Additional file 3: Figure S3. Biomarker levels in each study participant, with a hierarchical clu... more Additional file 3: Figure S3. Biomarker levels in each study participant, with a hierarchical cluster analysis based on Euclidian distances with complete linkage. Each column represents a participant and each row a biomarker. Heat map colors represent standardized log-transformed biomarker levels in all participants (red) and below mean biamarker levels (blue).
MOESM5 of Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers
Additional file 5: Table S2. Differences of biomarkers levels between mothers of children with in... more Additional file 5: Table S2. Differences of biomarkers levels between mothers of children with infantile autism and Asperger's syndrome.
MOESM1 of Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers
Additional file 1: Figure S1. Seasonal variations of studied biomarkers. The smooth line was fitt... more Additional file 1: Figure S1. Seasonal variations of studied biomarkers. The smooth line was fitted with locally weighted scatterplot smoothing (loess). a All participants. b Case group. c Control group.
Background: Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy co... more Background: Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy concentrations are partly determined by folate, cobalamin, and vitamin B6 status, and methylenetetrahydrofolate reductase (MTHFR) and other flavoenzymes are important for the biotransformation of these vitamins. This motivates the investigation of the possible relationship between riboflavin status and tHcy.Methods: The study had a cross-sectional design and included 423 healthy blood donors, ages 19–69 years. We determined plasma tHcy, serum folate, serum cobalamin, serum creatinine, and MTHFR C677T genotype. In addition, we measured riboflavin and its two coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, in EDTA plasma by capillary electrophoresis and laser-induced fluorescence detection.Results: Riboflavin determined tHcy independently in a multiple linear regression model with adjustment for sex, age, folate, cobalamin, creatinine, and MTHFR genotype (P = 0.008). t...
Hyperhomocysteinemia in cobalamin and folate deficiency reflects an imbalance between influx and ... more Hyperhomocysteinemia in cobalamin and folate deficiency reflects an imbalance between influx and elimination of paired methionine synthase function through increased Hcy flux through alternate metabolic pathways.
Klamydia ar den vanligaste anmalningspliktiga infektionen i Sverige: 37 791 fall rapporterades ti... more Klamydia ar den vanligaste anmalningspliktiga infektionen i Sverige: 37 791 fall rapporterades till Smittskyddsinstitutet ar 2009, och 87 procent av de smittade var i aldern 15–29 ar.Klamydiainfekt ...
The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T polymorphism modifies the r... more The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T polymorphism modifies the risk of coronary artery disease and colon cancer and is related to plasma concentrations of total homocysteine (tHcy). Riboflavin status modifies the metabolic effect of the polymorphism, and thyroid hormones increase the synthesis of flavin cofactors. The aim of the study was to investigate the phenotypic expression of the MTHFR 677C-->T polymorphism in terms of plasma tHcy concentrations in patients with thyroid dysfunction. The study population consisted of 182 patients with hyperthyroidism. We studied plasma tHcy in relation to MTHFR genotype, riboflavin, and folate before and during 6 mo of treatment with antithyroid drugs. Before treatment, tHcy was higher in patients with the mutant enzyme than in those with the wild-type enzyme. A genotype effect was observed only at low riboflavin or folate concentrations (P </= 0.05). During treatment, concentrations of flavin cofactors in...
Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment,... more Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment, but it is unclear whether low vitamin B-12 or folate status is responsible for cognitive decline. We examined the associations of cognitive decline with vitamin B-12 and folate status in a longitudinal cohort study performed from 1993 to 2003 in Oxford, United Kingdom. Cognitive function was assessed with the Mini-Mental State Examination on >/=3 occasions during 10 y and related to serum concentrations of vitamin B-12, holotranscobalamin (holoTC), tHcy, methylmalonic acid (MMA), and folate with the use of linear mixed models in 1648 participants who provided blood in 1995. Cognitive function declined abruptly at younger ages in some participants but remained intact in others until very old age. In multivariate regression analyses after adjustment for established risk factors, concentrations of holoTC (a marker of reduced vitamin B-12 status), tHcy, and MMA predicted cognitive declin...
