Effects of the 34c<T variant of the AMPD1 gene on immune function, multi-organ dysfunction, and mortality in sepsis patients

Abstract

Introduction: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C<T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. Methods: The effects of the presence of the 34C<T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n=285; replication cohort n=212) and ventilator-associated pneumonia (VAP, n=117; n=33) and control patients without infection (n=101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. Results: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P=0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P=0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P=0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-a by LPS-stimulated monocytes was attenuated (P=0.005), indicative of a more pronounced immunoparalytic state in these patients. Conclusions: Presence of the AMPD1 34C<T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation. © 2015 by the Shock Society