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Background Choline deficiency has numerous negative health consequences; although the preponderance of the US population consumes less than the recommended Adequate Intake (AI), clinical assessment of choline status is difficult. Further,... more
Background Choline deficiency has numerous negative health consequences; although the preponderance of the US population consumes less than the recommended Adequate Intake (AI), clinical assessment of choline status is difficult. Further, several pathways involved in primary metabolism of choline are estrogen-sensitive and the AI for premenopausal women is lower than that for men. Objectives We sought to determine whether in vivo magnetic resonance spectroscopy (MRS) of liver and/or isotope-dilution MS of plasma could identify biomarkers reflective of choline intake (preregistered primary outcomes 1 and 2, secondary outcome 1). Determination of whether biomarker concentrations showed sex dependence was a post hoc outcome. This substudy is a component of a larger project to identify a clinically useful biomarker panel for assessment of choline status. Methods In a double-blind, randomized, crossover trial, people consumed 3 diets, representative of ∼100%, ∼50%, and ∼25% of the cholin...
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OBJECTIVETo examine the association between dietary intake of choline and betaine and the risk of type 2 diabetes.RESEARCH DESIGN AND METHODSAmong 13,440 Atherosclerosis Risk in Communities (ARIC) study participants, the prospective... more
OBJECTIVETo examine the association between dietary intake of choline and betaine and the risk of type 2 diabetes.RESEARCH DESIGN AND METHODSAmong 13,440 Atherosclerosis Risk in Communities (ARIC) study participants, the prospective longitudinal association between dietary choline and betaine intake and the risk of type 2 diabetes was assessed using interval-censored Cox proportional hazards and logistic regression models adjusted for baseline potential confounding variables.RESULTSAmong 13,440 participants (55% women, mean age 54 [SD 7.4] years), 1,396 developed incident type 2 diabetes during median follow-up of 9 years from 1987 to 1998. There was no statistically significant association between every 1-SD increase in dietary choline and risk of type 2 diabetes (hazard ratio [HR] 1.01 [95% CI 0.87, 1.16]) nor between dietary betaine intake and the risk of type 2 diabetes (HR 1.01 [0.94, 1.10]). Those in the highest quartile of dietary choline intake did not have a statistically s...
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BackgroundCholine, an essential nutrient, serves as a methyl‐group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies... more
BackgroundCholine, an essential nutrient, serves as a methyl‐group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies suggest that choline supplementation during pregnancy can mitigate adverse effects of prenatal alcohol exposure on growth and neurocognitive function. We conducted a randomized, double‐blind exploratory trial to examine feasibility and acceptability of a choline supplementation intervention during pregnancy.MethodsSeventy heavy drinkers, recruited in mid‐pregnancy, were randomly assigned to receive a daily oral dose of 2 g of choline or a placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape‐flavored drink. Adherence was assessed by collecting used and unused drink packets on a monthly basis and tabulating the number used. Side effects...
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Research Interests: Engineering, Biology, Adolescent, DNA damage, Apoptosis, and 15 moreDNA, Caspases, American, Caspase, Comet Assay, Apoptose, Aged, Adult, Deficiency, Assay, Biological markers, Choline, Dosificación, Dosage, and déficit
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Using a mouse model, this study examined the impact of lack of betaine homocysteine S-methyltransferase (BHMT) on neurological function. Bhmt-/- mice maintained on a control diet had elevated concentrations of homocysteine, reduced total... more
Using a mouse model, this study examined the impact of lack of betaine homocysteine S-methyltransferase (BHMT) on neurological function. Bhmt-/- mice maintained on a control diet had elevated concentrations of homocysteine, reduced total brain MRI volume, as well as impaired reference and short- term memories. The results of this study indicate that the absence of BHMT may play a role in neurological function.