The observed effect of zinc supplementation on diarrheal morbidity varies between trials and ther... more The observed effect of zinc supplementation on diarrheal morbidity varies between trials and there is a need to identify subgroups most likely to benefit from improved zinc nutriture. In a randomized, double-blind trial in 2296 children in New Delhi, India, we assessed whether baseline cobalamin or folate status modified the effect of zinc supplementation on the incidence of prolonged ($7 d duration) and acute diarrhea. Children aged 6-30 mo received zinc or placebo daily for 4 mo. We measured plasma concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA) at enrollment and assessed the efficacy of zinc supplementation in subgroups based on these variables. The efficacy of zinc on reducing the risk of prolonged diarrhea was higher in those with plasma cobalamin concentrations below the 25th percentile and in those with tHcy and MMA concentrations above the 75th percentile. The OR (95% CI) for children below and above the 25th percentile for cobalamin were 0.53 (0.35-0.78) and 0.90 (0.73-1.11), respectively (P-interaction = 0.015). There were similar differences for the OR when comparing efficacy in those above and below the 75th percentile for tHcy and MMA (P-interaction = 0.045 and 0.188, respectively). Baseline folate status did not modify the effect of zinc on prolonged diarrhea. Neither cobalamin nor folate status influenced the effect of zinc on acute diarrhea. Children with poor cobalamin status benefited more from zinc supplementation for the prevention of prolonged diarrhea.
Different lifestyle patterns across Europe may influence plasma concentrations of B-vitamins and ... more Different lifestyle patterns across Europe may influence plasma concentrations of B-vitamins and one-carbon metabolites and their relation to chronic disease. Comparison of published data on one-carbon metabolites in Western European regions is difficult due to differences in sampling procedures and analytical methods between studies. The present study aimed, to compare plasma concentrations of one-carbon metabolites in Western European regions with one laboratory performing all biochemical analyses. We performed the present study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort among 5446 presumptively healthy individuals. Quantile regression was used to compare sex-specific median concentrations between Northern (Denmark and Sweden), Central (France, Germany, The Netherlands and United Kingdom) and Southern (Greece, Spain and Italy) European regions. The lowest folate concentrations were observed in Northern Europe (men, 10·4 nmol/l; women, 10·7 nm...
The association between body size at birth and risk of later cardiovascular disease is thought to... more The association between body size at birth and risk of later cardiovascular disease is thought to be a consequence of metabolic changes that accompany slow growth in utero. The metabolism of methionine and homocysteine has been investigated in relation to cardiovascular risk and has also been assigned an important role in organogenesis and normal fetal growth. We determined concentrations of cobalamin, folate, methionine, cysteine, cystathionine, and the marker of B-vitamin function, homocysteine, in 625 samples of amniotic fluid obtained in the second trimester from normal pregnancies. Both vitamins and metabolites varied according to gestational age. The most noticeable observation was that methionine in amniotic fluid during gestational weeks 13 to 17 strongly predicted final birth weight and length. Metabolism of methionine may be a critical factor affecting fetal growth.
Objectives. To investigate plasma total homocysteine levels and its relation to B-vitamins and sm... more Objectives. To investigate plasma total homocysteine levels and its relation to B-vitamins and smoking in Graves' disease before and after antithyroid therapy. Design. A longitudinal study taking place at four hospitals in Norway. Methods and subjects. Plasma total homocysteine, serum folate, serum cobalamin and riboflavin, flavin mononucleotide and flavin adenine dinucleotide in plasma were investigated in 182 patients with hyperthyroidism before treatment. The same parameters were reinvestigated in 112 of these patients after attaining euthyroid state. Results. In hyperthyroidism, plasma total homocysteine was low, and inversely related to folate, cobalamin and riboflavin, and positively related to serum creatinine and age. Following antithyroid therapy, total homocysteine increased and the concentration of folate, cobalamin, riboflavin, flavin mononucleotide and flavin adenine dinucleotide decreased significantly. The most pronounced reduction (35%) was observed for flavin mononucleotide. In the hyperthyroid state, smokers had lower levels of folate and flavin mononucleotide than non-smokers. After restoration of euthyroidism, both folate and riboflavin were significantly lower in smokers than non-smokers. Plasma total homocysteine increased according to decreasing quartiles of B-vitamins. For riboflavin, this relation was confined to smokers. Conclusion. Plasma total homocysteine changes according to thyroid status. These changes may be partly attributable to altered folate, cobalamin but also riboflavin status, particulary in smokers.
