IRAK1 functional genetic variant affects severity of septic shock.
OBJECTIVE
Excessive inflammation is closely related to severity and outcome of sepsis. Because interleukin-1-receptor-associated kinase 1 is a key signaling protein in the activation of NF-κB during infection, we aimed to evaluate the effect of functionally relevant haplotypes of IRAK1 on severity, development of acute lung injury, and mortality in septic shock.


METHODS
Prospective, observational, cohort study.


METHODS
Three medical intensive care units in three French university hospitals.


METHODS
Eight hundred forty-three Caucasian patients with septic shock and 800 sex-matched Caucasian control subjects were enrolled.


METHODS
Patients were genotyped for the IRAK1-1595C/T polymorphism, which tagged the IRAK1 functional haplotype.


RESULTS
No significant differences in IRAK1 genotypes were seen between patients and control subjects. Among the septic shock group, the IRAK1 variant haplotype was significantly associated with the need for prolonged mechanical ventilation (p=.02). In a prespecified subgroup, this genetic risk was most severe in the youngest patients (age<65 yrs, p=.005). Furthermore, in the more severe subgroup of patients, a higher mortality rate was found in patients carrying the IRAK-1 variant haplotype as compared with the wild type (p=.02) (odds ratio, 2.1; 95% confidence interval, 1.1-4.8).


CONCLUSIONS
The IRAK1 variant haplotype is associated with prolonged ventilation in septic shock. In the future, the IRAK1-1595C/T polymorphism might be included in scores such as PIRO (predisposition, insult, response, and organ dysfunction) to adapt preventive and therapeutic interventions in the intensive care unit.
Toubiana
Julie
J
Université Paris Descartes, Faculté de médecine, Cochin Institute, INSERM U567, CNRS UMR 8104, the Medical Intensive Care Unit, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, Paris France.
Courtine
Emilie
E
Pène
Frédéric
F
Viallon
Vivian
V
Asfar
Pierre
P
Daubin
Cédric
C
Rousseau
Christophe
C
Chenot
Claire
C
Ouaaz
Fatah
F
Grimaldi
David
D
Cariou
Alain
A
Chiche
Jean-Daniel
JD
Mira
Jean-Paul
JP
D018806:APACHE; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007362:Intensive Care Units; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000235:genetics* / Q000401:mortality / Q000628:therapy
D005819:Genetic Markers; D053592:Interleukin-1 Receptor-Associated Kinases