title: Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients.
abstract: BACKGROUND
  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-α 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.
authors.affiliation: *Department of Pharmacology and Toxicology †Intensive Care Medicine ‡Internal Medicine §Human Genetics ¶Anesthesiology ||Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands #4th Department of Internal Medicine, University of Athens, Medical School, Athens **Intensive Care Unit, "G. Gennimatas" General Hospital, Thessaloniki ††1st Department of Critical Care Medicine, University of Athens, Medical School ‡‡Intensive Care Unit, Tzaneion General Hospital of Piraeus §§Department of Respiratory Medicine, "Sismanogleion" General Hospital ¶¶Department of Therapeutics, Alexandra General Hospital ||||1st Department of Propedeutic Surgery, University of Athens, Medical School, Athens, Greece.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Ramakers
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.forename: Chronis
authors.initials: C
authors.lastname: Tasioudis
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Groothuismink
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Christina
authors.initials: C
authors.lastname: Routsi
authors.forename: Athina
authors.initials: A
authors.lastname: Savva
authors.forename: Athanassios
authors.initials: A
authors.lastname: Prekates
authors.forename: Filia
authors.initials: F
authors.lastname: Diamantea
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Sinapidis
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Toutouzas
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
mesh_terms: D000659:AMP Deaminase / Q000235:genetics*; D000241:Adenosine / Q000737:chemistry; D000368:Aged; D017714:Community-Acquired Infections / Q000453:epidemiology; D003422:Critical Care; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007107:Immune System; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D007239:Infections / Q000628:therapy; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D009102:Multiple Organ Failure / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D011014:Pneumonia / Q000453:epidemiology; D053717:Pneumonia, Ventilator-Associated / Q000453:epidemiology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000401:mortality
chemical_list: D016207:Cytokines; D000659:AMP Deaminase; C514117:AMPD1 protein, human; D000241:Adenosine