Abstract

Background: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor α (TNFα), a member of the immune system.

Methods: Three polymorphic loci in the promoter (−851c/t, −308g/a, −238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFα gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients’ medical records.

Results: An association was found between the TNFα +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV₁) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV₁ 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the −851c/t polymorphic locus. In the group of patients with more severe FEV₁% predicted, a higher proportion of patients were homozygous for the −851c allele than in the other group of patients (p = 0.04, likelihood ratio χ², odds ratio = 2.4).

Conlusion: TNFα polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.