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

Harriet Corvol, Scott M. Blackman, Pierre-Yves Boëlle, Paul J. Gallins, Rhonda G. Pace, Jaclyn R. Stonebraker, Frank J. Accurso, Annick Clement, Joseph M. Collaco, Hong Dang, Anthony T. Dang, Arianna Franca, Jiafen Gong, Loic Guillot, Katherine Keenan, Weili Li, Fan Lin, Michael V. Patrone, Karen S. Raraigh, Lei Sun, Yi-Hui Zhou, Wanda K. O’Neal, Marci K. Sontag, Hara Levy, Peter R. Durie, Johanna M. Rommens, Mitchell L. Drumm, Fred A. Wright, Lisa J. Strug (), Garry R. Cutting () and Michael R. Knowles ()
Additional contact information
Harriet Corvol: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau
Scott M. Blackman: Johns Hopkins University School of Medicine
Pierre-Yves Boëlle: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06
Paul J. Gallins: University of North Carolina at Chapel Hill
Rhonda G. Pace: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill
Jaclyn R. Stonebraker: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill
Frank J. Accurso: Colorado School of Public Health, University of Colorado Denver, Anschutz Medical Center
Annick Clement: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau
Joseph M. Collaco: Johns Hopkins University School of Medicine
Hong Dang: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill
Anthony T. Dang: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill
Arianna Franca: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Jiafen Gong: Program in Genetics and Genome Biology, The Hospital for Sick Children
Loic Guillot: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau
Katherine Keenan: Program in Physiology and Experimental Medicine, The Hospital for Sick Children
Weili Li: Program in Genetics and Genome Biology, The Hospital for Sick Children
Fan Lin: Program in Genetics and Genome Biology, The Hospital for Sick Children
Michael V. Patrone: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill
Karen S. Raraigh: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Lei Sun: University of Toronto
Yi-Hui Zhou: North Carolina State University
Wanda K. O’Neal: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill
Marci K. Sontag: Colorado School of Public Health, University of Colorado Denver, Anschutz Medical Center
Hara Levy: Stanley Manne Research Institute, Northwestern University Feinberg School of Medicine, Ann and Robert Lurie Children’s Hospital of Chicago
Peter R. Durie: Program in Physiology and Experimental Medicine, The Hospital for Sick Children
Johanna M. Rommens: Program in Genetics and Genome Biology, The Hospital for Sick Children
Mitchell L. Drumm: School of Medicine, Case Western Reserve University
Fred A. Wright: North Carolina State University
Lisa J. Strug: Program in Genetics and Genome Biology, The Hospital for Sick Children
Garry R. Cutting: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Michael R. Knowles: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9382

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