(1575) A Single Nucleotide Variant of TMEM100 Is Linked to Higher Odds of Pediatric Septic Shock Mortality

Introduction: Sepsis is a burdensome health problem and sepsis-associated acute respiratory distress syndrome (SA-ARDS) is a significant contributor to morbidity and mortality among children admitted to the pediatric ICU. Yet, current therapies for SA-ARDS are largely supportive. A better understanding of the pathobiology underlying SA-ARDS may facilitate targeted therapeutic interventions that improve clinical outcomes among those critically ill. TMEM100 is a gene that is highly expressed by lung endothelial cells, especially in response to inflammatory stimuli, and is essential for vascular integrity and repair after injury. We sought to test the hypothesis that genetic variants of TMEM100 would be independently associated with greater risk for poor clinical outcomes, including development of SA-ARDS, in pediatric patients with septic shock.

Methods: We utilized biobanked whole blood DNA samples from a multi-center cohort of pediatric septic shock patients. We conducted qualitative PCR using TaqMan Genotyping primers targeting 3 upstream transcript single nucleotide variants (SNVs) of TMEM100 (rs3760281, rs13380799, and rs8079126) with minor allelic frequencies >25%. We tested whether SNVs of interest were associated with increased sepsis mortality and SA-ARDS after accounting for covariates using logistic regression.

Results: We genotyped 242 critically ill pediatric patients. None of the 3 SNVs were in Hardy Weinberg Equilibrium (p < 0.001). Patients carrying at least one TMEM100 rs3760281 mutant allele had a significantly increased odds of 28-day mortality (Adjusted Odds Ratio 5.3, 95% CI 1.6-7.4, P=0.007) and a trend toward increased risk of persistent respiratory dysfunction (Adjusted Odds Ratio 1.7, CI 0.9-3.1, P=0.082) in models adjusted for age, sex, PRISM-III score, and presence of comorbidity. The other two SNVs were not associated with clinical outcomes of interest.

Conclusions: We identified that pediatric septic shock patients carrying at least one mutant allele of rs3760281 variant of TMEM100 gene had an increased odds of 28-day mortality and a trend toward day persistent respiratory dysfunction. Further research is necessary to identify whether this association represents a ‘treatable trait’ among critically ill children that is amenable to therapeutic modulation.