Pilot study of the association of the DDAH2-449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis

Scott L. Weiss, Min Yu, Lawrence J Jennings, Shannon Haymond, Gang Zhang, Mark Wainwright

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. Methodology/Principal Findings: 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/7g 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/7g 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/Significance: 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.

Original languageEnglish (US)
Article numbere33355
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 12 2012

Fingerprint

sepsis (infection)
Pediatrics
Hemodynamics
hemodynamics
Polymorphism
Shock
Sepsis
genetic polymorphism
septic shock
cold stress
fever
nitric oxide
genotype
Genotype
Septic Shock
alleles
Plasmas
Single Nucleotide Polymorphism
Nitric Oxide
Fever

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

@article{2a1ce3d03bfc43ba957fb939fcbdc471,
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. Methodology/Principal Findings: 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/7g 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/7g 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/Significance: 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.",
author = "Weiss, {Scott L.} and Min Yu and Jennings, {Lawrence J} and Shannon Haymond and Gang Zhang and Mark Wainwright",
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Pilot study of the association of the DDAH2-449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis. / Weiss, Scott L.; Yu, Min; Jennings, Lawrence J; Haymond, Shannon; Zhang, Gang; Wainwright, Mark.

In: PLoS One, Vol. 7, No. 3, e33355, 12.03.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pilot study of the association of the DDAH2-449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis

AU - Weiss, Scott L.

AU - Yu, Min

AU - Jennings, Lawrence J

AU - Haymond, Shannon

AU - Zhang, Gang

AU - Wainwright, Mark

PY - 2012/3/12

Y1 - 2012/3/12

N2 - 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. Methodology/Principal Findings: 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/7g 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/7g 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/Significance: 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.

AB - 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. Methodology/Principal Findings: 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/7g 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/7g 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/Significance: 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.

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