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Lüneburg, N.* ; Lieb, W.* ; Zeller, T.* ; Chen, M.H.* ; Maas, R.* ; Carter, A.M.* ; Xanthakis, V.* ; Glazer, N.L.* ; Schwedhelm, E.* ; Seshadri, S* ; Ikram, M.A.* ; Longstreth, W.T. Jr.* ; Fornage, M.* ; König, I.R.* ; Loley, C.* ; Ojeda, F.M.* ; Schillert, A.* ; Wang, T.J.* ; Sticht, H.* ; Kittel, A.* ; König, J.* ; Benjamin, E.J.* ; Sullivan, L.M.* ; Bernges, I.* ; Anderssohn, M.* ; Ziegler, A.* ; Gieger, C. ; Illig, T. ; Meisinger, C. ; Wichmann, H.-E. ; Wild, P.S.* ; Schunkert, H.* ; Psaty, B.M.* ; Wiggins, K.L.* ; Heckbert, S.R.* ; Smith, N.* ; Lackner, K.J.* ; Lunetta, K.L.* ; Blankenberg, S.* ; Erdmann, J.* ; Münzel, T.* ; Grant, P.J.* ; Vasan, R.S.* ; Böger, R.H.*

Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.

Circ. Cardiovasc. Genet. 7, 864-872 (2014)
Verlagsversion DOI
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Genome Wide Association Study ; Biomarker ; Endothelial Function ; Nitric Oxide
ISSN (print) / ISBN 1942-325X
e-ISSN 1942-3268
Quellenangaben Band: 7, Heft: 6, Seiten: 864-872 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Hagerstown, Md
Begutachtungsstatus Peer reviewed