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

Authors

  • PETCH WACHARASINT,

    1. University of British Columbia, Critical Care Research Laboratories, Institute for Heart+Lung Health, St. Paul's Hospital, Vancouver, BC, Canada
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  • TAKA-AKI NAKADA,

    1. University of British Columbia, Critical Care Research Laboratories, Institute for Heart+Lung Health, St. Paul's Hospital, Vancouver, BC, Canada
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  • JOHN H. BOYD,

    1. University of British Columbia, Critical Care Research Laboratories, Institute for Heart+Lung Health, St. Paul's Hospital, Vancouver, BC, Canada
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  • JAMES A. RUSSELL,

    1. University of British Columbia, Critical Care Research Laboratories, Institute for Heart+Lung Health, St. Paul's Hospital, Vancouver, BC, Canada
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  • KEITH R. WALLEY

    Corresponding author
    1. University of British Columbia, Critical Care Research Laboratories, Institute for Heart+Lung Health, St. Paul's Hospital, Vancouver, BC, Canada
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Keith R. Walley, Institute for Heart+Lung Health, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Email: keith.walley@hli.ubc.ca

ABSTRACT

Background and 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 PaO2/FiO2 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 PaO2/FiO2 < 200. IL-8 mRNA expression was measured in genotyped lymphoblastoid cells in vitro.

Results:  The frequency of the patients with PaO2/FiO2 <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 PaO2/FiO2 <200. The AA genotype was associated with greater IL-8 mRNA expression than the AT or TT genotypes.

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