Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients.

Abstract

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. 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. 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-α by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. 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.