title: Pilot study of the association of the DDAH2 -449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis.
abstract: BACKGROUND
  Genetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock.
  
  
  RESULTS
  In a prospective study, blood and buccal swabs were obtained from 82 patients ≤ 18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the -871 6g/7 g insertion/deletion and -449G/C single nucleotide polymorphisms. Shock type ("warm" versus "cold") was characterized by clinical assessment. The -871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between -871 6g/7 g genotypes. While genotype frequencies also did not vary between groups for the -449G/C SNP (p = 0.75), septic patients with at least one -449G allele had lower ADMA (median, IQR 0.36, 0.30-0.41 µmol/L) than patients with the -449CC genotype (0.55, 0.49-0.64 µmol/L, p = 0.008) and exhibited a higher incidence of "cold" shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration.
  
  
  CONCLUSIONS
  The -449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with "cold" shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology.
authors.affiliation: Division of Critical Care, Department of Pediatrics, Children's Memorial Hospital, Northwestern Feinberg School of Medicine, Chicago, Illinois, United States of America. WeissS@email.chop.edu
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Lawrence
authors.initials: L
authors.lastname: Jennings
authors.forename: Shannon
authors.initials: S
authors.lastname: Haymond
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wainwright
mesh_terms: D000293:Adolescent; D000581:Amidohydrolases / Q000235:genetics*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001483:Base Sequence; D002648:Child; D017931:DNA Primers / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D044469:Racial Groups / Q000235:genetics; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D012772:Shock, Septic / Q000235:genetics* / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase