Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Key Cite of National Clinical Research Center for Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.
Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hum Mutat. 2018 Sep;39(9):1238-1245. doi: 10.1002/humu.23566. Epub 2018 Jun 29.
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 ) 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.
特发性肺纤维化（IPF）是一种遗传异质性疾病，死亡率高，预后差。然而，很大一部分遗传原因仍未得到解释，尤其是在散发性 IPF（约 80%的 IPF）中。通过系统地回顾相关文献和潜在的致病途径，选择了 92 个可能与 IPF 相关的基因，并使用靶向大规模平行下一代测序技术对 253 例散发性 IPF 患者和 125 例匹配的健康对照者的基因组 DNA 进行测序。通过 Sanger 测序对鉴定出的风险变异进行了验证。我们鉴定出两个致病性和 10 个功能丧失（LOF）候选变异体，占所有 IPF 病例的 4.74%（253 例中的 12 例）。在负担测试中，三个基因（CSF3R、DSP 和 LAMA3）中的罕见错义变异与 IPF 具有统计学意义的关系。还观察到四个常见的 SNPs（rs3737002、rs2296160、rs1800470 和 rs35705950）与 IPF 的风险增加具有统计学相关性。在累积风险模型中，高危受试者发生 IPF 的风险是低危受试者的 3.47 倍（95%CI：2.07-5.81，P=2.34×10）。我们绘制了一张包含 IPF 患者遗传风险（包括罕见和常见候选变异体）的综合图谱，这可以帮助我们深入了解机制，提供遗传诊断，并预测 IPF 的风险。
