Biomedical subjects

John M Scott

Publications and source records attributed to John M Scott.

15 recordsLinked to original sources

PubMed2004

Facts and recommendations about total homocysteine determinations: an expert opinion.

BACKGROUND: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The purpose of this review is to provide an international expert opinion on the practical aspects of total homocysteine determinations in clinical practice and in the research setting and on the relevance of total homocysteine measurements as diagnostic or screening tests in several target populations. METHODS: Published data available on Medline were used as the basis for the recommendations. Drafts of the recommendations were critically discussed at meetings over a period of 3 years. OUTCOME: This review is divided into two sections: (a) determination of homocysteine (methods and their performance, sample collection and handling, biological determinants, reference intervals, within-person variability, and methionine loading test); and (b) risk assessment and disease diagnosis (homocystinuria, folate and cobalamin deficiencies, cardiovascular disease, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects, and screening of elderly and newborns). Each of these subsections concludes with a separate series of recommendations to assist the clinician and the research scientist in making informed decisions. The review concludes with a list of unresolved questions.

Blood Specimen Collection↗

PubMed2003

Protocol for the production of concentrated extracts of food folate for use in human bioavailability studies.

To provide a tool to study folate bioavailability under controlled conditions, a methodology was developed to produce extracts representative of natural food folates but removed from their matrix and sufficiently concentrated so as to elicit a response in biomarkers of folate status without distorting usual dietary intake patterns. Egg, spinach, and yeast were selected to represent the wide range in extent of folate conjugation found in foods (0, 60, and 100% polyglutamyl folate, respectively). The protocol, which was based on extracting food folates using only reagents safe for human consumption, was optimized in the laboratory (thermal extraction for 10 min in a 2% ascorbate solution at pH 5) and then adapted for industrial scale production in a food-processing facility. Results showed that the extracts were 2.3-12 times more concentrated in folate compared with their corresponding food sources. Neither the mono- to polyglutamate ratio nor the distribution of the main folate derivatives was altered during processing, making these extracts suitable for use in human bioavailability studies.

Biological Availability↗

PubMed2003

Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults.

A modestly elevated total plasma homocysteine concentration (tHcy) is generally accepted as an independent and graded risk factor for various pathologies, including vascular diseases, neural tube defects, Alzheimer disease, and pregnancy complications. We analyzed 5 common functional polymorphisms in enzymes involved in homocysteine metabolism (ie, methylenetetrahydrofolate reductase [MTHFR] 677C>T and 1298A>C, methionine synthase [MTR] 2756A>G, cystathionine beta-synthase [CBS] 844ins68, and methionine synthase reductase [MTRR] 66A>G) in 452 young adults, and quantified their independent and interactive effects on tHcy concentrations. Serum folate, red cell folate, vitamin B(12), and tHcy concentrations were significantly influenced by MTHFR 677C>T genotypes. A particularly strong interaction was observed between the MTHFR 677TT genotype and serum folate, which led to a high tHcy phenotype that was more pronounced in males. The genetic contribution to the variance in tHcy was estimated to be approximately 9%, compared with approximately 35% that could be attributed to low folate and vitamin B(12). Our study indicates that dietary factors are centrally important in the control of tHcy levels in young adults with additional, but somewhat weaker, genetic effects. These data underscore the potential benefits that may be gained by improving the dietary status of young adults, and provide support for the implementation of folate/B-vitamin food fortification programs.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed2003

Analysis of the MTHFR 1298A-->C and 677C-->T polymorphisms as risk factors for neural tube defects.

The thermolabile variant (677TT) of methylenetetrahydrofolate reductase (MTHFR) is a known risk factor for neural tube defects (NTDs). The relationship between a second MTHFR polymorphism (1298A-->C) and NTD risk has been inconsistent between studies. We genotyped 276 complete NTD triads (mother, father and child affected with an NTD) and 256 controls for MTHFR 1298A-->C. Our findings do not support a role for the 1298A-->C polymorphism in NTDs (OR 0.85 (95% CI 0.49-1.47), p= 0.55), nor do we observe a combined effect with the 677C-->T polymorphism.

Case-Control Studies↗

PubMed2003

Polymorphisms within the vitamin B12 dependent methylmalonyl-coA mutase are not risk factors for neural tube defects.

Methionine synthase and methylmalonyl-CoA mutase (mutase) are the only two known vitamin B(12) (B(12)) dependent enzymes in humans. A lower level of B(12) has been shown to be an independent maternal risk factor for neural tube defects (NTDs) prompting an investigation of common genetic variants within B(12) dependent enzymes. To investigate the role of methylmalonyl-CoA mutase variants we studied 279 complete NTD triads (NTD affected case and both parents) and 256 controls. Based on case-control and family based (transmission disequilibrium test) analyses we did not find an association between the mutase single nucleotide polymorphisms (SNPs) K212K (636A-->G), H532R (1595A-->G) and V671I (2011G-->A) and NTDs. However, there was a significant difference in the frequencies of these polymorphisms between a group of African Americans and American Caucasians (K212K, P=0.002; H532R, P</=0.001; V671I, P=0.006). In conclusion, common variants in the mutase gene do not appear to be risk factors for NTDs but their allele frequencies are significantly different between ethnic groups.

