Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing.

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

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