The University of Southampton
University of Southampton Institutional Repository

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

Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease
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-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.
0028-0836
1039-1042
YuanYuan, Gu
2e8c9615-f368-4939-8b2b-5333b458e98a
Harley, Isaac T.W.
4b948d5a-5e7a-402e-a394-519a6f1f0e3d
Bremer, Lindsay B.
1864e4a9-8ee8-402f-9211-f46cb99b4706
Aronow, Bruce J.
63b74f3b-b0ab-493a-852c-fa60013bc1f7
Vietor, Ilja
a7123114-9787-4759-a672-c03af44ed6d5
Harley, John B.
c03b5ca6-063a-46a7-b4f1-fd46ca7e3709
Kilpatrick, Jeffrey R.
3f87b519-32d1-432c-b9c9-1c2d8f8189c8
Langefeld, Carl D.
2bc95097-fda8-448f-b0a6-2ca1e2b78a4f
Williams, Adrienne H.
0fda34d0-9205-43ff-becd-90e8bc75e3d6
Jegga, Anil G.
a7127f15-485d-4b72-9004-fc5585a6a103
Chen, Jing
5d1f11be-b12a-4517-9035-1b8b16078087
Wills-Karp, Marsha
a59ab80a-d165-4078-aa11-dc597774cbb8
Flick, Leah M.
46d59964-1b92-4dd0-9969-334b4310fa0b
Arshad, S. Hasan
917e246d-2e60-472f-8d30-94b01ef28958
Ewart, Susan L.
48158071-d7b8-46b5-8aef-26ffb37eec3b
Thio, Chloe L.
9bb90dbe-60a7-4574-b16a-33d7a3ecb07b
Filippi, Marie-Dominique
1add4ae4-00ad-4f05-96ab-39ca6ba0980f
Leighton Grimes, H. Leighton
65fa6bd7-faa1-4e5f-b9ec-abda9c851502
Drumm, Mitchell L.
04b9d220-953d-46bf-8340-c6dc5f453b48
Cutting, Garry R.
79ae84f0-840a-46c9-92fa-5ef45c1590c5
Knowles, Michael R.
164069d2-1ec2-41ce-8bf8-b48462a5a206
Karp, Christopher L.
9d26ac22-9e31-46c8-aa0d-8f9b55ee708d
YuanYuan, Gu
2e8c9615-f368-4939-8b2b-5333b458e98a
Harley, Isaac T.W.
4b948d5a-5e7a-402e-a394-519a6f1f0e3d
Bremer, Lindsay B.
1864e4a9-8ee8-402f-9211-f46cb99b4706
Aronow, Bruce J.
63b74f3b-b0ab-493a-852c-fa60013bc1f7
Vietor, Ilja
a7123114-9787-4759-a672-c03af44ed6d5
Harley, John B.
c03b5ca6-063a-46a7-b4f1-fd46ca7e3709
Kilpatrick, Jeffrey R.
3f87b519-32d1-432c-b9c9-1c2d8f8189c8
Langefeld, Carl D.
2bc95097-fda8-448f-b0a6-2ca1e2b78a4f
Williams, Adrienne H.
0fda34d0-9205-43ff-becd-90e8bc75e3d6
Jegga, Anil G.
a7127f15-485d-4b72-9004-fc5585a6a103
Chen, Jing
5d1f11be-b12a-4517-9035-1b8b16078087
Wills-Karp, Marsha
a59ab80a-d165-4078-aa11-dc597774cbb8
Flick, Leah M.
46d59964-1b92-4dd0-9969-334b4310fa0b
Arshad, S. Hasan
917e246d-2e60-472f-8d30-94b01ef28958
Ewart, Susan L.
48158071-d7b8-46b5-8aef-26ffb37eec3b
Thio, Chloe L.
9bb90dbe-60a7-4574-b16a-33d7a3ecb07b
Filippi, Marie-Dominique
1add4ae4-00ad-4f05-96ab-39ca6ba0980f
Leighton Grimes, H. Leighton
65fa6bd7-faa1-4e5f-b9ec-abda9c851502
Drumm, Mitchell L.
04b9d220-953d-46bf-8340-c6dc5f453b48
Cutting, Garry R.
79ae84f0-840a-46c9-92fa-5ef45c1590c5
Knowles, Michael R.
164069d2-1ec2-41ce-8bf8-b48462a5a206
Karp, Christopher L.
9d26ac22-9e31-46c8-aa0d-8f9b55ee708d

YuanYuan, Gu, Harley, Isaac T.W., Bremer, Lindsay B., Aronow, Bruce J., Vietor, Ilja, Harley, John B., Kilpatrick, Jeffrey R., Langefeld, Carl D., Williams, Adrienne H., Jegga, Anil G., Chen, Jing, Wills-Karp, Marsha, Flick, Leah M., Arshad, S. Hasan, Ewart, Susan L., Thio, Chloe L., Filippi, Marie-Dominique, Leighton Grimes, H. Leighton, Drumm, Mitchell L., Cutting, Garry R., Knowles, Michael R. and Karp, Christopher L. (2009) Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature, 458 (7241), 1039-1042. (doi:10.1038/nature07811). (PMID:19673948)

Record type: Article

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-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.

This record has no associated files available for download.

More information

Published date: April 2009
Organisations: Infection Inflammation & Immunity, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 72694
URI: http://eprints.soton.ac.uk/id/eprint/72694
ISSN: 0028-0836
PURE UUID: e918f2ae-9a3f-49f7-8b41-fd1169d7a6a5

Catalogue record

Date deposited: 19 Feb 2010
Last modified: 13 Mar 2024 21:38

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×