ArticleThe Journal of clinical investigation2007
Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk.
Article in The Journal of clinical investigation, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis 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
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 90 citations in OpenAlex.
- Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration.Neurology · 2016Pooled it
- Ferroptosis and head and neck cancer: Mechanisms and therapeutic perspectives (Review).International journal of molecular medicine · 2025Review
- The Role of GCH1 Deficiency and Tetrahydrobiopterin in Mental Health.International journal of molecular sciences · 2025Article
- Genetics of ischemic stroke functional outcome.Journal of neurology · 2024Review
- Endothelial cell-specific roles for tetrahydrobiopterin in myocardial function, cardiac hypertrophy, and response to myocardial ischemia-reperfusion injury.American journal of physiology. Heart and circulatory physiology · 2023Article
- Marginal BH4 deficiencies, iNOS, and self-perpetuating oxidative stress in post-acute sequelae of Covid-19.Medical hypotheses · 2022Article
- Novel Immune-Related Ferroptosis Signature in Esophageal Cancer: An Informatics Exploration of Biological Processes Related to the TMEM161B-AS1/hsa-miR-27a-3p/GCH1 Regulatory Network.Frontiers in genetics · 2022Article
- Oxidative Stress, GTPCH1, and Endothelial Nitric Oxide Synthase Uncoupling in Hypertension.Antioxidants & redox signaling · 2021Review
- Chiropractic care for hypertension: Review of the literature and study of biological and genetic bases.Acta bio-medica : Atenei Parmensis · 2020Review
- GCH1 haplotypes and cardiovascular risk in HIV.AIDS (London, England) · 2019Article
- Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their RegulationPhysiological reviews · 2019Review
- A machine-learned analysis of human gene polymorphisms modulating persisting pain points to major roles of neuroimmune processes.European journal of pain (London, England) · 2018Article
- Oxidative stress induces BHBioscience reports · 2018Article
- Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Development of an AmpliSeqFrontiers in pharmacology · 2018Article
- A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin-deficient mice.British journal of pharmacology · 2017Article
- Nucleotide Variants of the BH4 Biosynthesis Pathway Gene GCH1 and the Risk of Orofacial Clefts.Molecular neurobiology · 2016Article
- Isoflurane favorably modulates guanosine triphosphate cyclohydrolase-1 and endothelial nitric oxide synthase during myocardial ischemia and reperfusion injury in rats.Anesthesiology · 2015Article
- Tetrahydrobiopterin in cardiovascular health and disease.Antioxidants & redox signaling · 2014Review
- Human heart rate: heritability of resting and stress values in twin pairs, and influence of genetic variation in the adrenergic pathway at a microribonucleic acid (microrna) motif in the 3'-UTR of cytochrome b561 [corrected].Journal of the American College of Cardiology · 2014Article
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
Abstract
GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants' contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3'-untranslated region (3'-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3'-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension.
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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.