Asthma and COPD in cystic fibrosis intron-8 5T carriers. A population-based study

Abstract

Background: Carriers of cystic fibrosis intron-8 5T alleles with high exon-9 skipping could have increased annual lung function decline and increased risk for asthma or chronic obstructive pulmonary disease (COPD).

Methods: We genotyped 9131 individuals from the adult Danish population for cystic fibrosis 5T, 7T, 9T, and F508del alleles, and examined associations between 11 different genotype combinations, and annual FEV1 decline and risk of asthma or COPD.

Results: 5T heterozygotes vs. 7T homozygous controls had no increase in annual FEV1 decline, self-reported asthma, spirometry-defined COPD, or incidence of hospitalization from asthma or COPD. In 5T/7T heterozygotes vs. 7T homozygous controls we had 90% power to detect an increase in FEV1 decline of 8 ml, an odds ratio for self-reported asthma and spirometry-defined COPD of 1.9 and 1.7, and a hazard ratio for asthma and COPD hospitalization of 1.8 and 1.6, respectively. Both 5T homozygotes identified in the study showed evidence of asthma, while none of four 5T/F508del compound heterozygotes had severe pulmonary disease. 7T/9T individuals had annual decline in FEV1 of 19 ml compared with 21 ml in 7T homozygous controls (t-test: P = 0.03). 6.7% of 7T homozygotes without an F508del allele in the cystic fibrosis transmembrane conductance regulator gene reported asthma vs. 11% of 7T/9T individuals with an F508del allele (chi2: P = 0.01) and 40% of 7T homozygotes with an F508del allele (P = 0.04). 7T homozygotes with vs. without an F508del allele also had higher incidence of asthma hospitalization (log-rank: P = 0.003); unadjusted and adjusted equivalent hazard ratios for asthma hospitalization were 11 (95%CI: 1.5-78) and 6.3 (0.84-47) in 7T homozygotes with vs. without an F508del allele.

Conclusion: Polythymidine 5T heterozygosity is not associated with pulmonary dysfunction or disease in the adult Caucasian population. Furthermore, our results support that F508del heterozygosity is associated with increased asthma risk independently of the 5T allele.

Figure 1

Annual FEV₁ decline by intron-8 polythymidine tract and F508del genotype. Values are mean and SEM. *P = 0.03 compared with 7T homozygotes without F508del.

Figure 2

Odds ratios for self-reported asthma by intron-8 polythymidine tract and F508del genotype. 7T homozygotes without F508del was used as reference group. The adjusted model included gender, age at study entry, and packyears at study entry. Error bars are 95% confidence intervals. Self-reported asthma = "Yes" at least once during the study period to the question "Do you suffer from asthma?".

Figure 3

Odds ratios for spirometry defined COPD by intron-8 polythymidine tract and F508del genotype. 7T homozygotes without F508del was used as reference group. The adjusted model included gender, age at study entry, and packyears at study entry. Error bars are 95% confidence intervals. COPD = FEV₁<80% predicted and FEV₁/FVC<0.7, excluding self-reported asthma.