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Background: There is a potential role of choline in cardiovascular and cerebrovascular disease through its involvement in lipid and one-carbon metabolism.Objective: We evaluated the associations of plasma choline and choline-related... more
Background: There is a potential role of choline in cardiovascular and cerebrovascular disease through its involvement in lipid and one-carbon metabolism.Objective: We evaluated the associations of plasma choline and choline-related compounds with cardiometabolic risk factors, history of cardiovascular disease, and cerebrovascular pathology.Design: A cross-sectional subset of the Nutrition, Aging, and Memory in Elders cohort who had undergone MRI of the brain (n = 296; mean ± SD age: 73 ± 8.1 y) was assessed. Plasma concentrations of free choline, betaine, and phosphatidylcholine were measured with the use of liquid-chromatography-stable-isotope dilution-multiple-reaction monitoring-mass spectrometry. A volumetric analysis of MRI was used to determine the cerebrovascular pathology (white-matter hyperintensities and small- and large-vessel infarcts). Multiple linear and logistic regression models were used to examine relations of plasma measures with cardiometabolic risk factors, his...
Research Interests: Engineering, Endocrinology, Magnetic Resonance Spectroscopy, Humans, Internal Medicine, and 15 moreHypertension, Diabetes mellitus, Cholesterol, Female, Disease, Male, Body Mass Index, Homocysteine, Aged, C reactive protein, Cardiovascular Diseases, Choline, Cross Sectional Studies, Cerebrovascular Disorders, and Betaine
A child with severe S-adenosylhomocysteine hydrolase (AHCY) deficiency (AHCY c.428A>G, p.Tyr143Cys; c.982T>G, p.Tyr328Asp) presented at 8months of age with growth failure, microcephaly, global developmental delay, myopathy,... more
A child with severe S-adenosylhomocysteine hydrolase (AHCY) deficiency (AHCY c.428A>G, p.Tyr143Cys; c.982T>G, p.Tyr328Asp) presented at 8months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency. Plasma methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) were markedly elevated and the molar concentration ratio of AdoMet:AdoHcy, believed to regulate a myriad of methyltransferase reactions, was 15% of the control mean. Dietary therapy failed to normalize biochemical markers or alter the AdoMet to AdoHcy molar concentration ratio. At 40months of age, the proband received a liver segment from a healthy, unrelated living donor. Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52±0.19 to 1.48±0.79mol:mol (control 4.10±2.11mol:mol). Blood methionine and AdoMet were normal and stable during 6months of follow-up on an unrestricted diet. Average calculated ti...
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Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice. We studied mice with disruptions in Nr0b2 (called SHP-null... more
Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice. We studied mice with disruptions in Nr0b2 (called SHP-null mice) Bhmt, or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls). Hyperhomocysteinemia was induced by feeding mice alcohol (the NIAAA binge model) or chow diets along with water containing 0.18% DL-homocysteine. Some mice were placed on diets containing cholic acid (1%) or cholestyramine (2%), or high-fat diets (60%). Serum and livers were collected over a 24 hr light-dark cycle and analyzed by RNA-seq, metabolomic, and quantitative PCR, immunoblot, and chromatin immunoprecipitation assays. SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism, compared with control mice. Oscillatory production of S-adenosylmethionine, betaine, choline, phosphocholine, glyceophos...
Research Interests: Endocrinology, Chemistry, Gastroenterology, Biology, Medicine, and 15 moreInternal Medicine, Blood Glucose, Liver, Circadian Rhythm, Animals, Ethanol, Homocysteine, Clinical Sciences, Homeostasis, Time Factors, Glucose Intolerance, Knockout Mice, Neurosciences, hyperhomocysteinemia, and Paediatrics and reproductive medicine
Fibroblasts from a patient with postural orthostatic tachycardia syndrome (POTS), who presented with low plasma choline and betaine, were studied to determine the metabolic characteristics of the choline deficiency. Choline is required... more
Fibroblasts from a patient with postural orthostatic tachycardia syndrome (POTS), who presented with low plasma choline and betaine, were studied to determine the metabolic characteristics of the choline deficiency. Choline is required for the synthesis of the phospholipid phosphatidylcholine (PC) and for betaine, an important osmoregulator. Here, choline transport, lipid homeostasis, and mitochondria function were analyzed in skin fibroblasts from POTS and compared with control cells. The choline transporter-like protein 1/solute carrier 44A1 (CTL1/SLC44A1) and mRNA expression were 2-3 times lower in POTS fibroblasts, and choline uptake was reduced 60% (P < 0.05). Disturbances of membrane homeostasis were observed by reduced ratios between PC:phosphatidylethanolamine and sphingomyelin:cholesterol, as well as by modified phospholipid fatty acid composition. Choline deficiency also impaired mitochondria function, which was observed by a reduction in oxygen consumption, mitochondri...
