Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

• Published in: Human mutation Vol. 39; no. 9; pp. 1238 - 1245
• Main Authors: Deng, Yanhan, Li, Zongzhe, Liu, Juan, Wang, Zheng, Cao, Yanyan, Mou, Yong, Fu, Bohua, Mo, Biwen, Wei, Jianghong, Cheng, Zhenshun, Luo, Liman, Li, Jingping, Shu, Ying, Wang, Xiaomei, Luo, Guangwei, Yang, Shuo, Wang, Yingnan, Zhu, Jing, Yang, Jingping, Wu, Ming, Xu, Xuyan, Ge, Renying, Chen, Xueqin, Peng, Qingzhen, Wei, Guang, Li, Yaqing, Yang, Hua, Fang, Shirong, Zhang, Xiaoju, Xiong, Weining
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.09.2018
• Subjects: common SNP; Fibrosis; genetic factors; Genetic screening; idiopathic pulmonary fibrosis; Lung diseases; next‐generation sequencing; Pulmonary fibrosis; risk stratification; Single-nucleotide polymorphism; Statistical analysis; common SNP; risk stratification; idiopathic pulmonary fibrosis; next-generation sequencing; genetic factors
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23566

Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. However, a large fraction of genetic cause remains unexplained, especially in sporadic IPF (∼80% IPF). By systemically reviewing related literature and potential pathogenic pathways, 92 potentially IPF‐related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls using targeted massively parallel next‐generation sequencing. The identified risk variants were confirmed by Sanger sequencing. We identified two pathogenic and 10 loss‐of‐function (LOF) candidate variants, accounting for 4.74% (12 out of 253) of all the IPF cases. In burden tests, rare missense variants in three genes (CSF3R, DSP, and LAMA3) were identified that have a statistically significant relationship with IPF. Four common SNPs (rs3737002, rs2296160, rs1800470, and rs35705950) were observed to be statistically associated with increased risk of IPF. In the cumulative risk model, high risk subjects had 3.47‐fold (95%CI: 2.07–5.81, P = 2.34 × 10−6) risk of developing IPF compared with low risk subjects. We drafted a comprehensive map of genetic risks (including both rare and common candidate variants) in patients with IPF, which could provide insights to help in understanding mechanisms, providing genetic diagnosis, and predicting risk for IPF. A total of 92 potentially IPF‐related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls. We not only identified multiple novel rare and common variants that are associated with increased risk of IPF, but also constructed a cumulative risk model that suggests the possibility of risk prediction and stratification for IPF in Chinese.