Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 200, Issue 11, Pages 1402-1413Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201903-0511OC
Keywords
genetics; genome-wide association study; interstitial lung abnormalities; idiopathic pulmonary fibrosis; SNP
Categories
Funding
- NIH [K08 HL136928, K08 HL140087, R01 CA203636, K23 HL140199, R01 HL142302, R01 EY009052, R01EY023704, P30 DK063491, K24 HL131937, R01 HL103676, R01 HL137234, R01 HL077612, R01 HL093081, R01 HL121270, R01 HL142028]
- Oddur Olafsson Fund from the Icelandic Research Fund [141513-051]
- Landspitali Scientific Fund [A-2015-030, A2016-023, A-2017-030, A-2018-022, A-2018-025]
- National Institute on Aging (NIA) [27120120022C]
- Icelandic Research Fund [141513-051, 141513051]
- Action Pulmonary Fibrosis Mike Bray Fellowship
- Medical Research Council [G0901226]
- National Institute for Health Research (NIHR) Clinician Scientist Fellowship [CS-2013-13-017]
- NIHR Leicester Biomedical Research Centre
- NIA [27120120022C]
- NIA Intramural Research Program
- Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- NHLBI
- National Center for Advancing Translational Sciences [ULTR001881]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant [DK063491]
- NHLBI [HHSN268200900013C, HSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C]
- NIH/NHLBI [U01 HL137880]
- COPD Foundation
- Foundation for the NIH
- 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
- Mylan
- [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]
- [UL1-TR-001420]
- [R33 HL120770]
- [R33 CA182360]
- [UH3 HL123442]
- [R01 HL116473]
- [R01 HL122464]
- [U01 HL133232]
- [R01 HL130974]
- [U01 HL089856]
- [R01 HL113264]
- [R01 HL137927]
- [R01 HL133135]
- [P01 HL114501]
- [R01 HL135142]
- [R01 HL111024]
- [R01 NR013700]
- [K23 HL138190]
- [R01 HL130796]
- [R01 HL114587]
- [P01 HL132821]
- [P01 HL092870]
- [R01 HL097163]
- [K08 HL118128]
- [R01 HL142992]
- [UG1 HL1390534]
- [U01 HL109164]
- [U01 HL120393]
- [DP3 DK111906]
- [P01 HL136275]
- [R01 HL117843]
- [U24 HL141762]
- [R01 135142]
- [U01 HL089897]
- [N01-HC-25195]
- [HHSN268201500001I]
- [OT2 OD026553]
- [N01-AG-1-2100]
- [HHSN27120120022C]
- MRC [MR/N005953/1] Funding Source: UKRI
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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 associations among 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 = 2.6x10(-27)) and subpleural ILAs (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 ILAs, and near HTRE1 (rs7744971, P = 4.2x10(-8)) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPFGWAS loci, 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.
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