Research Interests: Endocrinology, Physiology, Chemistry, Phospholipids, Mitochondria, and 15 moreMedicine, Humans, Internal Medicine, Female, Male, Medical Physiology, Cell Proliferation, Choline, Oxygen Consumption, Biochemistry and cell biology, Case Control Studies, Cell Membrane, fibroblasts, real time polymerase chain reaction, and reverse transcriptase polymerase chain reaction
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Research Interests: Physiology, Breast Cancer, Biology, Risk, Medicine, and 15 morePopulation, Humans, Internal Medicine, Female, Medical Physiology, Aged, Middle Aged, Adult, Single Nucleotide Polymorphism, Choline, Research communications, Biochemistry and cell biology, Case Control Studies, Betaine, and Breast Neoplasms
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Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate... more
Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate metabolism. We examined whether major genetic variants of folate metabolism modify susceptibility of humans to choline deficiency. Fifty-four adult men and women were fed diets containing adequate choline and folate, followed by a diet containing almost no choline, with or without added folate, until they were clinically judged to be choline-deficient, or for up to 42 days. Criteria for clinical choline deficiency were a more than five times increase in serum creatine kinase activity or a >28% increase of liver fat after consuming the low-choline diet that resolved when choline was returned to the diet. Choline deficiency was observed in more than half of the participants, usually within less than a month. Individuals who were carriers of the ver...
Research Interests: Endocrinology, Genetics, Carbon, Biology, Folic acid, and 15 moreMedicine, Humans, Internal Medicine, Female, Male, Aged, Middle Aged, Adult, Genetic Polymorphism, Genetic variation, Choline, Confidence Interval, creatine kinase activity, Methylenetetrahydrofolate Reductase, and Genetic predisposition to disease
Research Interests: Diet, Cardiovascular disease, Medicine, Humans, African American, and 15 moreFemale, Male, Food Frequency Questionnaire, Measurement Error, Homocysteine, Eating, Middle Aged, Methionine, Carbon Metabolism, European Continental Ancestry Group, Choline, Energy Intake, Cohort Studies, Betaine, and Dietary intake
Research Interests: Endocrinology, Physiology, Chemistry, Nutrition, Biology, and 15 moreDiet, Medicine, Humans, Internal Medicine, Male, Acetylcholine, Medical Physiology, Methionine, Alanine Aminotransferase, Choline, Phosphatidylcholine, Liver function tests, Control Group, Biochemistry and cell biology, and Medical and Health Sciences
The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Research Workshop, “Using Nutrigenomics and Metabolomics in Clinical Nutrition Research,” was held on January 21, 2012, in Orlando, Florida. The conference brought... more
The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Research Workshop, “Using Nutrigenomics and Metabolomics in Clinical Nutrition Research,” was held on January 21, 2012, in Orlando, Florida. The conference brought together experts in human nutrition who use nutrigenomic and metabolomic methods to better understand metabolic individuality and nutrition effects on health. We are beginning to understand how genetic variation and epigenetic events alter requirements for and responses to foods in our diet (the field of nutrigenetics/nutrigenomics and epigenetics). At the same time, methods for profiling almost all of the products of metabolism in plasma, urine, and tissues (metabolomics) are being refined. The relationships between diet and nutrigenomic‐metabolomic profiles, as well as between these profiles and health, are being elucidated, and this will dramatically alter clinical practice in nutrition.
