Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC, Ghaziabad, Uttar Pradesh, India; Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.
Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, New Delhi, India; Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.
Gene. 2024 Feb 15;895:147993. doi: 10.1016/j.gene.2023.147993. Epub 2023 Nov 15.
Idiopathic pulmonary fibrosis (IPF) is a rare and devastating fibrotic lung disorder with unknown etiology. Although it is believed that genetic component is an important risk factor for IPF, a comprehensive understanding of its genetic landscape is lacking. Hence, we aimed to highlight the susceptibility genes and pathways implicated in IPF pathogenesis through a two-staged systematic literature search of genetic association studies on IPF, followed by meta-analysis and pathway enrichment analysis.
This study was performed based on PRISMA guidelines (PROSPERO, registration number: CRD42022297970). The first search was performed (using PubMed and Web of Science) retrieving a total of 5642 articles, of which 52 were eligible for inclusion in the first stage. The second search was performed (using PubMed, Web of Science and Scopus) for ten polymorphisms, identified from the first search, with 2 or more studies. Finally, seven polymorphisms, [rs35705950/MUC5B, rs2736100/TERT, rs2609255/FAM13A, rs2076295/DSP, rs12610495/DPP9, rs111521887/TOLLIP and rs1800470/TGF-β1] qualified for meta-analyses. The epidemiological credibility was evaluated using Venice criteria.
From the systematic review, 222 polymorphisms in 118 genes showed a significant association with IPF susceptibility. Meta-analyses findings revealed significant association of rs35705950/T [OR = 3.92(3.26-4.57)], rs2609255/G [OR = 1.50(1.18-1.82)], rs2076295/G [OR = 1.19(0.82-1.756)], rs12610495/G [OR = 1.28(1.12-1.44)], rs2736100/C [OR = 0.68(0.54-0.82), rs111521887/G [OR = 1.34(1.06-1.61)] and suggestive evidence for rs1800470/T [OR = 1.08(0.82-1.34)] with IPF susceptibility. Four polymorphisms- rs35705950/MUC5B, rs2736100/TERT, rs2076295/DSP and rs111521887/TOLLIP, exhibited substantial epidemiological evidence supporting their association with IPF risk. Gene ontology and pathway enrichment analysis performed on IPF risk-associated genes identified a critical role of genes in mucin production, immune response and inflammation, host defence, cell-cell adhesion and telomere maintenance.
Our findings present the most prominent IPF-associated genetic risk variants involved in alveolar epithelial injuries (MUC5B, TERT, FAM13A, DSP, DPP9) and epithelial-mesenchymal transition (TOLLIP, TGF-β1), providing genetic and biological insights into IPF pathogenesis. However, further experimental research and human studies with larger sample sizes, diverse ethnic representation, and rigorous design are warranted.
特发性肺纤维化（IPF）是一种罕见且具有破坏性的纤维化肺部疾病，其病因不明。虽然人们认为遗传因素是 IPF 的一个重要危险因素，但对其遗传图谱的全面了解仍有所欠缺。因此，我们旨在通过对 IPF 的遗传关联研究进行两阶段系统文献检索，随后进行荟萃分析和途径富集分析，突出与 IPF 发病机制相关的易感基因和途径。
本研究基于 PRISMA 指南（PROSPERO，注册号：CRD42022297970）进行。首先进行了一次搜索（使用 PubMed 和 Web of Science），共检索到 5642 篇文章，其中 52 篇符合纳入第一阶段的标准。然后，对从第一次搜索中确定的 10 个具有 2 个或更多研究的多态性进行了第二次搜索（使用 PubMed、Web of Science 和 Scopus）。最后，有 7 个多态性[rs35705950/MUC5B、rs2736100/TERT、rs2609255/FAM13A、rs2076295/DSP、rs12610495/DPP9、rs111521887/TOLLIP 和 rs1800470/TGF-β1]符合荟萃分析的条件。采用威尼斯标准评估流行病学可信度。
从系统综述中，118 个基因中的 222 个多态性与 IPF 易感性显著相关。荟萃分析结果显示，rs35705950/T [OR=3.92(3.26-4.57)]、rs2609255/G [OR=1.50(1.18-1.82)]、rs2076295/G [OR=1.19(0.82-1.756)]、rs12610495/G [OR=1.28(1.12-1.44)]、rs2736100/C [OR=0.68(0.54-0.82)]、rs111521887/G [OR=1.34(1.06-1.61)]和 rs1800470/T [OR=1.08(0.82-1.34)]与 IPF 易感性具有显著相关性，而 rs1800470/T 则提示存在相关性。四项多态性(rs35705950/MUC5B、rs2736100/TERT、rs2076295/DSP 和 rs111521887/TOLLIP)具有显著的流行病学证据，支持它们与 IPF 风险相关。对与 IPF 风险相关的基因进行基因本体论和途径富集分析，确定了基因在粘蛋白产生、免疫反应和炎症、宿主防御、细胞-细胞粘附和端粒维持中的关键作用。
我们的研究结果提出了与肺泡上皮损伤（MUC5B、TERT、FAM13A、DSP、DPP9）和上皮-间充质转化（TOLLIP、TGF-β1）相关的最显著的 IPF 相关遗传风险变异，为 IPF 的发病机制提供了遗传和生物学方面的见解。然而，需要进一步进行实验研究和人类研究，以获得更大的样本量、更多样化的种族代表性和更严格的设计。
