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Nat Commun. 2015 Sep 29;6:8382. doi: 10.1038/ncomms9382.

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

Author information

1
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Pediatric Pulmonary Department; Institut National de la Santé et la Recherche Médicale (INSERM) U938, Paris 75012, France.
2
Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Paris 75005, France.
3
Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
4
AP-HP, Hôpital St Antoine, Biostatistics Department; Inserm U1136, Paris 75012, France.
5
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
6
Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
7
Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Anschutz Medical Center, Aurora, Colorado 80045, USA.
8
Children's Hospital Colorado, Anschutz Medical Center, Aurora, Colorado 80045, USA.
9
Department of Pediatrics, School of Medicine, Anschutz Medical Center, Aurora, Colorado 80045, USA.
10
Division of Pediatric Pulmonology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
11
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
12
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
13
Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
14
Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 3G3.
15
Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada M5T 3M7.
16
Bioinformatics Research Center and Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695, USA.
17
Division of Pulmonary Medicine, Department of Pediatrics, Stanley Manne Research Institute, Northwestern University Feinberg School of Medicine, Ann and Robert Lurie Children's Hospital of Chicago, Chicago, Illinois 60611, USA.
18
Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
19
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
20
Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
21
Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, North Carolina 27695, USA.
22
Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695, USA.
23
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Abstract

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.

PMID:
26417704
PMCID:
PMC4589222
DOI:
10.1038/ncomms9382
[Indexed for MEDLINE]
Free PMC Article

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