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Potential identification of vitamin B6 responsiveness in autism spectrum disorder utilizing phenotype variables and machine learning methods.
Obara, T, Ishikuro, M, Tamiya, G, Ueki, M, Yamanaka, C, Mizuno, S, Kikuya, M, Metoki, H, Matsubara, H, Nagai, M, et al
Scientific reports. 2018;(1):14840
Abstract
We investigated whether machine learning methods could potentially identify a subgroup of persons with autism spectrum disorder (ASD) who show vitamin B6 responsiveness by selected phenotype variables. We analyzed the existing data from our intervention study with 17 persons. First, we focused on signs and biomarkers that have been identified as candidates for vitamin B6 responsiveness indicators. Second, we conducted hypothesis testing among these selected variables and their combinations. Finally, we further investigated the results by conducting cluster analyses with two different algorithms, affinity propagation and k-medoids. Statistically significant variables for vitamin B6 responsiveness, including combination of hypersensitivity to sound and clumsiness, and plasma glutamine level, were included. As an a priori variable, the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores was also included. The affinity propagation analysis showed good classification of three potential vitamin B6-responsive persons with ASD. The k-medoids analysis also showed good classification. To our knowledge, this is the first study to attempt to identify subgroup of persons with ASD who show specific treatment responsiveness using selected phenotype variables. We applied machine learning methods to further investigate these variables' ability to identify this subgroup of ASD, even when only a small sample size was available.
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B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial.
Zhong, J, Karlsson, O, Wang, G, Li, J, Guo, Y, Lin, X, Zemplenyi, M, Sanchez-Guerra, M, Trevisi, L, Urch, B, et al
Proceedings of the National Academy of Sciences of the United States of America. 2017;(13):3503-3508
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Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 μg/m3) under placebo, and PM2.5 (250 μg/m3) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4+ T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks.
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Metabolite profile analysis reveals association of vitamin B-6 with metabolites related to one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in oral contraceptive users and reveals the effects of oral contraceptives on these processes.
Rios-Avila, L, Coats, B, Chi, YY, Midttun, Ø, Ueland, PM, Stacpoole, PW, Gregory, JF
The Journal of nutrition. 2015;(1):87-95
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BACKGROUND The use of oral contraceptives (OCs) has been associated with low plasma pyridoxal 5'-phosphate (PLP). The functional consequences are unclear. OBJECTIVES To determine whether functional vitamin B-6 insufficiency occurs in OC users and is attributable to OCs, we investigated the associations of PLP with metabolites of one-carbon metabolism, tryptophan catabolism, and inflammation in OC users, and evaluated the effects of OCs on these metabolites. METHODS Plasma metabolite concentrations were measured in 157 OC users (20-40 y of age). Associations between PLP and the metabolites were analyzed through use of generalized additive models and partial least squares-discriminant analysis (PLS-DA). Additionally, data from 111 of the 157 OC users were compared to previously reported data from 11 nonusers, at adequate and low vitamin B-6 status, with use of multivariate ANOVA. RESULTS PLP showed significant (P < 0.05) negative nonlinear association with homocysteine, glutathione, and ratios of asymmetric dimethylarginine to arginine, 3-hydroxykynurenine to 3-hydroxyanthranilic acid, and 3-hydroxykynurenine to kynurenic acid. PLS-DA supported these conclusions and identified 3-hydroxykynurenine and the 3-hydroxykynurenine-to-kynurenine ratio as discriminating biomarkers in women with PLP ≤30 nmol/L. Among the many differences, OC users had significantly higher plasma pyridoxal (157% at adequate and 195% at low vitamin B-6 status), 4-pyridoxic acid (154% at adequate and 300% at low vitamin B-6 status), xanthurenic acid (218% at low vitamin B-6 status), 3-hydroxyanthranilic acid (176% at adequate and 166% at low vitamin B-6 status), quinolinic acid (127% at low vitamin B-6 status), and nicotinamide (197% at low vitamin B-6 status). Biomarkers of inflammation were not associated with PLP, and no differences were found between the 2 groups. CONCLUSIONS PLP is associated with biomarkers of one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in OC users. Independent of vitamin B-6 status, OCs have effects on metabolites and ratios of one-carbon metabolism and tryptophan catabolism but not on biomarkers of inflammation. This study was registered at clinicaltrials.gov as NCT01128244. The study from which data for nonusers was derived was registered as NCT00877812.
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Comparative study of response to treatment with supraphysiologic doses of B-vitamins in hyperhomocysteinemic hemodialysis patients.