Case-Control Studies↗

PubMed2003

Analysis of the human folate receptor beta gene for an association with neural tube defects.

The folate receptor beta (FRbeta) gene encodes a receptor that binds and transports 5-methyltetrahydrofolate. FRbeta polymorphisms may potentially alter folate delivery and are likely candidates for an association with neural tube defect (NTD) risk. To look for association between FRbeta polymorphisms we studied NTD-affected children and their parents (254 triads) recruited throughout Ireland and a control population of 296 pregnant women who did not give birth to an NTD-affected child. Five potential single nucleotide polymorphisms (SNPs) were examined. These were located within the coding, intronic and 3(')-untranslated regions of the FRbeta gene. Four of these SNPs were not found to be variable within our Irish cohort. SNP rs651646 (A-->T), located upstream of exon 2 within an intronic region, is polymorphic and is thus a marker for an FRbeta NTD association study. The frequency of the SNP rs651646 "A" allele was not significantly different in cases (odds ratio [OR] 1.07, 95% CI. 0.84-1.36; P=0.60), their mothers (odds ratio [OR] 1.09, 95% CI. 0.86-1.38; P=0.51) or fathers (odds ratio [OR] 1.09, 95% CI. 0.86-1.38; P=0.50) when compared to controls. Comparisons of allele transmission from 255 informative heterozygous parents of NTD cases showed no preferential transmission of either the A or T alleles (A: 50.2%, n=128; T: 49.8%, n=127; P=1.00, McNemar chi(2) 0.0). We also measured allele frequencies in a sample of American-Caucasians and African-Americans. Highly significant allele frequency differences were observed between populations. In conclusion, SNP rs651646 within the FRbeta gene is polymorphic but is not associated with neural tube defects within the Irish population.

3' Untranslated Regions↗

PubMed2003

Elevated plasma homocysteine in early pregnancy: a risk factor for the development of nonsevere preeclampsia.

OBJECTIVE: We have recently demonstrated that an elevated plasma homocysteine in early pregnancy is associated with the development of severe preeclampsia. The aim of this study was to determine whether an elevated plasma homocysteine in early pregnancy is also associated with the development of nonsevere preeclampsia. STUDY DESIGN: Blood was obtained from patients attending for a first antenatal visit. Subjects were asymptomatic women who subsequently developed nonsevere preeclampsia. Controls were matched for parity, gestational age, and date of sample collection. Plasma homocysteine was measured using fluorescence polarization immunoassay. RESULTS: There were 71 cases of nonsevere preeclampsia sampled at a mean gestational age (+/-SD) of 15.9+/-3.6 weeks and 142 controls at 15.6+/-3.4 weeks. The preeclampsia cases had a mean (+/-SD) homocysteine level of 8.4+/-2.4 micromol/L, whereas controls had a mean homocysteine of 7.07+/-1.5 micromol/L (P</=.0001). CONCLUSION: Women who develop nonsevere preeclampsia have higher plasma homocysteine levels in early pregnancy compared with women who remain normotensive throughout pregnancy. An elevated plasma homocysteine value in early pregnancy may be associated with a 4-fold increased risk for development of nonsevere preeclampsia.

Adult↗

PubMed2003

Screening for vitamin B-12 and folate deficiency in older persons.

BACKGROUND: Vitamin B-12 deficiency is usually accompanied by elevated concentrations of serum total homocysteine (tHcy) and methylmalonic acid (MMA). Folate deficiency also results in elevated tHcy. Measurement of these metabolites can be used to screen for functional vitamin B-12 or folate deficiency. OBJECTIVE: We assessed the prevalence of vitamin B-12 and folate deficiency in a population-based study (n = 1562) of older persons living in Oxford City, United Kingdom. DESIGN: We postulated that, as vitamin B-12 or folate concentrations declined from adequate to impaired levels, tHcy (or MMA) concentrations would increase. Individuals were classified as being at high risk of vitamin B-12 deficiency if they had low vitamin B-12 (< 150 pmol/L) or borderline vitamin B-12 (150-200 pmol/L) accompanied by elevated MMA (> 0.35 micromol/L) or tHcy (> 15.0 micromol/L). Individuals were classified as being at high risk of folate deficiency if they had low folate (< 5 nmol/L) or borderline folate (5-7 nmol/L) accompanied by elevated tHcy (> 15 micromol/L). RESULTS: Cutoffs of 15.0 micro mol/L for tHcy and 0.35 micro mol/L for MMA identified persons with normal or elevated concentrations. Among persons aged 65-74 and >or= 75 y, respectively, approximately 10% and 20% were at high risk of vitamin B-12 deficiency. About 10% and 20%, respectively, were also at high risk of folate deficiency. About 10% of persons with vitamin B-12 deficiency also had folate deficiency. CONCLUSION: Use of tHcy or MMA among older persons with borderline vitamin concentrations may identify those at high risk of vitamin B-12 deficiency who should be considered for treatment.

