1. ¹Department of Genetics, Case Western Reserve University, Cleveland, OH, USA
2. ²Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
3. ³Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH, USA
4. ⁴Cystic Fibrosis Pulmonary Research Treatment Center, University of North Carolina, Chapel Hill, NC, USA

Correspondence: Dr ML Drumm, Departments of Pediatrics and Genetics, Case Western Reserve University, 831 Biomedical Research Building, 10900 Euclid Avenue, Cleveland, OH 44106-4948, USA. E-mail: mitchell.drumm@case.edu

⁵Reporting for the CF Gene Modifier Study Group.

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

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

Received 28 January 2008; Revised 25 April 2008; Accepted 29 April 2008; Published online 19 June 2008.

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 F508 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 TGF1 (P0.05). 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 (P0.01). The IL8 variants were in strong linkage disequilibrium with each other (R²0.82), while variants in neighboring genes CXCL6, RASSF6 and PF4V1 did not associate (P0.26) and were in weaker LD with each other and with the IL8 variants (0.01R²0.49). 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.