Communicated by Klaus Meyer Several polymorphisms of genes involved in one-carbon metabolism have... more Communicated by Klaus Meyer Several polymorphisms of genes involved in one-carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large-scale study of 10,601 population-based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one-carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B 12 (cobalamin), methylmalonic acid (MMA), vitamin B 2 (riboflavin), vitamin B 6 (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase (MTHFR) c.665C4T (known as 677C4T; p.Ala222Val) and c.1286A4C (known as 1298A4C; p.Glu429Ala); methionine synthase (MTR) c.2756A4G (p.Asp919Gly); methionine synthase reductase (MTRR) c.66A4G (p.Ile22Met); methylenetetrahydrofolate dehydrogenase (MTHFD1) c.1958G4A (p.Arg653Gln); betaine homocysteine methyltransferase (BHMT) c.716G4A (known as 742G4A; p.Arg239Gln); cystathionine b-synthase (CBS) c.844_845ins68 and c.699C4T (p.Tyr233Tyr); transcobalamin-II (TCN2) c.67A4G (p.Ile23Val) and c.776C4G (p.Pro259Arg); reduced folate carrier-1 (SLC19A1) c.80G4A (p.Arg27His); and paraoxonase-1 (PON1) c.163T4A (p.Leu55Met) and c.575A4G (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665C4T with tHcy and folate, but also observed significant (Po0.01) changes in metabolite concentrations according to other gene polymorphisms. These include MTHFR c.1286A4C (associations with tHcy, folate and betaine), MTR c.2756A4G (tHcy), BHMT c.716G4A (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699C4T (tHcy, betaine, cystathionine) and TCN2 c.776C4G (MMA). No associations were observed for the other polymorphisms investigated. Hum Mutat 28(9),
Objective: Assessment of functional vitamin B 12 status in a subset of the respondents in the Bri... more Objective: Assessment of functional vitamin B 12 status in a subset of the respondents in the British National Diet and Nutrition Survey of people aged 65 y and over. Setting: National Diet and Nutrition Survey: a British nationwide cross-sectional sample of people aged 65 y and over, living either in the community or in institutions such as nursing homes, during one calendar year spanning 1994-1995. Methods: Methylmalonic acid (MMA) concentrations were measured in plasma samples from 313 subjects (ca 14% of those originally enrolled in the survey). The results were compared with those for serum vitamin B 12 , vitamin B 12 intakes and other status and intake estimates and with socio-demographic indices. Results: Of the NDNS participants overall, 20% had serum vitamin B 12 concentrations < 150 pmol=l. In the subset studied here, 24% of free-living and 46% of institution-living participants had MMA >0.5 mmol=l. Geometric mean MMA increased with age, from 0.25 mmol=l in people aged 65-74 y to 0.38 mmol=l in people aged 85 þ y. There was little evidence for any gender difference in MMA. It was inversely correlated with serum vitamin B 12 and with red blood cell folate; it was positively correlated directly with total homocysteine, but not significantly with serum folate or with vitamin B 12 intake. Among respondents with high MMA, a subgroup had normal serum vitamin B 12 but higher-than-average plasma urea and creatinine. Socio-demographic co-variates of MMA included receipt of State income benefits, social class of head of household, and educational attainment. These indices were not correlated with serum vitamin B 12. Conclusions: The progressive increase in MMA with age is metabolic evidence for increasing risk of functional vitamin B 12 deficiency with increasing age in older people. There is evidence that renal function is linked to high MMA in some older people. Age and renal function are thus both important when establishing upper reference limits for MMA. The socio-demographic observations suggest a link between poverty and poor functional vitamin B 12 status in older British people.
