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

Nicole Lüneburg et al. Circ Cardiovasc Genet. 2014 Dec.

Abstract

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 population-based 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.

Keywords: biological markers; genome wide association study; nitric oxide.

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Conflict of interest statement

Disclosures.

The authors declare that there is no conflict of interest regarding the publication of this article.

Figures

Figure 1
Figure 1. Results of the computerized 3D structure analysis of AGXT2
a) Three-dimensional model of human AGXT2, which in the absence of a known crystal structure of this enzyme itself was based on the crystal structure of dialkylglycine decarboxylase (PDB code; 1D7R), which shares 50% sequence homology to human AGXT2. The subunits A and B of the homodimeric protein are colored in blue and red respectively, and are shown in a backbone ribbon presentation. The substrate SDMA and the cofactor pyridoxal phosphate (PLP) are highlighted as yellow sticks. The sites of mutation detected in the present study are shown in space-filled presentation for subunit A. Note that V140 from subunit A deeply penetrates into subunit B and is located close to the active site of subunit B. Location of the residue 140 in wildtype b) and V140I-mutant c) AGXT2. Residue 140 of subunit B and the adjacent Q83 of subunit A are shown in space-filled presentation, and colored by atom-type and in orange, respectively. The SDMA substrate and the PLP cofactor are shown in stick presentation and their spatial requirement is indicated by a yellow translucent surface. The green arrows in c) mark clashes of I140 with Q83 and with one N-methyl group of SDMA, which are not present in the wildtype. The thickness of the arrows reflects the relative magnitude of the clashes.
Figure 1
Figure 1. Results of the computerized 3D structure analysis of AGXT2
a) Three-dimensional model of human AGXT2, which in the absence of a known crystal structure of this enzyme itself was based on the crystal structure of dialkylglycine decarboxylase (PDB code; 1D7R), which shares 50% sequence homology to human AGXT2. The subunits A and B of the homodimeric protein are colored in blue and red respectively, and are shown in a backbone ribbon presentation. The substrate SDMA and the cofactor pyridoxal phosphate (PLP) are highlighted as yellow sticks. The sites of mutation detected in the present study are shown in space-filled presentation for subunit A. Note that V140 from subunit A deeply penetrates into subunit B and is located close to the active site of subunit B. Location of the residue 140 in wildtype b) and V140I-mutant c) AGXT2. Residue 140 of subunit B and the adjacent Q83 of subunit A are shown in space-filled presentation, and colored by atom-type and in orange, respectively. The SDMA substrate and the PLP cofactor are shown in stick presentation and their spatial requirement is indicated by a yellow translucent surface. The green arrows in c) mark clashes of I140 with Q83 and with one N-methyl group of SDMA, which are not present in the wildtype. The thickness of the arrows reflects the relative magnitude of the clashes.
Figure 1
Figure 1. Results of the computerized 3D structure analysis of AGXT2
a) Three-dimensional model of human AGXT2, which in the absence of a known crystal structure of this enzyme itself was based on the crystal structure of dialkylglycine decarboxylase (PDB code; 1D7R), which shares 50% sequence homology to human AGXT2. The subunits A and B of the homodimeric protein are colored in blue and red respectively, and are shown in a backbone ribbon presentation. The substrate SDMA and the cofactor pyridoxal phosphate (PLP) are highlighted as yellow sticks. The sites of mutation detected in the present study are shown in space-filled presentation for subunit A. Note that V140 from subunit A deeply penetrates into subunit B and is located close to the active site of subunit B. Location of the residue 140 in wildtype b) and V140I-mutant c) AGXT2. Residue 140 of subunit B and the adjacent Q83 of subunit A are shown in space-filled presentation, and colored by atom-type and in orange, respectively. The SDMA substrate and the PLP cofactor are shown in stick presentation and their spatial requirement is indicated by a yellow translucent surface. The green arrows in c) mark clashes of I140 with Q83 and with one N-methyl group of SDMA, which are not present in the wildtype. The thickness of the arrows reflects the relative magnitude of the clashes.
Figure 2
Figure 2. AGXT2 overexpression in human embryonic kidney cells
Degradation of stable isotope labeled d6-SDMA by HEK cells overexpressing wildtypeAGXT2 in comparison to HEK cells overexpressing the AGXT2 rs37369 variant and control cells transfected with empty pcDNA3.1 vector. n=10 in each group; (two-tailed t-test; *P=0.006)
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