American journal of respiratory and critical care medicine · 2019
Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Hobbs Brian D, Putman Rachel K, Araki Tetsuro, Nishino Mizuki, Gudmundsson Gunnar, Gudnason Vilmundur, Eiriksdottir Gudny, Zilhao Nogueira Nuno Rodrigues, Dupuis Josée, Xu Hanfei, O'Connor George T, Manichaikul Ani, Nguyen Jennifer, Podolanczuk Anna J, Madahar Purnema, Rotter Jerome I, Lederer David J, Barr R Graham, Rich Stephen S, Ampleford Elizabeth J, Ortega Victor E, Peters Stephen P, O'Neal Wanda K, Newell John D, Bleecker Eugene R, Meyers Deborah A, Allen Richard J, Oldham Justin M, Ma Shwu-Fan, Noth Imre, Jenkins R Gisli, Maher Toby M, Hubbard Richard B, Wain Louise V, Fingerlin Tasha E, Schwartz David A, Washko George R, Rosas Ivan O, Silverman Edwin K, Hatabu Hiroto, Cho Michael H, Hunninghake Gary M
Аннотация
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.