Exome-wide association study identifies a phosphatidylethanolamine-binding protein 4 variant associated with idiopathic pulmonary fibrosis risk in Koreans.

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, shaped by both environmental and genetic factors. While genome-wide association studies have identified several IPF risk loci, the genetic basis remains incomplete, especially in non-European populations.

Methods: We performed an exome-wide association study in 186 Korean IPF patients and 262 healthy controls using the Illumina HumanExome v1.1 BeadChip to discover novel exonic variants linked to IPF susceptibility. Logistic regression was used to test associations, adjusting for age, sex, and smoking history. Functional implications were evaluated through structural modeling and protein stability predictions.

Results: After quality control, 23 737 single-nucleotide polymorphisms (SNPs) were analyzed. The variant rs1047406 (T>C) in the PEBP4 gene was significantly associated with IPF under a codominant model (odds ratio = 1.94, 95% confidence interval = 1.42-2.65, P < 0.05 after correction). Haplotype analysis, including three nearby SNPs, further supported this association. In-silico analyses predicted that the E11G substitution caused by rs1047406 reduces protein stability and may disrupt proper folding. GTEx eQTL data showed that the minor allele is linked to altered PEBP4 expression in several tissues. PEBP4 is known to regulate phosphoinositide 3-kinase/protein kinase B and nuclear factor kappa B pathways, both implicated in fibrotic remodeling.

Conclusion: A novel PEBP4 variant associated with IPF was identified in a Korean population, likely affecting protein function and expression. These findings underscore the importance of ethnic-specific studies and support PEBP4 as a candidate gene in IPF, meriting further validation.