Department of Respiratory and Critical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
The Bioinformatics Department, Digital China Health Technologies Co., Ltd, Beijing, China.
Sci Rep. 2021 Jan 14;11(1):1443. doi: 10.1038/s41598-020-80944-4.
Genetic factors play a role in the risk of idiopathic pulmonary fibrosis (IPF). Specifically, MUC5B rs35705950 non-risk alleles and immunologic aberrations were associated with the IPF's progression. However, rare genetic variants have not been systematically investigated in Chinese IPF patients. In this study, we aimed to improve understanding of the genetic architecture of IPF in the Chinese population and to assess whether rare protein-coding variants in the immunity pathway genes are enriched in the IPF patients with non-risk alleles at rs35705950. A case-control exome-wide study including 110 IPF patients and 60 matched healthy controls was conducted. rs35705950 was genotyped by Sanger sequencing. To identify genes enriched in IPF, gene-based association analyses were performed. Identified genes were included for further pathway analyses using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Associations between rs35705950 and genes enriched in the immunity pathway were also tested. 226 genes that were enriched with deleterious variants were identified in IPF patients. Out of them, 36 genes were significantly enriched in GO and KEGG pathways in the IPF. Pathway analyses implicated that these genes were involved in the immune response and cell adhesion. Rare protein-altering variants in genes related to the immunity pathway did not significantly differ between patients with a MUC5B risk allele and individuals without risk allele. We drafted a comprehensive mutational landscape of rare protein-coding variants in the Chinese IPF and identified genes related to immune response and cell adhesion. These results partially explain changes in gene expression involved in the immunity/inflammatory pathways in IPF patients.
遗传因素在特发性肺纤维化 (IPF) 的发病风险中起作用。具体而言，MUC5B rs35705950 非风险等位基因和免疫异常与 IPF 的进展相关。然而，在中国人 IPF 患者中尚未系统地研究罕见遗传变异。在这项研究中，我们旨在深入了解中国人 IPF 的遗传结构，并评估免疫途径基因中的罕见蛋白编码变异是否在 rs35705950 非风险等位基因的 IPF 患者中富集。进行了一项包括 110 名 IPF 患者和 60 名匹配健康对照的病例对照外显子组全基因组研究。通过 Sanger 测序对 rs35705950 进行基因分型。为了确定在 IPF 中富集的基因，进行了基于基因的关联分析。鉴定的基因被包含在进一步的通路分析中，使用基因本体论 (GO) 和京都基因与基因组百科全书 (KEGG)。还测试了 rs35705950 与免疫途径中富集的基因之间的关联。在 IPF 患者中鉴定出 226 个富含有害变异的基因。其中，36 个基因在 GO 和 KEGG 通路中在 IPF 中显著富集。通路分析表明，这些基因参与免疫反应和细胞黏附。MUC5B 风险等位基因的患者和无风险等位基因的个体之间，与免疫途径相关的基因中的罕见蛋白改变变异没有显著差异。我们起草了中国人 IPF 中罕见蛋白编码变异的综合突变景观，并确定了与免疫反应和细胞黏附相关的基因。这些结果部分解释了 IPF 患者中涉及免疫/炎症途径的基因表达变化。
