Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing

Lorenzo-Salazar, Jose M.; Ma, Shwu-Fan; Jou, Jonathan; Hou, Pei-Chi; Guillen-Guio, Beatriz; Allen, Richard J.; Jenkins, R. Gisli; Wain, Louise V.; Oldham, Justin M.; Noth, Imre; Flores, Carlos

Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing

journal contribution

posted on 2019-06-11, 09:04 authored by Jose M. Lorenzo-Salazar, Shwu-Fan Ma, Jonathan Jou, Pei-Chi Hou, Beatriz Guillen-Guio, Richard J. Allen, R. Gisli Jenkins, Louise V. Wain, Justin M. Oldham, Imre Noth, Carlos Flores

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 (100X) across 11p15.5, 14q21.3, and 17q21.31 loci. Comparisons were performed against 501 unrelated controls and replication studies were assessed in 3,968 subjects. Results: Thirty-six SNVs were associated with IPF susceptibility in the discovery stage (p<5.0x10-8). After meta-analysis, the strongest association corresponded to rs35705950 (p=9.27x10-57) located upstream from the mucin 5B (MUC5B) gene. Additionally, a novel association was found for two co-inherited low-frequency SNVs (<5%) in MUC5AC gene, predicting a missense amino acid change in mucin 5AC (lowest p=2.27x10-22). Conditional and haplotype analyses in 11p15.5 supported the existence of 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.

Funding

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) (Carlos Flores, PhD) to strengthen scientific and technological education, training, research, development and innovation in Genomics, Personalized Medicine and Biotechnology; Pulmonary Fibrosis Foundation, Coalition for Pulmonary Fibrosis grants, and 1RO1HL130796-01A1 (Imre Noth, MD); Core Subsidy Mini Awards of the Institute of Translational Medicine and Clinical and Translational Science Award (UL1 RR024999) (Shwu-Fan Ma, PhD); and a fellowship from Agencia Canaria de Investigación, Innovación y Sociedad de la Información (TESIS2015010057) co-funded by European Social Fund (Bea 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 Department of Health. Louise V. Wain, PhD, holds a GSK/British Lung Foundation Chair in Respiratory Research. R. Gisli Jenkins, MD, is an NIHR Research Professor (RP-2017-08-014). The replication study has been conducted using the UK Biobank Resource under application 8389.

History

Citation

ERJ Open Research, 2019, 5 (2)

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

VoR (Version of Record)

Published in

ERJ Open Research

Publisher

European Respiratory Society

issn

2312-0541

Acceptance date

2019-04-07

Copyright date

2019

Available date

2019-06-10

Publisher DOI

https://doi.org/10.1183/23120541.00071-2019

Notes

The file associated with this record is under embargo until publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.