Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease

Yuanyuan Gu, Isaac T W Harley, Lindsay B. Henderson, Bruce J. Aronow, Ilja Vietor, Lukas A. Huber, John B. Harley, Jeffrey R. Kilpatrick, Carl D. Langefeld, Adrienne H. Williams, Anil G. Jegga, Jing Chen, Marsha Wills-Karp, S. Hasan Arshad, Susan L. Ewart, Chloe L Thio, Leah M. Flick, Marie Dominique Filippi, H. Leighton Grimes, Mitchell L. DrummGarry R Cutting, Michael R. Knowles, Christopher L. Karp

Research output: Contribution to journalArticle

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-B p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and diseasea 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.

Original languageEnglish (US)
Pages (from-to)1039-1042
Number of pages4
JournalNature
Volume458
Issue number7241
DOIs
StatePublished - Apr 23 2009

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Modifier Genes
Cystic Fibrosis
Lung Diseases
Neutrophils
Inflammation
Histone Deacetylases
Transcriptional Activation
Single Nucleotide Polymorphism
Macrophages
Genotype
Genome
Morbidity
Phenotype
Mutation
Mortality
Infection

ASJC Scopus subject areas

  • General

Cite this

Gu, Y., Harley, I. T. W., Henderson, L. B., Aronow, B. J., Vietor, I., Huber, L. A., ... Karp, C. L. (2009). Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature, 458(7241), 1039-1042. https://doi.org/10.1038/nature07811

Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. / Gu, Yuanyuan; Harley, Isaac T W; Henderson, Lindsay B.; Aronow, Bruce J.; Vietor, Ilja; Huber, Lukas A.; Harley, John B.; Kilpatrick, Jeffrey R.; Langefeld, Carl D.; Williams, Adrienne H.; Jegga, Anil G.; Chen, Jing; Wills-Karp, Marsha; Arshad, S. Hasan; Ewart, Susan L.; Thio, Chloe L; Flick, Leah M.; Filippi, Marie Dominique; Grimes, H. Leighton; Drumm, Mitchell L.; Cutting, Garry R; Knowles, Michael R.; Karp, Christopher L.

In: Nature, Vol. 458, No. 7241, 23.04.2009, p. 1039-1042.

Research output: Contribution to journalArticle

Gu, Y, Harley, ITW, Henderson, LB, Aronow, BJ, Vietor, I, Huber, LA, Harley, JB, Kilpatrick, JR, Langefeld, CD, Williams, AH, Jegga, AG, Chen, J, Wills-Karp, M, Arshad, SH, Ewart, SL, Thio, CL, Flick, LM, Filippi, MD, Grimes, HL, Drumm, ML, Cutting, GR, Knowles, MR & Karp, CL 2009, 'Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease', Nature, vol. 458, no. 7241, pp. 1039-1042. https://doi.org/10.1038/nature07811
Gu Y, Harley ITW, Henderson LB, Aronow BJ, Vietor I, Huber LA et al. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009 Apr 23;458(7241):1039-1042. https://doi.org/10.1038/nature07811
Gu, Yuanyuan ; Harley, Isaac T W ; Henderson, Lindsay B. ; Aronow, Bruce J. ; Vietor, Ilja ; Huber, Lukas A. ; Harley, John B. ; Kilpatrick, Jeffrey R. ; Langefeld, Carl D. ; Williams, Adrienne H. ; Jegga, Anil G. ; Chen, Jing ; Wills-Karp, Marsha ; Arshad, S. Hasan ; Ewart, Susan L. ; Thio, Chloe L ; Flick, Leah M. ; Filippi, Marie Dominique ; Grimes, H. Leighton ; Drumm, Mitchell L. ; Cutting, Garry R ; Knowles, Michael R. ; Karp, Christopher L. / Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. In: Nature. 2009 ; Vol. 458, No. 7241. pp. 1039-1042.
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