Genome-wide association study reveals CBX7 as a novel susceptibility gene associated with primary spontaneous pneumothorax in the Chinese Han population.

Abstract

Background: Primary spontaneous pneumothorax is a rare disease commonly found in young adults with unknown etiology. We aimed to investigate the susceptibility genes and the downstream signaling involved in the development of primary spontaneous pneumothorax.

Methods: We conducted the first large-scale genome-wide association study (GWAS) composed of 2223 patients and 3838 controls. The functional role of the novel susceptibility loci was investigated by both in-vivo and in-vitro assays. Gene expression profiling in lung epithelial cell lines was performed and conditional gene knockout mice were generated.

Results: We identified four novel susceptibility loci at 14q32.2 near C14orf177, at 15q26.3 near CHSY1, at 16q23.1 near CFDP1, and at 22q13.1 near CBX7. The fine-mapping of 22q13.1 revealed a functional variant which regulated CBX7 expression by disrupting the binding activity of transcription factor CREB1. Conditional knock-out of Cbx7 in mouse lung epithelial cells resulted in lung cyst formation. Meanwhile, down-regulation of the CBX7 elevated the expression of MMP9 and MMP16, which are part of extracellular matrix regulators and may lead to lung injury.

Conclusions: Our GWAS discovered four novel susceptibility loci of primary spontaneous pneumothorax and presented a mechanistic basis for the genetic association with primary spontaneous pneumothorax. The novel susceptibility gene CBX7 and downstream MMPs signaling give a new clue to the pathogenesis of primary spontaneous pneumothorax.