SynthesisPLoS genetics2014
Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke.
Synthesis in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
47 citing papers in PubMed, 3 syntheses or guidelines pooled it, 79 citations in OpenAlex.
- Microbiome and ischemic stroke: A systematic review.PloS one · 2021Pooled it
- Genetic Determinants of Circulating Glycine Levels and Risk of Coronary Artery Disease.Journal of the American Heart Association · 2019Pooled it
- Plasma homocysteine concentrations and risk of intracerebral hemorrhage: a systematic review and meta-analysis.Scientific reports · 2018Pooled it
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- Aberrant one-carbon metabolism and ancestral genetics underlie edematous severe acute malnutrition.Nature communications · 2026Article
- Role of one-carbon metabolism variants in the associations between perfluoroalkyl substances exposure and birth size in the Taiwan Birth Panel Study.Environmental epidemiology (Philadelphia, Pa.) · 2026Article
- Hyperhomocysteinemia-Driven Ischemic Stroke: Unraveling Molecular Mechanisms and Therapeutic Horizons.Food science & nutrition · 2025Review
- A Proactive Intervention Study in Metabolic Syndrome High-Risk Populations Using Phenome-Based Actionable P4 Medicine Strategy.Phenomics (Cham, Switzerland) · 2024Article
- Platelet Metabolic Profiling Reveals Glycolytic and 1-Carbon Metabolites Are Essential for GP VI-Stimulated Human Platelets-Brief Report.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- The Role of Methionine-Rich Diet in Unhealthy Cerebrovascular and Brain Aging: Mechanisms and Implications for Cognitive Impairment.Nutrients · 2023Review
- Review
- Genetic considerations in cerebral small vessel diseases.Frontiers in neurology · 2023Review
- Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children.The American journal of clinical nutrition · 2022Article
- Metabolic Changes Induced by Cerebral Ischemia, the Effect of Ischemic Preconditioning, and Hyperhomocysteinemia.Biomolecules · 2022Review
- Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis.International journal of molecular sciences · 2021Article
- Personalized Nutrition Approach in Pregnancy and Early Life to Tackle Childhood and Adult Non-Communicable Diseases.Life (Basel, Switzerland) · 2021Review
- A comprehensive association analysis between homocysteine metabolic pathway gene methylation and ischemic stroke in a Chinese hypertensive population.Journal of clinical laboratory analysis · 2021Article
- Exome-Wide Association Study Identifies East Asian-Specific Missense VariantFrontiers in genetics · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
23 authors at 8 institutions in 1 country.
Funding
Abstract
Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 × 10(-63)], CBS [p = 3.15 × 10(-26)], CPS1 [p = 9.10 × 10(-13)], ALDH1L1 [p = 7.3 × 10(-13)] and PSPH [p = 1.17 × 10(-16)]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.