Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis

TitleOverlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis
Publication TypePublication
Year2019
AuthorsHobbs BD, Putman RK, Araki T, Nishino M, Gudmundsson G, Gudnason V, Eiriksdottir G, Nogueira NRodrigues, Dupuis J, Xu H, O'Connor GT, Manichaikul A, Nguyen J, Podolanczuk AJ, Madahar P, Rotter JI, Lederer DJ, R Barr G, 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, R Jenkins G, Maher TM, Hubbard RB, Wain LV, Fingerlin TE, Schwartz DA, Washko GR, Rosas IO, Silverman EK, Hatabu H, Cho MH, Hunninghake GM
JournalAm J Respir Crit Care Med
Volume200
Issue11
Pagination1402-1413
Date Published2019 Dec 01
ISSN1535-4970
KeywordsAged, beta Karyopherins, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Idiopathic Pulmonary Fibrosis, Lung Diseases, Interstitial, Male, Middle Aged, Mucin-5B, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, TATA Box Binding Protein-Like Proteins
Abstract

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 associations among individuals with ILAs or additional overlap with IPF is not known. To perform a genome-wide association study (GWAS) of ILAs. 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. Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs ( = 2.6 × 10) and subpleural ILAs ( = 1.6 × 10). We discovered novel genome-wide associations near (rs6886640,  = 3.8 × 10) and (rs73199442,  = 4.8 × 10) with ILAs, and near (rs7744971,  = 4.2 × 10) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (, , , , and ) were significantly associated ( < 0.05/12) with ILAs. In a GWAS of ILAs in six studies, we confirmed the association with a 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.

DOI10.1164/rccm.201903-0511OC
Alternate JournalAm J Respir Crit Care Med
PubMed ID31339356
PubMed Central IDPMC6884045
Grant ListP01 HL092870 / HL / NHLBI NIH HHS / United States
K24 HL137013 / HL / NHLBI NIH HHS / United States
R01 HL135142 / HL / NHLBI NIH HHS / United States
RP-2017-08-ST2-014 / DH_ / Department of Health / United Kingdom
U01 HL137880 / HL / NHLBI NIH HHS / United States
R01 HL097163 / HL / NHLBI NIH HHS / United States
R33 HL120770 / HL / NHLBI NIH HHS / United States
R01 CA203636 / CA / NCI NIH HHS / United States
R01 HL131565 / HL / NHLBI NIH HHS / United States
G0901226 / MRC_ / Medical Research Council / United Kingdom
R01 HL130974 / HL / NHLBI NIH HHS / United States
U01 HL089897 / HL / NHLBI NIH HHS / United States
MR/N005953/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL130796 / HL / NHLBI NIH HHS / United States
K08 HL140087 / HL / NHLBI NIH HHS / United States
R01 HL111024 / HL / NHLBI NIH HHS / United States
U01 HL089856 / HL / NHLBI NIH HHS / United States
K08 HL136928 / HL / NHLBI NIH HHS / United States
T32 HL007085 / HL / NHLBI NIH HHS / United States
MS#: 
MS139
Manuscript Full Title: 
Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis
ECI: 
Manuscript Status: 
Published and Public