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

Academic Article

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 associationsamong 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 = 2.6310227) and subpleural ILAs (P = 1.6310229). We discovered novel genomewide associations near IPO11 (rs6886640, P = 3.831028) and FCF1P3 (rs73199442, P = 4.831028) with ILAs, and near HTRE1 (rs7744971, P = 4.231028) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPFGWASloci, 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.
  • Digital Object Identifier (doi)

    Author List

  • Hobbs BD; Putman RK; Araki T; Nishino M; Gudmundsson G; Gudnason V; Eiriksdottir G; Nogueira NRZ; Dupuis J; Xu H
  • Start Page

  • 1402
  • End Page

  • 1413
  • Volume

  • 200
  • Issue

  • 11