Clinical Chemistry and Laboratory Medicine (CCLM), 2005
A commercially available holotranscobalamin (holo-TC) radioimmunoassay (RIA) (Axis-Shield, Dundee... more A commercially available holotranscobalamin (holo-TC) radioimmunoassay (RIA) (Axis-Shield, Dundee, Scotland) was evaluated in four laboratories and compared with a holoTC ELISA run in one laboratory. The performance of the holoTC RIA assay was comparable in three of the four participating laboratories. The results from these three laboratories, involving at least 20 initial runs of “low”, “medium” and “high” serum-based controls (mean holoTC concentrations 34, 60 and 110pmol/L, respectively) yielded an intra-laboratory imprecision of 6–10%. No systematic inter-laboratory deviations were observed on runs involving 72 patient samples (holoTC concentration range 10–160pmol/L). A fourth laboratory demonstrated higher assay imprecision for control samples and systematic deviation of results for the patient samples. Measurement of holoTC by ELISA showed an imprecision of 4–5%, and slightly higher mean values for the controls (mean holoTC concentrations 40, 70 and 114pmol/L, respectively)....
Background: Newborn screening for total homocysteine (tHcy) in blood may identify babies with vit... more Background: Newborn screening for total homocysteine (tHcy) in blood may identify babies with vitamin B12 (B12) deficiency or homocystinuria, but data on the causes of increased tHcy in screening samples are sparse.Methods: Serum concentrations of tHcy, cystathionine, methionine, folate, and B12 and the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism were determined in 4992 capillary blood samples collected as part of the routine screening program in newborn children. Methylmalonic acid (MMA), gender (SRY genotyping), and the frequency of six cystathionine β-synthase (CBS) mutations were determined in 20–27% of the samples, including all samples with tHcy >15 μmol/L (n = 127), B12 <100 pmol/L (n = 159), or methionine >40 μmol/L (n = 154).Results: The median (5th–95th percentile) tHcy concentration was 6.8 (4.2–12.8) μmol/L. B12 status, as determined by serum concentrations of B12, tHcy, and MMA, was moderately better in boys than in girls. tHcy concentrat...
Additional file 3: Figure S3. Biomarker levels in each study participant, with a hierarchical clu... more Additional file 3: Figure S3. Biomarker levels in each study participant, with a hierarchical cluster analysis based on Euclidian distances with complete linkage. Each column represents a participant and each row a biomarker. Heat map colors represent standardized log-transformed biomarker levels in all participants (red) and below mean biamarker levels (blue).
MOESM5 of Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers
Additional file 5: Table S2. Differences of biomarkers levels between mothers of children with in... more Additional file 5: Table S2. Differences of biomarkers levels between mothers of children with infantile autism and Asperger's syndrome.
MOESM1 of Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers
Additional file 1: Figure S1. Seasonal variations of studied biomarkers. The smooth line was fitt... more Additional file 1: Figure S1. Seasonal variations of studied biomarkers. The smooth line was fitted with locally weighted scatterplot smoothing (loess). a All participants. b Case group. c Control group.
Background: Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy co... more Background: Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy concentrations are partly determined by folate, cobalamin, and vitamin B6 status, and methylenetetrahydrofolate reductase (MTHFR) and other flavoenzymes are important for the biotransformation of these vitamins. This motivates the investigation of the possible relationship between riboflavin status and tHcy.Methods: The study had a cross-sectional design and included 423 healthy blood donors, ages 19–69 years. We determined plasma tHcy, serum folate, serum cobalamin, serum creatinine, and MTHFR C677T genotype. In addition, we measured riboflavin and its two coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, in EDTA plasma by capillary electrophoresis and laser-induced fluorescence detection.Results: Riboflavin determined tHcy independently in a multiple linear regression model with adjustment for sex, age, folate, cobalamin, creatinine, and MTHFR genotype (P = 0.008). t...
Hyperhomocysteinemia in cobalamin and folate deficiency reflects an imbalance between influx and ... more Hyperhomocysteinemia in cobalamin and folate deficiency reflects an imbalance between influx and elimination of paired methionine synthase function through increased Hcy flux through alternate metabolic pathways.
