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. Wanda; Marci K. Sontag; Hara Levy; Peter R. Durie; Johanna M. Rommens; Mitchell L. Drumm; Fred A. Wright; Lisa J. Strug; Garry R. Cutting; Michael R. Knowles

doi:10.1038/ncomms9382

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 SunYi Hui Zhou, Wanda K. Wanda, Marci K. Sontag, Hara Levy, Peter R. Durie, Johanna M. Rommens, Mitchell L. Drumm, Fred A. Wright, Lisa J. Strug, Garry R. Cutting, Michael R. Knowles^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

222 Scopus citations

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.

Original language	English (US)
Article number	8382
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9382
State	Published - Sep 29 2015

Funding

National Heart, Lung and Blood Institute 1DP2OD007031, R01HL068890, R01HL095396, R01HL68927; National Institute of Diabetes and Digestive and Kidney Diseases 1R01DK61886-01, K23DK083551, P30DK079637; National Human Genome Research Institute R21HG007840; Cystic Fibrosis Foundation SONTAG07A0, KNOW-LE00A0, DRUMM0A00, CUTT00AO, CUTT06PO, COLLAC13IO; PES Clinical Scholars Award, Schwachman (COLLACO09A0); Canadian Institutes of Health Research (MOP 258916), Cystic Fibrosis Canada (CFC; #2626), Genome Canada through the Ontario Genomics Institute (2004-OGI-3-05); Institut National de la Santé et de la Recherche Médicale, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie Paris, Agence Nationale de la Recherche (R09186DS), DGS, Association Vaincre La Mucoviscidose, Chancellerie des Universités (Legs Poix), Association Agir Informer Contre la Mucoviscidose, GIS-Institut des Maladies Rares. Genome-wide genotyping of subjects in North America provided by the US and CFC Foundations. We thank the US CF Foundation for the use of CF Foundation Patient Registry data. We thank the patients, care providers and clinic coordinators at CF Centers throughout the US and Canada (see list in Supplementary Information) for their contributions to the CF Foundation Patient Registry and Canadian Gene Modifier Study. We thank the following: P-F. Busson, J-F. Vibert, A. Blondel, P. Touche (French study design/patient recruitment); R. Bersie, M. Reske (Children’s Hospitals of Wisconsin and Boston data collection); M. Anthony (Denver study design/patient recruitment); P. Diaz, S. Norris (UNC recruitment); A. Infanzon (UNC editorial assistance); H. Kelkar, A. Xu (UNC bioinformatics); W. Wolf (UNC genotyping); Canadian Genome Sequencing Resource for CF; M. Corey, R. Dorfman, A. Sandford, P. Pare, Y. Berthiaume (CGS recruitment); P. Hu (genotype calling/quality control, The Centre for Applied Genomics, The Hospital for Sick Children); K. Naughton, P. Cornwall, B. Vecchio (TSS recruitment/data analysis). We also acknowledge the contributions of our dear colleague, the late Dr. Julian Zielenski.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Corvol, H., Blackman, S. M., Boëlle, P. Y., Gallins, P. J., Pace, R. G., Stonebraker, J. R., Accurso, F. J., Clement, A., Collaco, J. M., Dang, H., Dang, A. T., Franca, A., Gong, J., Guillot, L., Keenan, K., Li, W., Lin, F., Patrone, M. V., Raraigh, K. S., ... Knowles, M. R. (2015). Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nature communications, 6, Article 8382. https://doi.org/10.1038/ncomms9382

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

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.",

author = "Harriet Corvol and Blackman, {Scott M.} and Bo{\"e}lle, {Pierre Yves} and Gallins, {Paul J.} and Pace, {Rhonda G.} and Stonebraker, {Jaclyn R.} and Accurso, {Frank J.} and Annick Clement and Collaco, {Joseph M.} and Hong Dang and Dang, {Anthony T.} and Arianna Franca and Jiafen Gong and Loic Guillot and Katherine Keenan and Weili Li and Fan Lin and Patrone, {Michael V.} and Raraigh, {Karen S.} and Lei Sun and Zhou, {Yi Hui} and Wanda, {Wanda K.} and Sontag, {Marci K.} and Hara Levy and Durie, {Peter R.} and Rommens, {Johanna M.} and Drumm, {Mitchell L.} and Wright, {Fred A.} and Strug, {Lisa J.} and Cutting, {Garry R.} and Knowles, {Michael R.}",

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day = "29",

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Corvol, H, Blackman, SM, Boëlle, PY, Gallins, PJ, Pace, RG, Stonebraker, JR, Accurso, FJ, Clement, A, Collaco, JM, Dang, H, Dang, AT, Franca, A, Gong, J, Guillot, L, Keenan, K, Li, W, Lin, F, Patrone, MV, Raraigh, KS, Sun, L, Zhou, YH, Wanda, WK, Sontag, MK, Levy, H, Durie, PR, Rommens, JM, Drumm, ML, Wright, FA, Strug, LJ, Cutting, GR & Knowles, MR 2015, 'Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis', Nature communications, vol. 6, 8382. https://doi.org/10.1038/ncomms9382

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AU - Corvol, Harriet

AU - Blackman, Scott M.

AU - Boëlle, Pierre Yves

AU - Gallins, Paul J.

AU - Pace, Rhonda G.

AU - Stonebraker, Jaclyn R.

AU - Accurso, Frank J.

AU - Clement, Annick

AU - Collaco, Joseph M.

AU - Dang, Hong

AU - Dang, Anthony T.

AU - Franca, Arianna

AU - Gong, Jiafen

AU - Guillot, Loic

AU - Keenan, Katherine

AU - Li, Weili

AU - Lin, Fan

AU - Patrone, Michael V.

AU - Raraigh, Karen S.

AU - Sun, Lei

AU - Zhou, Yi Hui

AU - Wanda, Wanda K.

AU - Sontag, Marci K.

AU - Levy, Hara

AU - Durie, Peter R.

AU - Rommens, Johanna M.

AU - Drumm, Mitchell L.

AU - Wright, Fred A.

AU - Strug, Lisa J.

AU - Cutting, Garry R.

AU - Knowles, Michael R.

PY - 2015/9/29

Y1 - 2015/9/29

N2 - 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.

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

Abstract

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UN SDGs

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