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Deciphering the role of oxidative stress genes in idiopathic pulmonary fibrosis: a multi-omics mendelian randomization approach

Genes & Immunity (2024)Cite this article

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Abstract

Oxidative stress (OS) is crucial in idiopathic pulmonary fibrosis (IPF) pathogenesis, with its genes potentially acting as both causes and consequences of the disease. We identified OS-related genes from GeneCards and performed a meta-analysis on pulmonary transcriptome datasets to discover differentially expressed genes (DEGs) related to OS in IPF. We integrated this data with the largest available IPF GWAS summaries, expression quantitative trait loci (eQTLs), and DNA methylation QTLs (mQTLs) from blood. This approach aimed to identify blood OS genes and regulatory elements linked to IPF risk, incorporating the latest pulmonary eQTLs and bronchoalveolar lavage fluid microbial QTLs (bmQTLs) for a comprehensive view of gene-lung microbiota interactions through SMR and colocalization analyses. Sensitivity analyses were conducted using two additional mendelian randomization (MR) methods. Meta-analysis revealed 1090 differentially expressed OS genes between IPF patients and controls. Integration with IPF GWAS, eQTL, and mQTL data identified key genes and regulatory elements involved in IPF pathogenesis, highlighting the role of specific genes such as KCNMA1 and SLC22A5 in modulating IPF risk through epigenetic mechanisms. Colocalization analysis further identified potential interactions between gene expression and lung microbiota. Our findings elucidate the complex interplay between OS genes and IPF, suggesting potential therapeutic targets and highlighting the importance of considering epigenetic and microbial interactions in the disease’s etiology and progression.

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Fig. 1: Schematic diagram of the mendelian randomization framework.
Fig. 2: Meta-analysis of four RNA-seq datasets between IPF and control groups.
Fig. 3: A three-step SMR analysis prioritizing blood tissue to identify presumed causal OS genes and mechanisms in IPF.
Fig. 4: SMR and colocalization analyses prioritize the interaction between pQTL proteins and OS_DEG.

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Data availability

All the data in this study are from the public data of personal research papers. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

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Acknowledgements

We thank all the researchers for providing their GWAS data.

Funding

This study was supported by Hebei Medical Research Project Plan (No. 20210373).

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Author notes

  1. These authors contributed equally: Xin Liu, Dengfeng Zhang, Fangchao Zhao, Shujun Li, Haiyong Zhu, Xu Zhang

Authors and Affiliations

  1. Second Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Xin Liu

  2. Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Dengfeng Zhang

  3. Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Fangchao Zhao, Shujun Li, Haiyong Zhu & Xu Zhang

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  1. Xin Liu
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Contributions

SL and XZ contributed to the conception and design. DZ and FZ did the acquisition of data and data analysis. XL drafted the article. HZ and XZ did the revision of the article. All authors approved the final version of manuscript.

Corresponding authors

Correspondence to Shujun Li, Haiyong Zhu or Xu Zhang.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All methods in this study were conducted in strict accordance with relevant guidelines and regulations to ensure compliance and scientific integrity. The data we use are from published studies approved by the appropriate ethics committees, so no further ethical approval is required for this study. The data used in this study were sourced from publicly available databases, and no new informed consent procedures were conducted. However, all data used had received ethical approval in the original studies, and the use of publicly available data complies with all relevant ethical and legal requirements. This study did not involve the publication of identifiable human images; therefore, written informed consent for image publication is not applicable.

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Liu, X., Zhang, D., Zhao, F. et al. Deciphering the role of oxidative stress genes in idiopathic pulmonary fibrosis: a multi-omics mendelian randomization approach. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00292-5

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