IL1B polymorphisms modulate cystic fibrosis lung disease

Abstract

Summary 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 ≤ 0.5or > 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 < 0.06 for both SNPs) in both the analysis of lung disease severity in the UNC/CWRU cohort and the family-based analysis of affection status. Conclusion: Our findings suggest that IL1β is a clinically relevant modulator of CF lung disease.

Interleukin-23-Mediated Inflammation in Pseudomonas aeruginosa Pulmonary Infection

“…Further, this autoamplification can significantly promote IL-17A, IL-17F, and IL-22 production and downstream inflammation. These findings also have direct disease relevance to CF, because we have shown that IL-23 levels are correlated with active infection (15,38) and that IL-1␤ is highly expressed in CF airways, is expressed concurrently with IL-23 and IL-17 during infection (15,38), and is associated with more severe CF disease (5,6,8,36 (37) reported that in their model of acute P. aeruginosa pulmonary infection, early IL-17 production is responsible for control of infection, a finding that contrasts with our current and prior studies (14). We believe that this difference in findings and conclusions between our studies might be explained on the basis of experimental technique.…”

Cytokines of the Immune System

“…25 IL1B SNPs rs1143634 and rs1143639 showed a consistent association with lung disease severity in cystic fibrosis, suggesting that IL-1β is a clinically relevant modulator of the lung disease. 26 …”

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

“…STAT3, IL1B and IFNGR1 as CF modifiers H Labenski et al carries the causative variant, followed by re-sequencing of contrasting haplotypes to describe the sequence variants for which cases and control differ comprehensively by the base (IFNGR1). Although modern high-throughput technology allows for genomewide scans using SNP, 43,44 microsatellites 45 or in-depth investigation of candidate genes with multiple SNPs, 27 reports of modifying variants that have been systematically mapped and functionally validated by means of modifier-genotype/patient's-phenotype correlation are still the exception in the CF modifier field. In the light of this, we admit that the direct correlation between the length of the intronic microsatellite STAT3Sat and STAT3 expression levels among F508del-CFTR homozygous patients was an unexpected finding by serendipity as STAT3Sat was purely genotyped to capture inherited variants of the candidate gene.…”

“…48 The gold standard for genetic association studies has always been the replication of findings in different study populations. For IL1B, described recently as a modifier by a North-American consortium, 27 we have compared both studies (author's comment: by chance, the two SNPs rs1143634 (Levy et al) and rs1143643 (this work) differ by the last two digits only -discriminative ciphers have been underlined for your convenience). Levy et al 27 emphasize an association to SNPs rs1143634 and rs1143639 in IL1B while our data implicate rs3917356 and rs4848306 for an association with CF disease severity and detect a transmission disequilibrium at rs1143643 (Table 2).…”