1. Division of Molecular Immunology,
2. Division of Biomedical Informatics,
3. Division of Immunobiology, and,
4. Division of Experimental Hematology & Cancer Biology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
5. McKusick-Nathans Institute of Genetic Medicine, and,
6. Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
7. Biocenter, Division of Cell Biology, Innsbruck Medical University, Innsbruck A-6020, Austria
8. Arthritis & Immunology Program, Oklahoma Medical Research Foundation, and JK Autoimmunity Inc., Oklahoma City, Oklahoma 73104, USA
9. Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA
10. The David Hide Asthma and Allergy Research Centre, Newport, Isle of Wight, PO30 5TG, UK
11. Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA
12. Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA
13. Cystic Fibrosis–Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA

Correspondence to: Christopher L. Karp¹ Correspondence and requests for materials should be addressed to C.L.K. (Email: chris.karp@chmcc.org).

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 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-B 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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