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Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.
Circ. Cardiovasc. Genet. 7, 864-872 (2014)
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BACKGROUND: -Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers. METHODS AND RESULTS: -This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (FHS (n=2992), GHS (n=4354) and MONICA/KORA F3 (n=581)) and identified replicated loci (DDAH1, MED23, Arg1 and AGXT2) associated with the inter-individual variability in ADMA, L-arginine and SDMA. Experimental in-silico and in-vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants and various cardiometabolic risk factors. AGXT2 variants were not associated with post-stroke survival in the Leeds study, nor were they associated with incident stroke in the CHARGE consortium. CONCLUSIONS: -These GWAS support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and L-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Genome Wide Association Study ; Biomarker ; Endothelial Function ; Nitric Oxide
Language
english
Publication Year
2014
HGF-reported in Year
2014
ISSN (print) / ISBN
1942-325X
e-ISSN
1942-3268
Quellenangaben
Volume: 7,
Issue: 6,
Pages: 864-872
Publisher
Lippincott Williams & Wilkins
Publishing Place
Hagerstown, Md
Reviewing status
Peer reviewed
Institute(s)
Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
Institute of Epidemiology (EPI)
POF-Topic(s)
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
30202 - Environmental Health
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-504100-001
G-504091-001
G-504000-006
G-504000-007
G-504090-001
G-504091-001
G-504000-006
G-504000-007
G-504090-001
PubMed ID
25245031
WOS ID
WOS:000346358800017
Erfassungsdatum
2014-09-25