Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing

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.