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ERJ Open Res. 2019 Jun 10;5(2). pii: 00071-2019. doi: 10.1183/23120541.00071-2019. eCollection 2019 Apr.

Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing.

Author information

1
Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain.
2
These authors contributed equally to this work.
3
Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA.
4
College of Medicine, University of Illinois, Chicago, IL, USA.
5
Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
6
Dept of Health Sciences, University of Leicester, Leicester, UK.
7
NIHR Biomedical Research Centre, Respiratory Research Unit, University of Nottingham, Nottingham, UK.
8
National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
9
Pulmonary and Critical Care Medicine, University of California at Davis, Sacramento, CA, USA.
10
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.

Abstract

Background:

Specific common and rare single nucleotide variants (SNVs) increase the likelihood of developing sporadic idiopathic pulmonary fibrosis (IPF). We performed target-enriched sequencing on three loci previously identified by a genome-wide association study to gain a deeper understanding of the full spectrum of IPF genetic risk and performed a two-stage case-control association study.

Methods:

A total of 1.7 Mb of DNA from 181 IPF patients was deep sequenced (>100×) across 11p15.5, 14q21.3 and 17q21.31 loci. Comparisons were performed against 501 unrelated controls and replication studies were assessed in 3968 subjects.

Results:

36 SNVs were associated with IPF susceptibility in the discovery stage (p<5.0×10-8). After meta-analysis, the strongest association corresponded to rs35705950 (p=9.27×10-57) located upstream from the mucin 5B gene (MUC5B). Additionally, a novel association was found for two co-inherited low-frequency SNVs (<5%) in MUC5AC, predicting a missense amino acid change in mucin 5AC (lowest p=2.27×10-22). Conditional and haplotype analyses in 11p15.5 supported the existence of an additional contribution of MUC5AC variants to IPF risk.

Conclusions:

This study reinforces the significant IPF associations of these loci and implicates MUC5AC as another key player in IPF susceptibility.

Conflict of interest statement

Conflict of interest: J.M. Lorenzo-Salazar has nothing to disclose. Conflict of interest: S-F. Ma has nothing to disclose. Conflict of interest: J. Jou has nothing to disclose. Conflict of interest: P-C. Hou has nothing to disclose. Conflict of interest: B. Guillen-Guio has nothing to disclose. Conflict of interest: R.J. Allen has nothing to disclose. Conflict of interest: R.G. Jenkins reports grants from GlaxoSmithKline, during the conduct of the study; grants from Biogen and Galecto, personal fees from Boehringer Ingelheim, Galapagos, Heptares, Pliant and Roche, grants and personal fees from GlaxoSmithKline and MedImmune, and has been on advisory boards for NuMedii and Redex, outside the submitted work. He is a trustee of the British Thoracic Society and Action for Pulmonary Fibrosis, and is an NIHR Research Professor (RP-2017-08-014). Conflict of interest: L.V. Wain reports grants from GlaxoSmithKline, outside the submitted work, and holds a GlaxoSmithKline/British Lung Foundation Chair in Respiratory Research. Conflict of interest: J.M. Oldham has nothing to disclose. Conflict of interest: I. Noth reports personal fees and consultancy fees from Boehringer Ingelheim, and personal fees from Genentech/Hoffman La Roche, Global Blood therapeutics, Sanofi Aventis and Zambon, outside the submitted work. In addition, I. Noth has a patent TOLLIP and NAC in IPF pending. Conflict of interest: C. Flores reports grants from Instituto de Salud Carlos III and Instituto Tecnológico y de Energías Renovables (ITER), during the conduct of the study.

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