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Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis

journal contribution
posted on 18.07.2019, 10:55 by Brian D. Hobbs, Rachel K. Putman, Tetsuro Araki, Mizuki Nishino, Gunnar Gudmundsson, Vilmundur Gudnason, Gudny Eiriksdottir, Nuno Rodrigues Zilhao Nogueira, Josée Dupuis, Hanfei Xu, George T. O’Connor, Ani Manichaikul, Jennifer Nguyen, Anna J. Podolanczuk, Purnema Madahar, Jerome I. Rotter, David J. Lederer, R. Graham Barr, Stephen S. Rich, Elizabeth J. Ampleford, Victor E. Ortega, Stephen P. Peters, Wanda K. O’Neal, John D. Newell Jr., Eugene R. Bleecker, Deborah A. Meyers, Richard J. Allen, Justin M. Oldham, Shwu-Fan Ma, Imre Noth, R. Gisli Jenkins, Toby M. Maher, Richard B. Hubbard, Louise V. Wain, Tasha E. Fingerln, David A. Schwartz, George R. Washko, Ivan O. Rosas, Edwin K. Silverman, Hiroto Hatabu, Michael H. Cho, Gary M. Hunninghake, COPDGene Investigators, ECLIPSE Investigators, SPIROMICS Research Group, UK ILD Consortium
Rationale Interstitial lung abnormalities (ILA) are associated with the highest genetic risk locus for IPF; however, the extent to which there is additional overlap with IPF, or unique associations among those with ILA is not known. Objectives To perform a genome-wide association study (GWAS) of ILA. Methods: ILA and the subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES, COPDGene, Framingham Heart, ECLIPSE, MESA, and SPIROMICS studies. We performed a GWAS of ILA in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results Genome-wide genotyping data were available in 1,699 ILA cases and 10,274 controls. The MUC5B promoter variant rs35705950 was significantly associated with both ILA (p=2.6x10-27) and subpleural ILA (p=1.6x10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, p=3.8x10-8 ) and FCF1P3 (rs73199442, p=4.8x10-8 ) with ILA, and HTRE1 (rs7744971, p=4.2x10-8 ) with subpleural-predominant ILA. These novel associations were not associated with IPF. Of 12 previously reported IPF GWAS loci, 5 (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (p<0.05/12) with ILA. Conclusions In a GWAS of ILA in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common and suggest distinct genetically-driven biologic pathways between ILA and IPF.

Funding

Dr. Hobbs is supported by NIH grant K08 HL136928. Dr. Putman is supported by NIH grant K08 HL140087. Dr. Nishino is supported by NIH grant R01 CA203636. Dr. Gudmundsson is supported by Oddur Olafsson Fund, project grant 141513-051 from the Icelandic Research Fund and Landspitali Scientific Fund A-2015-030, A-2016-023, A-2017-030, A-2018-022 and A2018-025. Dr. Gudnason is supported by NIA grant: 27120120022C and project grant 141513- 051 from the Icelandic Research Fund. Dr. O’Connor is supported by NIH grant OT2 OD026553. Dr. Manichaikul is supported by NIH grant R01 HL131565. Dr. Podolanczuk is supported by NIH grant K23 HL140199. Dr. Rotter is supported by NIH grants R01 HL142302, R01 EY009052, R01EY023704, and P30 DK063491. Dr. Lederer is supported by NIH grants K24 HL131937, R01 HL103676 and R01 HL137234. Dr. Barr is supported by NIH grants R01 HL077612, R01 HL093081, R01 HL121270, and R01 HL142028. Dr. Rich is supported by NIH grants U01 HL120393, DP3 DK111906, and P01 HL136275. Dr. O’Neal is supported by NIH grants R01 HL117843 and U24 HL141762. Dr. Ortega is supported by NIH grants K08 HL118128 and R01 HL142992. Dr. Bleecker is supported by NIH grants UG1 HL1390534 and U01 HL109164. Dr. Meyers is supported by NIH grants R01 NR013700 and U01 HL109164. Dr. Allen is supported by an Action Pulmonary Fibrosis Mike Bray Fellowship. Dr. Oldham is supported by NIH grant K23 HL138190. Dr. Noth is supported by NIH grant R01 HL130796. Dr. Jenkins is supported by MRC Grant G0901226. Dr. Maher is supported by an NIHR Clinician Scientist Fellowship (NIHR reference CS-2013-13-017). Dr. Wain holds a GlaxoSmithKline/British Lung Foundation Chair in Respiratory Research. The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Dr. Fingerlin is supported by NIH grants R01 HL114587, R01 HL097163, and P01 HL

History

Citation

American Journal of Respiratory and Critical Care Medicine, 2019, 200 (11)

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

AM (Accepted Manuscript)

Published in

American Journal of Respiratory and Critical Care Medicine

Volume

200

Issue

11

Publisher

American Thoracic Society

issn

1073-449X

Acceptance date

17/07/2019

Copyright date

2019

Available date

01/12/2019

Notes

This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org.;The file associated with this record is under embargo until publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en