@article{76342d7fe86743c9b9c73b41269590fa,
title = "Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis",
abstract = "Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associationsamong individuals with ILAs or additional overlap with IPF is not known. Objectives: To perform a genome-wide association study (GWAS) of ILAs. Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs 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 for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6310227) and subpleural ILAs (P = 1.6310229). We discovered novel genomewide associations near IPO11 (rs6886640, P = 3.831028) and FCF1P3 (rs73199442, P = 4.831028) with ILAs, and near HTRE1 (rs7744971, P = 4.231028) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPFGWASloci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P,0.05/12) with ILAs. Conclusions: In a GWAS of ILAs 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 genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.",
keywords = "Genetics, Genome-wide association study, Idiopathic pulmonary fibrosis, Interstitial lung abnormalities, SNP",
author = "{COPDGene Investigators} and {ECLIPSE Investigators} and {SPIROMICS Research Group} and {UK ILD Consortium} and Hobbs, {Brian D.} and Putman, {Rachel K.} and Tetsuro Araki and Mizuki Nishino and Gunnar Gudmundsson and Vilmundur Gudnason and Gudny Eiriksdottir and Nogueira, {Nuno Rodrigues Zilhao} and Jos{\'e}e Dupuis and Hanfei Xu and O'Connor, {George T.} and Ani Manichaikul and Jennifer Nguyen and Podolanczuk, {Anna J.} and Purnema Madahar and Rotter, {Jerome I.} and Lederer, {David J.} and {Graham Barr}, R. and Rich, {Stephen S.} and Ampleford, {Elizabeth J.} and Ortega, {Victor E.} and Peters, {Stephen P.} and O'Neal, {Wanda K.} and Newell, {John D.} and Bleecker, {Eugene R.} and Meyers, {Deborah A.} and Allen, {Richard J.} and Oldham, {Justin M.} and Ma, {Shwu Fan} and Imre Noth and {Gisli Jenkins}, R. and Maher, {Toby M.} and Hubbard, {Richard B.} and Wain, {Louise V.} and Fingerlin, {Tasha E.} and Schwartz, {David A.} and Washko, {George R.} and Rosas, {Ivan O.} and Silverman, {Edwin K.} and Hiroto Hatabu and Cho, {Michael H.} and Hunninghake, {Gary M.} and Alexis, {Neil E.} and Anderson, {Wayne H.} and Mehrdad Arjomandi and Igor Barjaktarevic and {Graham Barr}, R. and Bateman, {Lori A.} and Bhatt, {Surya P.} and Boucher, {Richard C.}",
note = "Funding Information: B.D.H. is supported by NIH grant K08 HL136928. R.K.P. is supported by NIH grant K08 HL140087. M.N. is supported by NIH grant R01 CA203636. G.G. is supported by the Oddur Olafsson Fund, project grant 141513-051 from the Icelandic Research Fund, and Landspitali Scientific Fund grants A-2015-030, A-2016-023, A-2017-030, A-2018-022, and A-2018-025. G.G. is supported by National Institute on Aging (NIA) grant 27120120022C and project grant 141513-051 from the Icelandic Research Fund. G.T.O{\textquoteright}C. is supported by NIH grant OT2 OD026553. A.M. is supported by NIH grant R01 HL131565. A.J.P. is supported by NIH grant K23 HL140199. J.I.R. is supported by NIH grants R01 HL142302, R01 EY009052, R01EY023704, and P30 DK063491. D.J.L. is supported by NIH grants K24 HL131937, R01 HL103676, and R01 HL137234. R.G.B. is supported by NIH grants R01 HL077612, R01 HL093081, R01 HL121270, and R01 HL142028. S.S.R. is supported by NIH grants U01 HL120393, DP3 DK111906, and P01 HL136275. W.K.O{\textquoteright}N. is supported by NIH grants R01 HL117843 and U24 HL141762. V.E.O. is supported by NIH grants K08 HL118128 and R01 HL142992. E.R.B. is supported by NIH grants UG1 HL1390534 and U01 HL109164. D.A.M. is supported by NIH grants R01 NR013700 and U01 HL109164. R.J.A. is supported by an Action Pulmonary Fibrosis Mike Bray Fellowship. J.M.O. is supported by NIH grant K23 HL138190. I.N. is supported by NIH grant R01 HL130796. R.G.J. is supported by Medical Research Council grant G0901226. T.M.M. is supported by a National Institute for Health Research (NIHR) Clinician Scientist Fellowship (CS-2013-13-017). L.V.W. 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 National Health Service, the NIHR, or the Department of Health. T.E.F. is supported by NIH grants R01 HL114587, R01 HL097163, and P01 HL132821. D.A.S. is supported by NIH grants P01 HL092870, R01 HL097163, R33 HL120770, R33 CA182360, and UH3 HL123442. G.R.W. is supported by NIH grants R01 HL116473 and R01 HL122464. I.O.R. is supported by NIH grants U01 HL133232 and R01 HL130974. E.K.S. is supported by NIH grants U01 HL089856, R01 HL113264, R01 HL137927, R01 HL133135, and P01 HL114501. M.H.C. is supported by NIH grants R01 HL135142, R01 HL113264, and R01 HL137927. G.M.H. is supported by NIH grants R01 HL111024, R01 HL130974, R01 135142, and project grant 141513-051 from the Icelandic Research Fund. The Framingham Heart Study is supported by NIH contracts N01-HC-25195 and HHSN268201500001I. COPDGene is supported by NIH grants U01 HL089897 and U01 HL089856. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. The Age, Gene/Environment Susceptibility-Reykjavik Study was supported by NIA grant 27120120022C, NIH contracts N01-AG-1-2100 and HHSN27120120022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420, and by National Center for Advancing Translational Sciences grant ULTR001881 and National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici, Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Co., Theravance Biopharma, and Mylan. Publisher Copyright: {\textcopyright} 2019 American Thoracic Society. All rights reserved.",
year = "2021",
doi = "10.1164/rccm.201903-0511oc",
language = "English (US)",
volume = "200",
pages = "1402--1413",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "11",
}