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Research Interests: Endocrinology, Chemistry, Biology, Biological Chemistry, Medicine, and 15 moreEnergy Metabolism, Biological Sciences, Lipids, Adipose tissue, Internal Medicine, Glucose, Animals, Lipolysis, Biological, Energy Expenditure, Homocysteine, CHEMICAL SCIENCES, Adipocytes, Betaine, and Medical and Health Sciences
This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S-adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel... more
This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S-adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respiratory failure. Metabolic abnormalities included elevated plasma S-adenosylhomocysteine, S-adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122...
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Research Interests: Oncology, Polymorphism, Cancer, Breast Cancer, Biology, and 14 moreMedicine, Humans, Internal Medicine, Breast Cancer Early Detecion and Treatment, Methylation, Female, Population based study, DNA methylation, Middle Aged, Prognosis, Carbon Metabolism, CpG island, DNA mutational analysis, and Breast Neoplasms
Research Interests: Cardiology, Atherosclerosis, Diet, Medicine, Humans, and 15 moreInternal Medicine, Female, Male, Food Frequency Questionnaire, Measurement Error, Incidence, Homocysteine, Middle Aged, Coronary heart disease, Choline, Energy Intake, Betaine, Dietary intake, NUTRIENT COMPOSITION, and Cardiovascular medicine and haematology
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Choline is a dietary component essential for the structural integrity and signaling functions of cell membranes; it directly affects cholinergic neurotransmission and lipid transport from liver, and it is the major source of methyl groups... more
Choline is a dietary component essential for the structural integrity and signaling functions of cell membranes; it directly affects cholinergic neurotransmission and lipid transport from liver, and it is the major source of methyl groups in the diet (betaine, one of choline’s metabolites, participates in the methylation of homocysteine to form methionine) (1). In many mammals, including baboons, prolonged (weeks to months) ingestion of a diet deficient in choline but adequate, though limited, in methionine and folate has consequences that include hepatic, renal, pancreatic, memory, and growth disorders (1). A sign of organ dysfunction that occurs when humans are deprived of choline is the development of fatty liver (2, 3), because a lack of phosphatidylcholine limits the export of excess triacylglycerols from the liver (4). Also, choline deficiency is associated with liver cell death (2). An additional sign of choline deficiency is muscle cell damage, which is measured by greatly e...
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Epigenetics is the study of heritable mechanisms that can modify gene activity and phenotype without modifying the genetic code. The basis for the concept of epigenetics originated more than 2,000 yr ago as a theory to explain organismal... more
Epigenetics is the study of heritable mechanisms that can modify gene activity and phenotype without modifying the genetic code. The basis for the concept of epigenetics originated more than 2,000 yr ago as a theory to explain organismal development. However, the definition of epigenetics continues to evolve as we identify more of the components that make up the epigenome and dissect the complex manner by which they regulate and are regulated by cellular functions. A substantial and growing body of research shows that nutrition plays a significant role in regulating the epigenome. Here, we critically assess this diverse body of evidence elucidating the role of nutrition in modulating the epigenome and summarize the impact such changes have on molecular and physiological outcomes with regards to human health.
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Academic achievement in adolescents is correlated with 1-carbon metabolism (1-CM), as folate intake is positively related and total plasma homocysteine (tHcy) negatively related to academic success. Because another 1-CM nutrient, choline... more
Academic achievement in adolescents is correlated with 1-carbon metabolism (1-CM), as folate intake is positively related and total plasma homocysteine (tHcy) negatively related to academic success. Because another 1-CM nutrient, choline is essential for fetal neurocognitive development, we hypothesized that choline and betaine could also be positively related to academic achievement in adolescents. In a sample of 15-yr-old children (n = 324), we measured plasma concentrations of homocysteine, choline, and betaine and genotyped them for 2 polymorphisms with effects on 1-CM, methylenetetrahydrofolate reductase (MTHFR) 677C>T, rs1801133, and phosphatidylethanolamine N-methyltransferase (PEMT), rs12325817 (G>C). The sum of school grades in 17 major subjects was used as an outcome measure for academic achievement. Lifestyle and family socioeconomic status (SES) data were obtained from questionnaires. Plasma choline was significantly and positively associated with academic achievem...
