AA genotype of IL-8 -251A/T is associated with low PaO(2)/FiO(2) in critically ill patients and with increased IL-8 expression.
OBJECTIVE
Interleukin-8 (IL-8) is a central chemokine in acute respiratory distress syndrome (ARDS), and the IL-8 gene contains a functional single nucleotide polymorphism (SNP) -251A/T in its promoter region. We hypothesized that IL-8 -251A/T SNP is associated with PaO(2)/FiO(2) in critically ill patients.


METHODS
We conducted genetic-association studies in intensive care units at academic teaching centres using a derivation septic shock cohort (vasopressin and septic shock trial (VASST), n = 467) and a validation post-cardiopulmonary bypass surgery cohort (CPB, n = 739) of Caucasian patients. Patients in both cohorts were genotyped for IL-8 -251A/T. The primary outcome variable in both cohorts was the fraction of patients who had a PaO(2) /FiO(2) < 200. IL-8 mRNA expression was measured in genotyped lymphoblastoid cells in vitro.


RESULTS
The frequency of the patients with PaO(2)/FiO(2) <200 was significantly greater in patients who had the AA genotype of -251A/T than in patients who had the AT or TT genotypes in both VASST (AA = 60.8% vs AT and TT = 53.8% and 48.0%, P = 0.038) and the CPB cohort (AA = 37.0% vs AT and TT = 27.0% and 26.0%, P = 0.039). Patients having the AA genotype had a higher probability to remain on mechanical ventilation (P = 0.047) in the first 14 days. Lymphoblastoid cells having the AA genotype had significantly higher IL-8 mRNA expression than cells having the AT or TT genotype (P = 0.022).


CONCLUSIONS
Critically ill Caucasian patients who had the AA genotype of IL-8 -251A/T had an increased risk of PaO(2)/FiO(2) <200. The AA genotype was associated with greater IL-8 mRNA expression than the AT or TT genotypes.
University of British Columbia, Critical Care Research Laboratories, Institute for Heart+Lung Health, St. Paul's Hospital, Vancouver, BC, Canada.
Petch
P
Wacharasint
Taka-aki
TA
Nakada
John H
JH
Boyd
James A
JA
Russell
Keith R
KR
Walley
D000368:Aged; D002315:Cardiopulmonary Bypass; D002478:Cells, Cultured; D015331:Cohort Studies; D016638:Critical Illness; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007362:Intensive Care Units; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000235:genetics / Q000503:physiopathology / Q000601:surgery / Q000628:therapy
C508606:CXCL8 protein, human; D016209:Interleukin-8; D010100:Oxygen