Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing

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

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Article number00071-2019
JournalERJ Open Research
Issue number2
StatePublished - Apr 1 2019

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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