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Modulation of cystic fibrosis lung disease by variants in interleukin-8

Genes & Immunity volume 9, pages 501–508 (2008)Cite this article

Abstract

Cystic fibrosis pulmonary disease is characterized by excessive and prolonged inflammation. CF Pulmonary disease severity exhibits considerable variation that, to some extent, appears to be due to the presence of modifier genes. Several components of the inflammatory response are known to have altered regulation in the CF lung. Genetic variants in 52 inflammatory genes were tested for associations with lung disease indices in a CF patient population (n=737) homozygous for the ΔF508 cystic fibrosis transmembrane conductance regulator mutation. Variants in three inflammatory genes showed significant genotypic associations with CF lung disease severity, including IL8 and previously reported TGFβ1 (P⩽0.05). When analyzed by gender, it was apparent that IL8 variant associations were predominantly due to males. The IL8 variants were tested in an additional CF population (n=385) and the association in males verified (P⩽0.01). The IL8 variants were in strong linkage disequilibrium with each other (R2⩾0.82), while variants in neighboring genes CXCL6, RASSF6 and PF4V1 did not associate (P⩾0.26) and were in weaker LD with each other and with the IL8 variants (0.01⩽R2⩽0.49). Studies revealed differential expression between the IL8 promoter variant alleles (P<0.001). These results suggest that IL8 variants modify CF lung disease severity and have functional consequences.

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Acknowledgements

This work was supported by NIH Grants HL68890, P30 DK27651, T32 HL07515, DK066368 GCRC RR00046 and grants from the Cystic Fibrosis Foundation.

Author information

Author notes

  1. D Londono

    Present address: 6Current address: Rockefeller University, New York, NY, USA.,

  2. K A B Goddard

    Present address: 7Current address: The Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.,

  3. M L Drumm: Reporting for the CF Gene Modifier Study Group.

Authors and Affiliations

  1. Department of Genetics, Case Western Reserve University, Cleveland, OH, USA

    A D Hillian & M L Drumm

  2. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA

    D Londono & K A B Goddard

  3. Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH, USA

    J M Dunn & M L Drumm

  4. Cystic Fibrosis Pulmonary Research Treatment Center, University of North Carolina, Chapel Hill, NC, USA

    R G Pace & M R Knowles

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  1. A D Hillian
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Correspondence to M L Drumm.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Hillian, A., Londono, D., Dunn, J. et al. Modulation of cystic fibrosis lung disease by variants in interleukin-8. Genes Immun 9, 501–508 (2008). https://doi.org/10.1038/gene.2008.42

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