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


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 genotype1. 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-κB 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.

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Figure 1: IFRD1-deficient neutrophils exhibit blunted effector functions.
Figure 2: Genetic deficiency of Ifrd1 is associated with delayed bacterial clearance, but decreased neutrophilic inflammation and ameliorated disease, after airway challenge with mucoid P. aeruginosa.
Figure 3: IFRD1 polymorphisms are associated with variation in human neutrophil effector function.


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This work was funded by grants from the National Cystic Fibrosis Foundation (C.L.K., M.L.D., G.R.C. and M.R.K.), the National Heart Lung and Blood Institute (G.R.C., M.R.K. and C.L.K.), the Wake Forest University Health Sciences Center for Public Health Genomics (C.D.L. and A.H.W.) and the Austrian Science Fund (I.V. and L.A.H). We thank R. Pace and J. Yeatts for technical assistance, and D. Hassett for the P. aeruginosa FRD1 strain.

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Correspondence to Christopher L. Karp.

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Competing interests

J.B.H. and J.R.K. hold equity interest in and receive consulting income from JK Autoimmunity Inc.

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Gu, Y., Harley, I., Henderson, L. et al. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 458, 1039–1042 (2009).

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