Klamydia ar den vanligaste anmalningspliktiga infektionen i Sverige: 37 791 fall rapporterades ti... more Klamydia ar den vanligaste anmalningspliktiga infektionen i Sverige: 37 791 fall rapporterades till Smittskyddsinstitutet ar 2009, och 87 procent av de smittade var i aldern 15–29 ar.Klamydiainfekt ...
The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T polymorphism modifies the r... more The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T polymorphism modifies the risk of coronary artery disease and colon cancer and is related to plasma concentrations of total homocysteine (tHcy). Riboflavin status modifies the metabolic effect of the polymorphism, and thyroid hormones increase the synthesis of flavin cofactors. The aim of the study was to investigate the phenotypic expression of the MTHFR 677C-->T polymorphism in terms of plasma tHcy concentrations in patients with thyroid dysfunction. The study population consisted of 182 patients with hyperthyroidism. We studied plasma tHcy in relation to MTHFR genotype, riboflavin, and folate before and during 6 mo of treatment with antithyroid drugs. Before treatment, tHcy was higher in patients with the mutant enzyme than in those with the wild-type enzyme. A genotype effect was observed only at low riboflavin or folate concentrations (P </= 0.05). During treatment, concentrations of flavin cofactors in...
Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment,... more Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment, but it is unclear whether low vitamin B-12 or folate status is responsible for cognitive decline. We examined the associations of cognitive decline with vitamin B-12 and folate status in a longitudinal cohort study performed from 1993 to 2003 in Oxford, United Kingdom. Cognitive function was assessed with the Mini-Mental State Examination on >/=3 occasions during 10 y and related to serum concentrations of vitamin B-12, holotranscobalamin (holoTC), tHcy, methylmalonic acid (MMA), and folate with the use of linear mixed models in 1648 participants who provided blood in 1995. Cognitive function declined abruptly at younger ages in some participants but remained intact in others until very old age. In multivariate regression analyses after adjustment for established risk factors, concentrations of holoTC (a marker of reduced vitamin B-12 status), tHcy, and MMA predicted cognitive declin...
The observed effect of zinc supplementation on diarrheal morbidity varies between trials and ther... more The observed effect of zinc supplementation on diarrheal morbidity varies between trials and there is a need to identify subgroups most likely to benefit from improved zinc nutriture. In a randomized, double-blind trial in 2296 children in New Delhi, India, we assessed whether baseline cobalamin or folate status modified the effect of zinc supplementation on the incidence of prolonged ($7 d duration) and acute diarrhea. Children aged 6-30 mo received zinc or placebo daily for 4 mo. We measured plasma concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA) at enrollment and assessed the efficacy of zinc supplementation in subgroups based on these variables. The efficacy of zinc on reducing the risk of prolonged diarrhea was higher in those with plasma cobalamin concentrations below the 25th percentile and in those with tHcy and MMA concentrations above the 75th percentile. The OR (95% CI) for children below and above the 25th percentile for cobalamin were 0.53 (0.35-0.78) and 0.90 (0.73-1.11), respectively (P-interaction = 0.015). There were similar differences for the OR when comparing efficacy in those above and below the 75th percentile for tHcy and MMA (P-interaction = 0.045 and 0.188, respectively). Baseline folate status did not modify the effect of zinc on prolonged diarrhea. Neither cobalamin nor folate status influenced the effect of zinc on acute diarrhea. Children with poor cobalamin status benefited more from zinc supplementation for the prevention of prolonged diarrhea.
Different lifestyle patterns across Europe may influence plasma concentrations of B-vitamins and ... more Different lifestyle patterns across Europe may influence plasma concentrations of B-vitamins and one-carbon metabolites and their relation to chronic disease. Comparison of published data on one-carbon metabolites in Western European regions is difficult due to differences in sampling procedures and analytical methods between studies. The present study aimed, to compare plasma concentrations of one-carbon metabolites in Western European regions with one laboratory performing all biochemical analyses. We performed the present study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort among 5446 presumptively healthy individuals. Quantile regression was used to compare sex-specific median concentrations between Northern (Denmark and Sweden), Central (France, Germany, The Netherlands and United Kingdom) and Southern (Greece, Spain and Italy) European regions. The lowest folate concentrations were observed in Northern Europe (men, 10·4 nmol/l; women, 10·7 nm...
