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

File Description SizeFormat 
ILA_GWAS_v1_20190215_circulate copy.docxFile embargoed until 24 July 2020227.59 kBMicrosoft Word    Request a copy
Title: Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis.
Authors: Hobbs, BD
Putman, RK
Araki, T
Nishino, M
Gudmundsson, G
Gudnason, V
Eiriksdottir, G
Zilhao Nogueira, NR
Dupuis, J
Xu, H
O'Connor, GT
Manichaikul, A
Nguyen, J
Podolanczuk, AJ
Madahar, P
Rotter, JI
Lederer, DJ
Barr, RG
Rich, SS
Ampleford, EJ
Ortega, VE
Peters, SP
O'Neal, WK
Newell, JD
Bleecker, ER
Meyers, DA
Allen, RJ
Oldham, JM
Ma, S-F
Noth, I
Jenkins, RG
Maher, TM
Hubbard, RB
Wain, LV
Fingerlin, TE
Schwartz, DA
Washko, GR
Rosas, IO
Silverman, EK
Hatabu, H
Cho, MH
Hunninghake, GM
COPDGene Investigators, ECLIPSE Investigators, SPIROMICS Research Group, and UK ILD Consortium
Item Type: Journal Article
Abstract: 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.
Issue Date: 24-Jul-2019
Date of Acceptance: 17-Jul-2019
URI: http://hdl.handle.net/10044/1/72042
DOI: https://doi.org/10.1164/rccm.201903-0511OC
ISSN: 1073-449X
Publisher: American Thoracic Society
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Copyright Statement: © 1987-2018 American Thoracic Society, All Rights Reserved.
Sponsor/Funder: National Institute for Health Research
British Lung Foundation
Funder's Grant Number: CS-2013-13-017
C17-3
Keywords: genetics
genome-wide association study
idiopathic pulmonary fibrosis
interstitial lung abnormalities
single-nucleotide polymorphism
genetics
genome-wide association study
idiopathic pulmonary fibrosis
interstitial lung abnormalities
single-nucleotide polymorphism
Respiratory System
11 Medical and Health Sciences
Publication Status: Published online
Conference Place: United States
Embargo Date: 2020-07-24
Online Publication Date: 2019-07-24
Appears in Collections:National Heart and Lung Institute



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commons