title: Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, Tampere University School of Medicine, Finn-Medi 2, 3rd floor, PO Box 2000, Tampere FI-33521, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.forename: Jussi A
authors.initials: JA
authors.lastname: Hernesniemi
authors.forename: Kari-Matti
authors.initials: KM
authors.lastname: Mäkelä
authors.forename: Niku
authors.initials: N
authors.lastname: Oksala
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.forename: Stefan
authors.initials: S
authors.lastname: Pilz
authors.forename: Andreas
authors.initials: A
authors.lastname: Tomaschitz
authors.forename: Günther
authors.initials: G
authors.lastname: Silbernagel
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Tanja B
authors.initials: TB
authors.lastname: Grammer
authors.forename: Tuomas
authors.initials: T
authors.lastname: Koskinen
authors.forename: Markus
authors.initials: M
authors.lastname: Juonala
authors.forename: Nina
authors.initials: N
authors.lastname: Hutri-Kähönen
authors.forename: Georg
authors.initials: G
authors.lastname: Alfthan
authors.forename: Jorma S A
authors.initials: JS
authors.lastname: Viikari
authors.forename: Mika
authors.initials: M
authors.lastname: Kähonen
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinitzer
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
mesh_terms: D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000637:Transaminases / Q000235:genetics* / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C000592571:Slc25a45 protein, human; C487735:dimethylarginine; D001120:Arginine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase
keywords: Asymmetric dimethylarginine; Genetics; Genome-wide association study; Heart rate variability; Mortality; Sudden cardiac death; Symmetric dimethylarginine