4.5 Article

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

期刊

HUMAN MUTATION
卷 39, 期 9, 页码 1238-1245

出版社

WILEY
DOI: 10.1002/humu.23566

关键词

common SNP; genetic factors; idiopathic pulmonary fibrosis; next-generation sequencing; risk stratification

资金

  1. Integrated Innovative Teamfor Major Human Diseases Program of Tongji Medical College, Huazhong University of Science and Technology
  2. Clinical Research Physician Program of Tongji Medical College, Huazhong University of Science and Technology

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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 (similar to 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 x 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.

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