Age Factors↗

PubMed2002

A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group.

Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C-->T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate-dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 "Q" allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16-1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.

Aminohydrolases↗

PubMed2002

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.

Alleles↗

PubMed2002

Maternal and fetal plasma homocysteine concentrations at birth: the influence of folate, vitamin B12, and the 5,10-methylenetetrahydrofolate reductase 677C-->T variant.

OBJECTIVE: The purpose of this study was to determine the nutritional and genetic factors that influence fetal plasma homocysteine concentrations. STUDY DESIGN: Maternal and umbilical cord venous blood was taken from 201 women who were delivered after uncomplicated pregnancies of 37 to 41 gestational weeks. Red blood cell folate, plasma folate, plasma vitamin B12, and plasma homocysteine concentrations were measured in all samples. Cord and maternal bloods were also genotyped for the 677C-->T variant. RESULTS: The fetal circulation had lower homocysteine concentrations (7.87 +/- 2.87 micromol/L; mean +/- SD) than the maternal circulation (8.34 +/- 2.94 micromol/L; P =.003), but there was a strong linear association between the levels in these 2 compartments (r = 0.72; P <.0001). Overall, the maternal homocysteine level had the strongest influence on the fetal homocysteine concentration (P <.0001), with the fetal and maternal vitamin B12 having important additional effects (P =.016 and P =.0045, respectively). Fetal plasma folate and 5,10-methylenetetrahydrofolate reductase 677C-->T genotype had no significant effects (P =.23 and P =.54, respectively), probably because of folic acid supplement use. CONCLUSION: The maternal homocysteine level is the primary predictor of blood homocysteine in the developing fetus. If lowering maternal blood homocysteine proves critical to preventing pregnancy complications, it will be important to maintain optimal vitamin B12 status in addition to optimal tissue folate status.

Female↗

PubMed2002

The effect of different cooking methods on folate retention in various foods that are amongst the major contributors to folate intake in the UK diet.

Folate intake is strongly influenced by various methods of cooking that can degrade the natural forms of the vitamin in foods. The aim of the present study was to determine the effect of different cooking methods on folate retention in various foods that contribute to folate intake in the UK diet. Typical purchasing and cooking practices of representative food folate sources were determined from a questionnaire survey of local shoppers (n 100). Total folate was determined by microbiological assay (Lactobacillus casei NCIMB 10463) following thermal extraction and tri-enzyme (alpha-amylase, protease and conjugase) treatment in raw foods and after typical methods of cooking. Boiling for typical time periods resulted in only 49 % retention of folate in spinach (191.8 and 94.4 microg/100 g for raw and boiled spinach respectively; P<0.005), and only 44 % in broccoli (177.1 and 77.0 microg/100 g for raw and boiled broccoli respectively, P<0.0001). Steaming of spinach or broccoli, in contrast, resulted in no significant decrease in folate content, even for the maximum steaming periods of 4.5 min (spinach) and 15.0 min (broccoli). Prolonged grilling of beef for the maximum period of 16.0 min did not result in a significant decrease in folate content (54.3 and 51.5 microg/100 g for raw and grilled beef respectively). Compared with raw values, boiling of whole potatoes (skin and flesh) for 60.0 min did not result in a significant change in folate content (125.1 and 102.8 microg/100 g for raw and boiled potato respectively), nor was there any effect on folate retention whether or not skin was retained during boiling. These current results show that the retention of folate in various foods is highly dependent both on the food in question and the method of cooking. Thus, public health efforts to increase folate intake in order to improve folate status should incorporate practical advice on cooking.