The association between body size at birth and risk of later cardiovascular disease is thought to... more The association between body size at birth and risk of later cardiovascular disease is thought to be a consequence of metabolic changes that accompany slow growth in utero. The metabolism of methionine and homocysteine has been investigated in relation to cardiovascular risk and has also been assigned an important role in organogenesis and normal fetal growth. We determined concentrations of cobalamin, folate, methionine, cysteine, cystathionine, and the marker of B-vitamin function, homocysteine, in 625 samples of amniotic fluid obtained in the second trimester from normal pregnancies. Both vitamins and metabolites varied according to gestational age. The most noticeable observation was that methionine in amniotic fluid during gestational weeks 13 to 17 strongly predicted final birth weight and length. Metabolism of methionine may be a critical factor affecting fetal growth.
Objectives. To investigate plasma total homocysteine levels and its relation to B-vitamins and sm... more Objectives. To investigate plasma total homocysteine levels and its relation to B-vitamins and smoking in Graves' disease before and after antithyroid therapy. Design. A longitudinal study taking place at four hospitals in Norway. Methods and subjects. Plasma total homocysteine, serum folate, serum cobalamin and riboflavin, flavin mononucleotide and flavin adenine dinucleotide in plasma were investigated in 182 patients with hyperthyroidism before treatment. The same parameters were reinvestigated in 112 of these patients after attaining euthyroid state. Results. In hyperthyroidism, plasma total homocysteine was low, and inversely related to folate, cobalamin and riboflavin, and positively related to serum creatinine and age. Following antithyroid therapy, total homocysteine increased and the concentration of folate, cobalamin, riboflavin, flavin mononucleotide and flavin adenine dinucleotide decreased significantly. The most pronounced reduction (35%) was observed for flavin mononucleotide. In the hyperthyroid state, smokers had lower levels of folate and flavin mononucleotide than non-smokers. After restoration of euthyroidism, both folate and riboflavin were significantly lower in smokers than non-smokers. Plasma total homocysteine increased according to decreasing quartiles of B-vitamins. For riboflavin, this relation was confined to smokers. Conclusion. Plasma total homocysteine changes according to thyroid status. These changes may be partly attributable to altered folate, cobalamin but also riboflavin status, particulary in smokers.
Communicated by Klaus Meyer Several polymorphisms of genes involved in one-carbon metabolism have... more Communicated by Klaus Meyer Several polymorphisms of genes involved in one-carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large-scale study of 10,601 population-based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one-carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B 12 (cobalamin), methylmalonic acid (MMA), vitamin B 2 (riboflavin), vitamin B 6 (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase (MTHFR) c.665C4T (known as 677C4T; p.Ala222Val) and c.1286A4C (known as 1298A4C; p.Glu429Ala); methionine synthase (MTR) c.2756A4G (p.Asp919Gly); methionine synthase reductase (MTRR) c.66A4G (p.Ile22Met); methylenetetrahydrofolate dehydrogenase (MTHFD1) c.1958G4A (p.Arg653Gln); betaine homocysteine methyltransferase (BHMT) c.716G4A (known as 742G4A; p.Arg239Gln); cystathionine b-synthase (CBS) c.844_845ins68 and c.699C4T (p.Tyr233Tyr); transcobalamin-II (TCN2) c.67A4G (p.Ile23Val) and c.776C4G (p.Pro259Arg); reduced folate carrier-1 (SLC19A1) c.80G4A (p.Arg27His); and paraoxonase-1 (PON1) c.163T4A (p.Leu55Met) and c.575A4G (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665C4T with tHcy and folate, but also observed significant (Po0.01) changes in metabolite concentrations according to other gene polymorphisms. These include MTHFR c.1286A4C (associations with tHcy, folate and betaine), MTR c.2756A4G (tHcy), BHMT c.716G4A (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699C4T (tHcy, betaine, cystathionine) and TCN2 c.776C4G (MMA). No associations were observed for the other polymorphisms investigated. Hum Mutat 28(9),
