IL1B polymorphisms modulate cystic fibrosis lung disease

• Published in: Pediatric pulmonology 2009-06, Vol.44 (6), p.580-593
• Main Authors: Levy, Hara, Murphy, Amy, Zou, Fei, Gerard, Craig, Klanderman, Barbara, Schuemann, Brooke, Lazarus, Ross, García, K. Christopher, Celedón, Juan C., Drumm, Mitch, Dahmer, Mary, Quasney, Michael, Schneck, Kaitlyn, Reske, Melissa, Knowles, Michael R., Pier, Gerald B., Lange, Christoph, Weiss, Scott T.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Case-Control Studies; CFTR; Child; cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Errors of metabolism; Female; gene modifiers; General aspects; Genotype; Humans; IL-1 gene family; Interleukin-1 - genetics; Male; Medical sciences; Metabolic diseases; Middle Aged; Miscellaneous hereditary metabolic disorders; Odds Ratio; Phenotype; Pneumology; Polymorphism, Single Nucleotide - genetics; Severity of Illness Index; Young Adult
• ISSN: 8755-6863; 1099-0496
• DOI: 10.1002/ppul.21026

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