AA genotype of IL‐8 −251A/T is associated with low PaO2/FiO2 in critically ill patients and with increased IL‐8 expression

Abstract

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. 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. 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). 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.