TY - JOUR
T1 - Genome-wide association study of l-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine
AU - Lüneburg, Nicole
AU - Lieb, Wolfgang
AU - Zeller, Tanja
AU - Chen, Ming Huei
AU - Maas, Renke
AU - Carter, Angela M.
AU - Xanthakis, Vanessa
AU - Glazer, Nicole L.
AU - Schwedhelm, Edzard
AU - Seshadri, Sudha
AU - Ikram, Mohammad Arfan
AU - Longstreth, William T.
AU - Fornage, Myriam
AU - König, Inke R.
AU - Loley, Christina
AU - Ojeda, Francisco M.
AU - Schillert, Arne
AU - Wang, Thomas J.
AU - Sticht, Heinrich
AU - Kittel, Anja
AU - König, Jörg
AU - Benjamin, Emelia J.
AU - Sullivan, Lisa M.
AU - Bernges, Isabel
AU - Anderssohn, Maike
AU - Ziegler, Andreas
AU - Gieger, Christian
AU - Illig, Thomas
AU - Meisinger, Christa
AU - Wichmann, H. Erich
AU - Wild, Philipp S.
AU - Schunkert, Heribert
AU - Psaty, Bruce M.
AU - Wiggins, Kerri L.
AU - Heckbert, Susan R.
AU - Smith, Nicholas
AU - Lackner, Karl
AU - Lunetta, Kathryn L.
AU - Blankenberg, Stefan
AU - Erdmann, Jeanette
AU - Munzel, Thomas
AU - Grant, Peter J.
AU - Vasan, Ramachandran S.
AU - Böger, Rainer H.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Background-Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [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 characterize the environmental and genetic contributions to interindividual variability of these biomarkers. Methods and Results-This study comprised a genome-wide association analysis of 3 well-characterized populationbased cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual 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 poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Conclusions-These genome-wide association study 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.
AB - Background-Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [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 characterize the environmental and genetic contributions to interindividual variability of these biomarkers. Methods and Results-This study comprised a genome-wide association analysis of 3 well-characterized populationbased cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual 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 poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Conclusions-These genome-wide association study 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.
UR - http://www.scopus.com/inward/record.url?scp=84925876908&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.113.000264
DO - 10.1161/CIRCGENETICS.113.000264
M3 - Journal articles
C2 - 25245031
AN - SCOPUS:84925876908
SN - 1942-325X
VL - 7
SP - 864
EP - 872
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 6
ER -