Objective: Assessment of functional vitamin B 12 status in a subset of the respondents in the Bri... more Objective: Assessment of functional vitamin B 12 status in a subset of the respondents in the British National Diet and Nutrition Survey of people aged 65 y and over. Setting: National Diet and Nutrition Survey: a British nationwide cross-sectional sample of people aged 65 y and over, living either in the community or in institutions such as nursing homes, during one calendar year spanning 1994-1995. Methods: Methylmalonic acid (MMA) concentrations were measured in plasma samples from 313 subjects (ca 14% of those originally enrolled in the survey). The results were compared with those for serum vitamin B 12 , vitamin B 12 intakes and other status and intake estimates and with socio-demographic indices. Results: Of the NDNS participants overall, 20% had serum vitamin B 12 concentrations < 150 pmol=l. In the subset studied here, 24% of free-living and 46% of institution-living participants had MMA >0.5 mmol=l. Geometric mean MMA increased with age, from 0.25 mmol=l in people aged 65-74 y to 0.38 mmol=l in people aged 85 þ y. There was little evidence for any gender difference in MMA. It was inversely correlated with serum vitamin B 12 and with red blood cell folate; it was positively correlated directly with total homocysteine, but not significantly with serum folate or with vitamin B 12 intake. Among respondents with high MMA, a subgroup had normal serum vitamin B 12 but higher-than-average plasma urea and creatinine. Socio-demographic co-variates of MMA included receipt of State income benefits, social class of head of household, and educational attainment. These indices were not correlated with serum vitamin B 12. Conclusions: The progressive increase in MMA with age is metabolic evidence for increasing risk of functional vitamin B 12 deficiency with increasing age in older people. There is evidence that renal function is linked to high MMA in some older people. Age and renal function are thus both important when establishing upper reference limits for MMA. The socio-demographic observations suggest a link between poverty and poor functional vitamin B 12 status in older British people.
Clinical Chemistry and Laboratory Medicine (CCLM), 2005
A commercially available holotranscobalamin (holo-TC) radioimmunoassay (RIA) (Axis-Shield, Dundee... more A commercially available holotranscobalamin (holo-TC) radioimmunoassay (RIA) (Axis-Shield, Dundee, Scotland) was evaluated in four laboratories and compared with a holoTC ELISA run in one laboratory. The performance of the holoTC RIA assay was comparable in three of the four participating laboratories. The results from these three laboratories, involving at least 20 initial runs of “low”, “medium” and “high” serum-based controls (mean holoTC concentrations 34, 60 and 110pmol/L, respectively) yielded an intra-laboratory imprecision of 6–10%. No systematic inter-laboratory deviations were observed on runs involving 72 patient samples (holoTC concentration range 10–160pmol/L). A fourth laboratory demonstrated higher assay imprecision for control samples and systematic deviation of results for the patient samples. Measurement of holoTC by ELISA showed an imprecision of 4–5%, and slightly higher mean values for the controls (mean holoTC concentrations 40, 70 and 114pmol/L, respectively)....
Background: Newborn screening for total homocysteine (tHcy) in blood may identify babies with vit... more Background: Newborn screening for total homocysteine (tHcy) in blood may identify babies with vitamin B12 (B12) deficiency or homocystinuria, but data on the causes of increased tHcy in screening samples are sparse.Methods: Serum concentrations of tHcy, cystathionine, methionine, folate, and B12 and the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism were determined in 4992 capillary blood samples collected as part of the routine screening program in newborn children. Methylmalonic acid (MMA), gender (SRY genotyping), and the frequency of six cystathionine β-synthase (CBS) mutations were determined in 20–27% of the samples, including all samples with tHcy >15 μmol/L (n = 127), B12 <100 pmol/L (n = 159), or methionine >40 μmol/L (n = 154).Results: The median (5th–95th percentile) tHcy concentration was 6.8 (4.2–12.8) μmol/L. B12 status, as determined by serum concentrations of B12, tHcy, and MMA, was moderately better in boys than in girls. tHcy concentrat...
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