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_

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. Access through your institution Buy or subscribe This is a preview of

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_Methods in Molecular Biology_ Vol. 120 (ed Lianos, E. A.) 119–144 (Humana Press, 1999) Google Scholar  Download references ACKNOWLEDGEMENTS 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Molecular Immunology,, YuanYuan Gu, Isaac T. W. Harley, Leah M. Flick & Christopher L. Karp * Division of

Biomedical Informatics,, Bruce J. Aronow, Anil G. Jegga & Jing Chen * Division of Immunobiology, and, Marsha Wills-Karp & H. Leighton Grimes * Division of Experimental Hematology

& Cancer Biology, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA, Marie-Dominique Filippi *

McKusick-Nathans Institute of Genetic Medicine, and,, Lindsay B. Henderson & Garry R. Cutting * Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School

of Medicine, Baltimore, Maryland 21205, USA, Chloe L. Thio * Division of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck A-6020, Austria Ilja Vietor & Lukas A. Huber *

Arthritis & Immunology Program, Oklahoma Medical Research Foundation, and JK Autoimmunity Inc., Oklahoma City, Oklahoma 73104, USA , John B. Harley & Jeffrey R. Kilpatrick *

Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA, Carl D. Langefeld & Adrienne H. Williams * The David Hide

Asthma and Allergy Research Centre, Newport, Isle of Wight, PO30 5TG, UK , S. Hasan Arshad * Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State

University, East Lansing, Michigan 48824, USA, Susan L. Ewart * Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA, Mitchell L. Drumm *

Cystic Fibrosis–Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA , Michael R. Knowles Authors * YuanYuan Gu View author

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DECLARATIONS COMPETING INTERESTS J.B.H. and J.R.K. hold equity interest in and receive consulting income from JK Autoimmunity Inc. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This

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Identification of _IFRD1_ as a modifier gene for cystic fibrosis lung disease. _Nature_ 458, 1039–1042 (2009). https://doi.org/10.1038/nature07811 Download citation * Received: 03 December

2008 * Accepted: 20 January 2009 * Published: 25 February 2009 * Issue Date: 23 April 2009 * DOI: https://doi.org/10.1038/nature07811 SHARE THIS ARTICLE Anyone you share the following link

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