Brian D Hobbs1,2, Rachel K Putman2, Tetsuro Araki3,4, Mizuki Nishino3,4, Gunnar Gudmundsson5, Vilmundur Gudnason6,7, Gudny Eiriksdottir7, Nuno Rodrigues Zilhao Nogueira7, Josée Dupuis8,9, Hanfei Xu8, George T O'Connor9,10, Ani Manichaikul11,12, Jennifer Nguyen11, Anna J Podolanczuk13, Purnema Madahar13, Jerome I Rotter14,15,16, David J Lederer13,17, R Graham Barr13,17, Stephen S Rich11,12, Elizabeth J Ampleford18, Victor E Ortega18, Stephen P Peters18, Wanda K O'Neal19, John D Newell20,21, Eugene R Bleecker22, Deborah A Meyers22, Richard J Allen23, Justin M Oldham24, Shwu-Fan Ma25, Imre Noth25, R Gisli Jenkins26, Toby M Maher27,28, Richard B Hubbard26,29, Louise V Wain30, Tasha E Fingerlin31,32, David A Schwartz32,33,34, George R Washko2,4, Ivan O Rosas2, Edwin K Silverman1,2, Hiroto Hatabu3,4, Michael H Cho1,2, Gary M Hunninghake2,4. 1. Channing Division of Network Medicine. 2. Division of Pulmonary and Critical Care Medicine. 3. Department of Radiology, and. 4. Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Boston, Massachusetts. 5. Department of Respiratory Medicine, Landspital University Hospital, and. 6. Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 7. Icelandic Heart Association, Kopavogur, Iceland. 8. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. 9. NHLBI Framingham Heart Study, Framingham, Massachusetts. 10. Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts. 11. Center for Public Health Genomics. 12. Department of Public Health Sciences, and. 13. Department of Medicine, College of Physicians and Surgeons, and. 14. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and. 15. Division of Genomic Outcomes, Department of Pediatrics and. 16. Department of Medicine, Harbor-UCLA Medical Center, Torrance, California. 17. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York. 18. Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina. 19. Marsico Lung Institute, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 20. Division of Cardiovascular and Pulmonary Imaging, Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa. 21. Department of Radiology, University of Washington, Seattle, Washington. 22. Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona. 23. Department of Health Sciences, University of Leicester, Leicester, United Kingdom. 24. Department of Internal Medicine, University of California Davis, Davis, California. 25. Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia. 26. National Institute for Health Research, Biomedical Research Centre, Respiratory Research Unit, School of Medicine, and. 27. National Institute for Health Research, Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom. 28. Fibrosis Research Group, Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London, United Kingdom. 29. Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom. 30. National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom. 31. Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado; and. 32. Department of Biostatistics and Informatics. 33. Department of Medicine, School of Medicine, and. 34. Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, Colorado.
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 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 = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS 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.
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 = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS 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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