title: Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease.
abstract: Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease-a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.
authors.affiliation: Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: YuanYuan
authors.initials: Y
authors.lastname: Gu
authors.forename: Isaac T W
authors.initials: IT
authors.lastname: Harley
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Henderson
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Ilja
authors.initials: I
authors.lastname: Vietor
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kilpatrick
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Williams
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.forename: S Hasan
authors.initials: SH
authors.lastname: Arshad
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ewart
authors.forename: Chloe L
authors.initials: CL
authors.lastname: Thio
authors.forename: Leah M
authors.initials: LM
authors.lastname: Flick
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Filippi
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000472:pathogenicity; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C490045:IFRD1 protein, human; D017874:Immediate-Early Proteins; D051996:Transcription Factor RelA