Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality

Eur Heart J. 2014 Feb;35(8):524-31. doi: 10.1093/eurheartj/eht447. Epub 2013 Oct 24.


Aims: The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality.

Methods and results: We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10(-40) and rs16899974; P = 1.5 × 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 × 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography.

Conclusions: AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.

Keywords: Asymmetric dimethylarginine; Genetics; Genome-wide association study; Heart rate variability; Mortality; Sudden cardiac death; Symmetric dimethylarginine.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arginine / analogs & derivatives*
  • Arginine / genetics
  • Arginine / metabolism
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / mortality
  • Death, Sudden, Cardiac / etiology
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Mitochondrial Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Transaminases / genetics*
  • Transaminases / physiology


  • Membrane Proteins
  • Mitochondrial Proteins
  • Slc25a45 protein, human
  • dimethylarginine
  • Arginine
  • Transaminases
  • Alanine-glyoxylate transaminase