Brassica↗

PubMed2002

Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR; EC 1.7.99.5) supplies the folate needed for the metabolism of homocysteine. A reduction in MTHFR activity, as occurs in the homozygous state for the 677C-->T (so-called thermolabile) enzyme variant (TT genotype), is associated with an increase in plasma total homocysteine (tHcy). OBJECTIVE: In vitro studies suggest that the reduced activity of thermolabile MTHFR is due to the inappropriate loss of its riboflavin cofactor. We investigated the hypothesis that MTHFR activity in the TT genotype group is particularly sensitive to riboflavin status. DESIGN: We studied tHcy and relevant B-vitamin status by MTHFR genotype in a cross-sectional study of 286 healthy subjects aged 19-63 y (median: 27 y). The effect of riboflavin status was examined by dividing the sample into tertiles of erythrocyte glutathionine reductase activation coefficient, a functional index of riboflavin status. RESULTS: Lower red blood cell folate (P = 0.0001) and higher tHcy (P = 0.0082) concentrations were found in the TT group than in the heterozygous (CT) or wild-type (CC) groups. However, these expected relations in the total sample were driven by the TT group with the lowest riboflavin status, whose mean tHcy concentration (18.09 micromol/L) was almost twice that of the CC or CT group. By contrast, adequate riboflavin status rendered the TT group neutral with respect to tHcy metabolism. CONCLUSIONS: The high tHcy concentration typically associated with homozygosity for the 677C-->T variant of MTHFR occurs only with poor riboflavin status. This may have important implications for governments considering new fortification policies aimed at the prevention of diseases for which this genotype is associated with increased risk.

Adult↗

PubMed2002

The pregnancy-related decrease in fasting plasma homocysteine is not explained by folic acid supplementation, hemodilution, or a decrease in albumin in a longitudinal study.

BACKGROUND: Fasting plasma total homocysteine (tHcy) decreases during pregnancy. Previous reports suggested that this is due to folic acid supplementation, hemodilution, or a decrease in albumin. However, these hypotheses have not been tested in a longitudinal study. OBJECTIVE: We investigated the relation between pregnancy-related physiologic changes and tHcy in a group of healthy women who were either unsupplemented or supplemented with folic acid. DESIGN: In a longitudinal study from preconception throughout pregnancy, we studied 54 unsupplemented women and 39 women who were supplemented with folic acid during the second or third trimester of pregnancy. tHcy, hematocrit, and serum albumin were determined preconceptionally and at 8, 20, and 32 wk of pregnancy. RESULTS: For the entire group, geometric mean tHcy concentrations at preconception (8.2 micro mol/L) were significantly greater (P < 0.001) than those at 8 wk of pregnancy (6.4 micro mol/L). When the unsupplemented and supplemented groups were regarded separately, geometric mean tHcy concentrations at preconception were significantly greater than those at 20 (5.22 and 4.18 micro mol/L, respectively) and 32 (5.16 and 4.42 micro mol/L, respectively) wk of pregnancy (P < 0.001 for both). Mean reductions from preconception concentrations at 8, 20, and 32 wk of pregnancy were significantly greater (P < 0.001) for tHcy (-11.5%, -25.5%, and -24.5%, respectively) than for hematocrit (-1.9%, -4.2%, and -4.3%, respectively) or serum albumin (-1.1%, -9.8%, and -13.4%, respectively). There was no correlation between changes in either hematocrit or serum albumin and changes in tHcy. CONCLUSIONS: This study refutes the previous explanations for the reduction in plasma tHcy known to occur in pregnancy, namely, folic acid supplementation, hemodilution, and a decrease in serum albumin. We suggest that the changes may be endocrine-based.

Adolescent↗

PubMed2002

Riboflavin, flavin mononucleotide, and flavin adenine dinucleotide in human plasma and erythrocytes at baseline and after low-dose riboflavin supplementation.

BACKGROUND: Vitamin B(2) exists in blood as riboflavin and its cofactors, flavin mononucleotide (FMN) and FAD. The erythrocyte glutathione reductase activation coefficient (EGRAC) has traditionally been used to assess vitamin B(2) status in humans. We investigated the relationships of EGRAC and plasma and erythrocyte concentrations of riboflavin, FMN, and FAD in elderly volunteers and their responses to riboflavin administration. METHODS: EGRAC and plasma and erythrocyte concentrations of riboflavin, FMN, and FAD were determined in 124 healthy individuals with a mean age of 69 years. The same measurements were made in a subgroup of 46 individuals with EGRAC > or =1.20 who participated in a randomized double-blind 12-week intervention study and received riboflavin (1.6 mg/day; n = 23) or placebo (n = 23). RESULTS: Median plasma concentrations were 10.5 nmol/L for riboflavin, 6.6 nmol/L for FMN, and 74 nmol/L for FAD. In erythrocytes, there were only trace amounts of riboflavin, whereas median FMN and FAD concentrations were 44 and 469 nmol/L, respectively. Erythrocyte FMN and FAD correlated with each other and with EGRAC and plasma riboflavin (P <0.05). All variables except plasma FAD responded significantly to riboflavin supplementation compared with placebo (P < or =0.04). The strongest increases were for riboflavin in plasma (83%) and for FMN in erythrocytes (87%). CONCLUSIONS: Concentrations of all B(2) vitamers except plasma FAD are potential indicators of vitamin B(2) status, and plasma riboflavin and erythrocyte FMN may be useful for the assessment of vitamin B(2) status in population studies.

Aged↗