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

ABSTRACT: 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.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.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.

SUBMITTER: Weiss SL

PROVIDER: S-EPMC3299781 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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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 SL Yu Min M Jennings Lawrence L Haymond Shannon S Zhang Gang G Wainwright Mark S MS

PloS one 20120312 3

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>In a prospective study, blo ...[more]

PMID: 22428028

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Project description:BACKGROUND:While the process of sepsis-induced immunosuppression is now well described in adults, very little information is available on immune functions in pediatric sepsis. The current study investigated this in children with septic shock by performing immunomonitoring, including both innate (monocyte human leukocyte antigen-DR, mHLA-DR, expression) and adaptive immunity (lymphocyte subsets count), as well as cytokine concentrations (IL-6, IL-8, IL-10, IL-1Ra, TNF-?, IFN-?). Subsequent objectives were to assess the associations between inflammatory response, potential immunosuppression and secondary acquired infection occurrence. METHODS:Single-center prospective observational study, including children aged between 1 month and 18 years admitted to pediatric intensive care unit (PICU) for septic shock. Age-matched controls were children hospitalized for elective surgery without any infectious criteria. Blood was sampled at day 1-2, 3-5, and 7-9 after sepsis onset. mHLA-DR and lymphocyte subsets count were measured by flow cytometry and cytokine concentrations by Luminex technology. RESULTS:A total of 26 children and 30 controls were included. Patients had lymphopenia, and mHLA-DR levels were significantly lower than controls at each time point (p?<?0.0001). All cytokines peaked at day 1-2. Children with secondary acquired infection had lower day 3-5 mHLA-DR and higher pro-inflammatory cytokine concentrations (IL-6, IL-8 and TNF-?) at day 1-2 compared to children without secondary acquired infection. CONCLUSIONS:The higher initial inflammatory cytokine production was, the more innate immunity was altered, while evaluated by low mHLA-DR expression. Children with decreased mHLA-DR expression developed more secondary acquired infections. Upon confirmation in multicenter cohorts, these results pave the way for immunostimulation for the most immunosuppressed children in order to prevent nosocomial infections in PICU. Trial registration PedIRIS study NCT02848144. Retrospectively registered 28 July 2016.

Project description:Background and objectivesLevels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase, are elevated in kidney disease and associated with mortality in white European hemodialysis populations. Nitric oxide production and degradation are partially genetically determined and differ by racial background. No studies have measured asymmetric dimethylarginine in African Americans on dialysis and assessed whether differences exist in its association with mortality by race.Design, setting, participants, & measurementsAsymmetric dimethylarginine was measured in 259 patients on maintenance hemodialysis assembled from 2004 to 2012 in Boston area outpatient centers. Cox proportional hazards models were used to determine the association between asymmetric dimethylarginine and all-cause mortality, and an interaction with race was tested.ResultsMean (SD) age was 63 (17) years, 46% were women, and 22% were African American. Mean asymmetric dimethylarginine in non-African Americans was 0.79 µmol/L (0.16) versus 0.70 µmol/L (0.11) in African Americans (P<0.001); 130 patients died over a median follow-up of 2.3 years. African Americans had lower mortality risk than non-African Americans (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.50) that was robust to adjustment for age, comorbidity, and asymmetric dimethylarginine (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.69). An interaction was noted between race and asymmetric dimethylarginine (P=0.03), such that asymmetric dimethylarginine was associated with higher mortality in non-African Americans (adjusted hazard ratio, 1.29; 95% confidence interval, 1.06 to 1.57 per 1 SD higher asymmetric dimethylarginine) but not in African Americans (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28 to 1.18). Additional adjustment for fibroblast growth factor 23 partially attenuated the association for non-African Americans (adjusted hazard ratio, 1.22; 95% confidence interval, 0.98 to 1.50).ConclusionsAfrican Americans have lower asymmetric dimethylarginine levels and lower hazard for mortality compared with non-African Americans. Levels of asymmetric dimethylarginine did not explain lower hazard for mortality in non-African American patients. High asymmetric dimethylarginine was a risk factor for mortality exclusively in non-African Americans. Mechanisms explaining these relationships need to be evaluated.

Dataset Information

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

Publications

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

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