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.
Abstract
Deep sequencing of genome-wide association study hits identified novel low-frequency variants associated with IPF susceptibility. http://bit.ly/2IF4AT8
Footnotes
This article has supplementary material available from openres.ersjournals.com
Author contributions: S.F. Ma and J. Jou collected DNA samples, designed the experiments, and generated the sequencing data. S.F. Ma and P-C. Hou performed the validation experiments and interpreted the trace results. J.M. Lorenzo-Salazar, J.M. Oldham and C. Flores analysed and interpreted data. B. Guillen-Guio, R.J. Allen, R.G. Jenkins and L.V. Wain performed the replication study. I. Noth and C. Flores were the principal investigators of the discovery study and conceived the project. R.G. Jenkins was the principal investigator on the replication study. All authors contributed to the drafting, revision and coordination of the manuscript. All authors read and approved of the final manuscript. C. Flores takes full responsibility for the content of the manuscript, including the data and analysis.
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.
Support statement: This research was funded by the Instituto de Salud Carlos III (grant PI17/00610) and the Spanish Ministry of Science, Innovation and Universities (grant RTC-2017-6471-1; MINECO/AEI/FEDER, UE), which were co-financed by the European Regional Development Funds “A Way of Making Europe” from the European Union, and by the agreement OA17/008 with Instituto Tecnológico y de Energías Renovables (ITER) (C. Flores). Funding was also received from the Pulmonary Fibrosis Foundation, Coalition for Pulmonary Fibrosis grants, and 1RO1HL130796-01A1 (I. Noth); Core Subsidy Mini Awards of the Institute of Translational Medicine and Clinical and Translational Science Award (UL1 RR024999) (S-F. Ma); and a fellowship from Agencia Canaria de Investigación, Innovación y Sociedad de la Información (TESIS2015010057) co-funded by European Social Fund (B. Gillen-Guio). The research was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Dept of Health. The replication study has been conducted using the UK Biobank Resource under application 8389. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received March 18, 2019.
- Accepted April 7, 2019.
- Copyright ©ERS 2019
This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.