Whole-exome sequencing identifies susceptibility genes and pathways for idiopathic pulmonary fibrosis in the Chinese population

Genetic factors play a role in the risk of idiopathic pulmonary fibrosis (IPF). Specifically, MUC5B rs35705950 non-risk alleles and immunologic aberrations were associated with the IPF’s progression. However, rare genetic variants have not been systematically investigated in Chinese IPF patients. In this study, we aimed to improve understanding of the genetic architecture of IPF in the Chinese population and to assess whether rare protein-coding variants in the immunity pathway genes are enriched in the IPF patients with non-risk alleles at rs35705950. A case–control exome-wide study including 110 IPF patients and 60 matched healthy controls was conducted. rs35705950 was genotyped by Sanger sequencing. To identify genes enriched in IPF, gene-based association analyses were performed. Identified genes were included for further pathway analyses using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Associations between rs35705950 and genes enriched in the immunity pathway were also tested. 226 genes that were enriched with deleterious variants were identified in IPF patients. Out of them, 36 genes were significantly enriched in GO and KEGG pathways in the IPF. Pathway analyses implicated that these genes were involved in the immune response and cell adhesion. Rare protein-altering variants in genes related to the immunity pathway did not significantly differ between patients with a MUC5B risk allele and individuals without risk allele. We drafted a comprehensive mutational landscape of rare protein-coding variants in the Chinese IPF and identified genes related to immune response and cell adhesion. These results partially explain changes in gene expression involved in the immunity/inflammatory pathways in IPF patients.