Hara Levy

Mutations in both alleles of the cystic fibrosis transmembrane conductance regulator gene result in the disease cystic fibrosis, which usually manifests as chronic sinopulmonary disease, pancreatic insufficiency, elevated sodium chloride loss in sweat, infertility among men due to agenesis of the vas deferens and other symptoms including liver disease.

Rationale: Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin‐1 (IL‐1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection.Methods: We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL‐1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for ΔF508, and categories of “severe” (cases) or “mild” (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV₁) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR ≤0.5 or >1.5, were selected for further testing. To replicate the case‐control study results, we genotyped the same nine SNPs in a second population of CF parent–offspring trios (recruited from Children's Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family‐based and population‐based associations were performed.Results: SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case‐control and family‐based studies. In females, there was a consistent association (false discovery rate adjusted joint P‐value IL1β is a clinically relevant modulator of CF lung disease. Pediatr Pulmonol. 2009; 44:580–593.

Rationale: Chronic mucoid Pseudomonas aeruginosa within the airway in cystic fibrosis (CF) patients can determine prognosis. Understanding the risk factors of mucoid P. aeruginosa acquisition may change how we deliver care. This study aims to evaluate whether presence of risk factors reported to predict disease severity including gender, CFTR genotype, bacterial organisms in airway cultures, and serum levels of vitamins A and E, albumin, C‐reactive protein, alpha 1‐antitrypsin, and immunoglobulins increased the risk of mucoid P. aeruginosa acquisition.Methods: Primary endpoint was age at first transition from negative to positive culture for mucoid P. aeruginosa. Cox proportional hazards regression with time‐dependent covariates examined development of mucoid P. aeruginosa infection and its association with longitudinally measured serum biomarkers, pulmonary function, and culture results for other organisms.Results: Median ages at CF diagnosis and at first culture were 0.55 and 5.7 years, respectively. Median number of cultures/patient was 17. Of the 323 subjects, 150 developed mucoid P. aeruginosa during a median 8.1 years' follow‐up. In multivariate analysis, gender (relative hazard [RH] 0.55 for male vs. female, P = 0.001), number of DF508 alleles (RH 1.66 for 1 or 2 vs. 0, P = 0.04), FEV₁ % (RH 1.16 for 10% decrease, P = 0.008), and most recent Staphylococcus aureus status (RH 0.24 for positive vs. negative, P < 0.0001) remained statistically significant.Conclusion: Female gender, number of DF508 alleles, decreased lung function, and lack of S. aureus on recent sputum culture are important risk factors for early detection of mucoid P. aeruginosa. Pediatr Pulmonol. 2008; 43:463–471.