Abstract 12560: Genome-Wide Association Study of Dimethylarginines Reveals Novel Metabolic Pathway for SDMA
Background: Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and cellular L-arginine uptake into the cell (both ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a novel cardiovascular risk marker wheras SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. Due to the prognostic importance of ADMA and SDMA, identifying the enviromental and genetic factors contributing to interindividual variability of these biomarkers is a key. Genome-wide association studies (GWAS) provide a tool to investigate the genetic contributions to biomarker variability.
Methods: Whole genome scan in the community-based Offspring Cohort of the Framingham Heart Study (FHS) (n=2992), the Gutenberg Heart Study (GHS) (n=3175) and the KORA/MONICA F3 cohort (n=581) was used to identify genetic variations associated with plasma concentrations of DMA. A candidate-gene approach was used to genotype 371 patients of the LEEDS-stroke cohort. DMA levels were measured by using a fully validated high throughput LC-MS/MS assay.
Results: ADMA plasma concentrations were associated with various SNPs at a locus on chromosome 1p22 including DDAH1 (p=2.4x10-9-6.3x10-23), the ADMA degrading enzyme. SDMA concentrations were associated with several SNPs at a locus on chromosome 5p13. The p-values for all hits showed strong genome-wide significance (p=2.9x10-30- 3.5x10-9). This locus includs the AGXT2 gene that encodes one of the two mitochondrial alanine-glyoxylate-aminotransferases mainly expressed in the kidney and liver. In a cohort including 371 patients with ischemic stroke statistically differences between AGXT2 genotypes and different subtypes of ischemic stroke were found.
Conclusion: The strong association of SDMA and AGXT2 disclose a new elimination pathway of SDMA. The AGXT2 genotype is associated with different subtypes of ischemic stroke, underscoring the potential role of SDMA as a risk marker in stroke. Furthermore the GWAS support the importance of DDAH1 in regulating ADMA metabolism.
- © 2011 by American Heart Association, Inc.