Nakhoul, F, Abassi, Z, Plawner, M, Khankin, E, Ramadan, R, Lanir, N, Brenner, B, Green, J
The Israel Medical Association journal : IMAJ. 2004;(4):213-7
Abstract
BACKGROUND Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodialysis patients. OBJECTIVES To examine the effects of two doses of vitamins B6 and B12 and folic acid on homocysteine levels in hemodialysis patients and assess the functional impact of the methylenetetrahydrofolate reductase genotype on the response to treatment. METHODS In a randomized prospective study, we assessed the effects of folic acid and two doses of B-vitamins in 50 hemodialysis patients with hyperhomocysteinemia. Patients were divided into two groups: 26 patients (group A) who received 25 mg of vitamin B6 daily and one monthly injection of 200 microg vitamin B12, and 24 patients (group B) who received 100 mg of vitamin B6 daily and one monthly injection of 1,000 microg vitamin B12. In addition, both groups received 15 mg folic acid daily. Patients were evaluated for homocysteine levels as well as for coagulation and a thorough lipid profile. Baseline Hcy levels were determined after at least 4 weeks washout from all folic acid and B-vitamins that were given. MFTHR alleles were analyzed, as were activated protein C resistance, von Willebrand factor and lupus anticoagulant. RESULTS Basal plasma Hcy levels were significantly elevated in hemodialysis patients compared with normal subjects (33.8 +/- 4.3 vs. 4.5 to 14.0 micromol/L). Following treatment, Hcy levels were significantly reduced to 21.2 +/- 1.6 in group A and 18.6 +/- 1.4 micromol/L in group B (P < 0.01). There was no difference in Hcy reduction following the administration of either high or low dosage of vitamins B6 and B12 utilized in the present study. There was no correlation between Hcy levels or thrombophilia and high incidence of thrombotic episodes in hemodialysis patients. Genotypic evaluation of MTHFR revealed that the presence of homozygous thermolabile MTHFR (n = 5) was associated with higher Hcy levels and better response to treatment (Hcy levels decreased by 58%, from 46.2 +/- 14.6 to 19.48 + 4.1 micromol/ L following treatment). In patients with heterozygous thermolabile MTHFR (n = 25), Hcy levels decreased by 34%, from 31.2 +/- 3.7 to 18.1 +/- 1.1 micromol/L following treatment. The efficacy of high and low doses of B-vitamins on the reduction of homocysteine levels was comparable. CONCLUSIONS Treatment with B-vitamins in combination with folic acid significantly decreased homocysteine levels in hemodialysis patients, independently of the tested doses. In addition, mutations in MTHFR were associated with elevated plasma levels of Hcy. Neither vascular access nor the presence of diabetes was associated with higher pre- or post-treatment homocysteine level.
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Changes in basal and postmethionine load concentrations of total homocysteine and cystathionine after B vitamin intervention.
Bleie, Ø, Refsum, H, Ueland, PM, Vollset, SE, Guttormsen, AB, Nexo, E, Schneede, J, Nordrehaug, JE, Nygård, O
The American journal of clinical nutrition. 2004;(3):641-8
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BACKGROUND Vitamin B-6 is necessary for the metabolism of homocysteine and is often used in combination with folic acid and vitamin B-12 in clinical trials that investigate whether the lowering of plasma total homocysteine (tHcy) can prevent vascular disease. OBJECTIVE We compared the effects of vitamin B-6 with the effects of folic acid and vitamin B-12, as used in the Western Norway B-vitamin Intervention Trial (WENBIT), on basal and postmethionine load (PML) tHcy and cystathionine concentrations. DESIGN Ninety patients with suspected coronary artery disease were randomly assigned to 1 of 4 groups to receive daily oral treatment with 1) 0.8 mg folic acid, 0.4 mg vitamin B-12, and 40 mg vitamin B-6 (group A); 2) 0.8 mg folic acid and 0.4 mg vitamin B-12 (group B); 3) 40 mg vitamin B-6 (group C); or 4) placebo (group D). For the first 2 wk, groups A and B received additional folic acid (5 mg/d). A methionine-loading test was performed at baseline and after 3 mo. RESULTS Treatment with folic acid and vitamin B-12 caused a rapid and significant lowering of basal (31%) and PML tHcy concentrations (22%), with no effect on cystathionine. Vitamin B-6 did not change basal tHcy and had a significant but limited effect on PML tHcy concentrations. However, vitamin B-6 treatment markedly lowered basal and PML cystathionine by 31% and 42%, respectively. CONCLUSION The folic acid and vitamin B-12 combination applied in WENBIT provides rapid, substantial, and long-term tHcy-lowering effects, whereas the effect of vitamin B-6 on tHcy was relatively small and confined to PML tHcy. However, vitamin B-6 treatment caused a marked reduction in plasma cystathionine. Cystathionine could be a useful marker for assessment of the vitamin B-6 effect and should, together with tHcy, be related to clinical outcome in ongoing trials.