Original article
IL6 gene-wide haplotype is associated with susceptibility to acute lung injury

https://doi.org/10.1016/j.trsl.2008.05.006Get rights and content

Experimental and clinical studies support the key role of interleukin 6 (IL-6), a potent proinflammatory cytokine, in the development of acute lung injury (ALI). Plasma IL-6 levels are influenced mainly by genetic determinants, and a −174G/C polymorphism of the gene has been recently associated with susceptibility to ALI. Here we aimed to validate the association of the IL6 gene with ALI in a case-control sample from Spain. DNA was isolated from 67 consecutive patients who fulfilled international criteria for severe sepsis and for ALI and 96 population-based controls drawn from the general population. Genotypes of the −174G/C polymorphism along with other 14 tagging variants of the IL6 gene were evaluated. Twenty polymorphisms unlinked to IL6 gene were additionally compared between cases and controls to rule out population stratification. None of the individual single-nucleotide polymorphisms was significantly associated with susceptibility to ALI. However, we found that a common haplotype from −1363 to +4835 from the transcription start site, and spanning the gene, conferred risk for susceptibility to ALI (odds ratio, 2.73; 95% confidence interval, 1.39–5.37; P = 0.003). Adjustment for relevant covariates did not modify this result. These data support the association of the IL6 gene with ALI susceptibility and illustrate the value of haplotype analysis as a robust approach for evaluating IL6 gene effects in association studies.

Section snippets

Subjects, definitions, and study design

This study was approved by the Hospital Universitario N.S. de Candelaria (Canary Islands, Spain) Ethics Committee. The association of IL6 gene variants with ALI was evaluated using a European case-control sample that included 96 population-based controls drawn from a large representative cohort of the general population.24 Patients with severe sepsis derived-ALI were admitted into the postsurgical and intensive care units of the hospital. Patients were admitted within 24 h of the diagnosis of

Results

A total of 67 patients who fulfilled the criteria for severe sepsis and ALI were enrolled in the study. Demographic and clinical features from patients and controls are summarized in Table I. The overall ICU mortality was 44.1%.

The −174G/C SNP was not significantly associated with ALI in this sample of sepsis-induced ALI patients, which demonstrated an unadjusted odds ratio (OR) of 1.09 [95% confidence interval (CI), 0.66–1.80; P = 0.73] (Table II). After testing an additional set of 14 IL6

Discussion

We attempted to replicate prior associations of IL6 gene with ALI susceptibility using similar numbers of case-control samples.19, 20, 21 Unlike 2 of these studies,19, 21 we did not find −174G/C SNP to be individually associated with ALI. The other 14 tSNPs of the gene also were not significantly associated with ALI, and an exploration of different genotype-based tests did not alter this result as the best uncorrected P-value obtained was 0.049 (for the SNP at −572 in a codominant model), which

References (45)

  • J. Michalek et al.

    Interleukin-6 gene variants and the risk of sepsis development in children

    Hum Immunol

    (2007)
  • G.R. Bernard et al.

    The American-European Consensus Conference on ARDSDefinitions, mechanisms, relevant outcomes, and clinical trial coordination

    Am J Respir Crit Care Med

    (1994)
  • G.D. Rubenfeld et al.

    Incidence and outcomes of acute lung injury

    N Engl J Med

    (2005)
  • D.R. Prows et al.

    Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice

    Nat Genet

    (1997)
  • D.R. Prows et al.

    Quantitative trait analysis of nickel-induced acute lung injury in mice

    Am J Respir Cell Mol Biol

    (2001)
  • J.F. Pittet et al.

    Biological markers of acute lung injury: prognostic and pathogenetic significance

    Am J Respir Crit Care Med

    (1997)
  • D.N. Grigoryev et al.

    Orthologous gene-expression profiling in multi-species models: search for candidate genes

    Genome Biol

    (2004)
  • L.B. Ware

    Prognostic determinants of acute respiratory distress syndrome in adults: impact on clinical trial design

    Crit Care Med

    (2005)
  • W.Y. Park et al.

    Cytokine balance in the lungs of patients with acute respiratory distress syndrome

    Am J Respir Crit Care Med

    (2001)
  • A. Takala et al.

    A prospective study of inflammation markers in patients at risk of indirect acute lung injury

    Shock

    (2002)
  • V.M. Ranieri et al.

    Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome

    JAMA

    (2000)
  • M.A. Worns et al.

    Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels—a study in twins

    Genes Immun

    (2006)
  • Cited by (0)

    C.F. and S-F.M. contributed equally to this work.

    Supported by NHLBI HL58064 and HL 073994, by the Lowell Coggeshall Endowment, and by the Fundación Canaria Dr. Manuel Morales (to C.F.).

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