Research Interests: Physiology, Adolescent, Medicine, Social Class, Linear models, and 15 moreHumans, Female, Academic achievement, Male, Medical Physiology, Homocysteine, Genotype, Educational Status, Choline, Cross Sectional Studies, Biochemistry and cell biology, Betaine, phosphatidylethanolamine N-methyltransferase, Surveys and Questionnaires, and Methylenetetrahydrofolate Reductase
Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline... more
Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary choline would be under negative selection pressure in settings where choline intake is low: choline dehydrogenase (CHDH) rs12676, methylenetetrahydrofolate reductase 1 (MTHFD1) rs2236225, and phosphatidylethanolamine-N-methyltransferase (PEMT) rs12325817. Evidence of negative selection was assessed in 2 populations: 1 in The Gambia, West Africa, where there is historic evidence of a choline-poor diet, and the other in the United States, with a comparatively choline-rich diet. We used 2 independent methods, and confirmation of our hypothesis was sought via a comparison with SNP data from the Maasai, an East African population with a genetic...
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Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. PEMT knockout mice have fatty livers, and it is possible that, in humans, nonalcoholic fatty liver disease (NAFLD) might be associated with PEMT... more
Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. PEMT knockout mice have fatty livers, and it is possible that, in humans, nonalcoholic fatty liver disease (NAFLD) might be associated with PEMT gene polymorphisms. DNA samples from 59 humans without fatty liver and from 28 humans with NAFLD were genotyped for a single nucleotide polymorphism in exon 8 of PEMT, which leads to a V175M substitution. V175M is a loss of function mutation, as determined by transiently transfecting McArdle-RH7777 cells with constructs of wild-type PEMT open reading frame or the V175M mutant. Met/Met at residue 175 (loss of function SNP) occurred in 67.9% of the NAFLD subjects and in only 40.7% of control subjects (P<0.03). For the first time we report that a polymorphism of the human PEMT gene (V175M) is associated with diminished activity and may confer susceptibility to NAFLD.
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Elevated concentrations of homocysteine in blood may be an independent risk factor for the development of atherosclerosis. Elevated homocysteine concentrations can be caused by decreased methylation of homocysteine to form methionine, as... more
Elevated concentrations of homocysteine in blood may be an independent risk factor for the development of atherosclerosis. Elevated homocysteine concentrations can be caused by decreased methylation of homocysteine to form methionine, as occurs in folate deficiency. A parallel pathway exists for methylation of homocysteine, in which choline, by way of betaine, is the methyl donor. Our goal was to determine whether choline deficiency results in a decreased capacity to methylate homocysteine. C57BL/6J mice were fed diets containing 0, 10, or 35 mmol choline/kg diet for 3 wk. We then administered an oral methionine load to the animals and measured plasma homocysteine concentrations. Also, in a pilot study, we examined 8 men who were fed a diet providing 550 mg choline/d per 70 kg body weight for 10 d, followed by a diet providing almost no choline, until the subjects were clinically judged to be choline deficient or for <or=42 d. A methionine load was administered at the end of each...
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Epidemiologic studies of choline and betaine intakes have been sparse because a food-composition database was not available until recently. The physiologic relevance of a variation in dietary choline and betaine in the general population... more
Epidemiologic studies of choline and betaine intakes have been sparse because a food-composition database was not available until recently. The physiologic relevance of a variation in dietary choline and betaine in the general population and the validity of intake assessed by food-frequency questionnaire (FFQ) have not been evaluated. This study was conducted to examine the physiologic relevance and validity of choline and betaine intakes measured by an FFQ. We examined the relations between choline and betaine intakes measured by FFQ and plasma total homocysteine (tHcy) concentrations in 1960 participants from the Framingham Offspring Study. Higher intakes of dietary choline and betaine were related to lower tHcy concentrations independent of other determinants, including folate and other B vitamins. For the lowest and highest quintiles of dietary choline plus betaine, the multivariate geometric means for tHcy were 10.9 and 9.9 mumol/L (P for trend < 0.0001). The inverse associa...