype had a lower risk of colorectal cancer with an odds ratio of 0.27 (95% CI, 0.09-0.81) compared with those with the asp/asp genotype. The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our study had limited statistical power because of the low frequency of the MTR variant genotype, which is reflected in the wide CIs. Hence, these findings need to be confirmed in larger populations.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1998

Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip.

Studies have reported an association between homozygosity for a variant form of the methylenetetrahydrofolate reductase (MTHFR) gene and risk for neural tube defects. Because of MTHFR's involvement with folate metabolism and evidence that maternal use of a multivitamin with folic acid in early pregnancy reduces risk for cleft lip with or without cleft palate (CLP), we hypothesized that infants homozygous for the C677T genotype would be at increased risk for CLP because of lower MTHFR enzymatic activity. Data were derived from a large population-based, case-control study of fetuses and liveborn infants among a cohort of 1987 to 1989 California births. The analyses involved 310 infants with isolated CLP whose mothers completed a telephone interview and whose DNA was available from newborn screening blood specimens and involved 383 control infants without a congenital anomaly whose mothers completed a telephone interview and whose DNA was available. Cases and controls were genotyped TT if homozygous for the C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild-type) allele. Odds ratios for CLP were 0.89 (0.55 to 1.4) and 0.78 (0.56 to 1.1) for infants with TT versus CC and infants with CT versus CC genotypes, respectively. Compared with the CC genotype, the odds ratios for CLP among infants with the TT genotype were 0.74 (0.39 to 1.4) for those infants whose mothers were users and 1.4 (0.54 to 3.6) for those infants whose mothers were not users of multivitamins containing folic acid periconceptionally. The two estimates were not statistically heterogeneous (P = 0.30). Our results did not indicate increased risks for CLP among infants homozygous for the C677T genotype, nor do they indicate an interaction between infant C677T genotype and maternal multivitamin use on the occurrence of CLP.

Case-Control Studies↗
PubMed1998

Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida.

Maternal periconceptional use of vitamin supplements containing folic acid substantially reduces the risk of neural tube defects (NTDs) in the offspring. The mechanism underlying this reduction in risk is unknown. Several recent studies have reported an association between homozygosity for a variant form (the C677T genotype) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and risk for NTDs in individuals. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme. Using data from two California case-control interview studies (1987-1991 birth cohorts), the authors investigated whether an interaction for spina bifida risk existed between infant MTHFR C677T genotype and maternal use of supplements containing folic acid. The authors genotyped the allelic variants of MTHFR in 214 liveborn case infants with spina bifida and 503 control infants for whom information on maternal periconceptional vitamin use was available. The percentage of all case infants with the C677T MTHFR mutation, for both homozygous (TT) and heterozygous (TC) genotypes, was slightly higher than that of controls. The C677T genotype was substantially more frequent among both case and control Hispanic infants than among non-Hispanic infants. Among all infants whose mothers did not periconceptionally use vitamins containing folic acid, the risk of spina bifida, as measured by the odds ratio, was 1.6 (95% confidence interval (CI) 0.8-3.1) for all infants with the TT genotype and 2.0 (95% CI 0.5-7.4) for non-Hispanic white infants with the TT genotype, as compared with infants with the CC genotype. This result indicates a modestly increased risk associated with the C677T genotype. A lower risk estimate (odds ratio=1.2, 95% CI 0.4-4.0) was observed among infants whose mothers periconceptionally used vitamin supplements containing folic acid. This population-based California study found a modestly increased risk of spina bifida among infants who were homozygous for the C677T genotype, but only minimal evidence of an interaction between the C677T genotype and maternal folic acid intake in the occurrence of spina bifida. If this mutant MTHFR genotype plays a role in the association between maternal vitamin use and NTD risk, it may be a small role, or it may be conditional on maternal genotype.

Case-Control Studies↗
PubMed1998

A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic-nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common variant in MTHFR (A1298C), an E to A substitution. Homozygosity was observed in approximately 10% of Canadian individuals. This polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. Heterozygotes for both the C677T and the A1298C mutation, approximately 15% of individuals, had 50-60% of control activity, a value that was lower than that seen in single heterozygotes for the C677T variant. No individuals were homozygous for both mutations. Additional studies of the A1298C mutation, in the absence and presence of the C677T mutation, are warranted, to adequately address the role of this new genetic variant in complex traits. A silent genetic variant, T1317C, was identified in the same exon. It was relatively infrequent (allele frequency 5%) in our study group, but was quite common in a small sample of African individuals (allele frequency 39%).

Adult↗