Genome-wide association study reveals CBX7 as a novel susceptibility gene associated with primary spontaneous pneumothorax in the Chinese Han population.
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Xu Leilei, Ma Dehua, Wang Bingjian, Cai Mengru, Wu Zhichong, Cheng Shuwen, Cai Minghui, Ding Yibing, Zhang Xinxin, Sun Qi, Niu Fengnan, Wu Hongyan, Dai Zhicheng, Min Haiyan, Wen Yanting, Song Shiyu, Zou Wei, Wang Chao, Li Sufen, Wang Jiaochen, Shen Jianfei, Wang Xinxin, Lin Aifen, Cao Xingbing, Yuan Xinxin, Xia Chao, Guo Zhongying, Feng Zhenhua, Du Ronghui, Qiao Jun, Gao Qi, Shi Benlong, Mao Saihu, Chen Tianming, Ren Haozhen, Ye Minhua, Hu Xiaowen, Hu Ping, Xu Zhengfeng, Chen Shilin, Qiu Yong, Wang Yong, Gao Qian, Zhu Chengchu, Zhu Zezhang, Yi Long
Аннотация
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 knockout of Cbx7 in mouse lung epithelial cells resulted in lung cyst formation. Meanwhile, downregulation 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 MMP signalling give a new clue to the pathogenesis of primary spontaneous pneumothorax.