Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

中文翻译：

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肺纤维化的遗传学和基因组学：绘制分子图谱并塑造精准医学。


最近的遗传学和基因组进展阐明了特发性肺纤维化（IPF）和其他进行性纤维化间质性肺疾病（ILD）的复杂病因，强调了遗传因素的贡献。这篇最先进的综述综合了肺纤维化 (PF) 的重要遗传因素的证据，包括罕见的遗传变异和常见的 SNP。 MUC5B 启动子变异很不寻常，是一种常见的 SNP，可显着提高早期和已形成 PF 的风险。我们探讨遗传变异在增强对疾病发病机制和临床表型的理解、改进疾病定义以及告知预后和治疗反应方面的效用。强调了关键的研究差距，特别是在 PF 遗传学研究中非欧洲血统的代表性不足以及对普通间质性肺炎/IPF 之外的 PF 表型的探索。我们讨论了端粒长度（在 PF 中通常非常短）的作用及其与进展和死亡率的联系，强调了涉及端粒生物学基因（TERT、TERC）以及其他基因（如 SFTPC 和 MUC5B）的遗传复杂性。此外，我们还探讨了基因与环境相互作用调节疾病表现的潜力，倡导肺纤维化的精准医疗。基因表达谱研究和多组学分析的见解凸显了了解疾病发病机制的前景，并为临床护理、治疗药物开发和生物标志物发现提供了新方法。最后，我们讨论了 PF 基因组研究和治疗的伦理、法律和社会影响，强调需要良好的实践和知情的临床遗传学讨论。 展望未来，我们主张进行全面的基因检测和多基因风险评分，以改善不同人群对 PF 和相关 ILD 的管理。