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<p>Interstitial lung disease (ILD) is a progressive fibrotic condition that markedly reduces survival and increases mortality rates in patients with rheumatoid arthritis (RA). Currently, the treatment of RA-ILD remains highly challenging. This study aims to identify potential therapeutic targets for RA-ILD through a systematic druggable genome-wide Mendelian randomization (MR) analysis. We performed a genome-wide MR analysis by integrating expression quantitative trait loci (eQLT) of 6888 druggable genes and genetic summary statistics from a genome-wide association study of RA-ILD. A colocalization analysis was performed to prioritize genes strongly associated with RA-ILD. Enrichment analysis, protein–protein interaction network construction, drug prediction, and molecular docking were further conducted to provide valuable guidance for the development of targeted therapies. A total of 33 druggable genes showed significant association with RA-ILD, one of which, CISD1, was robustly validated through colocalization analysis. Notably, three key target genes—CST7, ATN1, and FCER2—were identified as potential mediators of the treatment effect of cyclophosphamide, a current clinical treatment for RA-ILD. This study employed MR and colocalization analysis to identify 33 potential drug-target genes for RA-ILD, including three genes associated with the mechanism of action of cyclophosphamide. These findings offer a promising roadmap for developing targeted therapies, potentially shifting treatment strategies from broad immunosuppression to precise molecular interventions.</p>

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Identifying therapeutic target genes for rheumatoid arthritis-associated interstitial lung disease by systematic druggable genome-wide Mendelian randomization analysis

  • 期刊论文

  • 发表日期：

    2026年5月5日

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  • Lianzhi Chen,
  • Mingxi Gu,
  • Ziyu Chen,
  • Gengmin Zhou,
  • Ren Chen,
  • Jintao Chen,
  • Qingwen Wang

摘要

Interstitial lung disease (ILD) is a progressive fibrotic condition that markedly reduces survival and increases mortality rates in patients with rheumatoid arthritis (RA). Currently, the treatment of RA-ILD remains highly challenging. This study aims to identify potential therapeutic targets for RA-ILD through a systematic druggable genome-wide Mendelian randomization (MR) analysis. We performed a genome-wide MR analysis by integrating expression quantitative trait loci (eQLT) of 6888 druggable genes and genetic summary statistics from a genome-wide association study of RA-ILD. A colocalization analysis was performed to prioritize genes strongly associated with RA-ILD. Enrichment analysis, protein–protein interaction network construction, drug prediction, and molecular docking were further conducted to provide valuable guidance for the development of targeted therapies. A total of 33 druggable genes showed significant association with RA-ILD, one of which, CISD1, was robustly validated through colocalization analysis. Notably, three key target genes—CST7, ATN1, and FCER2—were identified as potential mediators of the treatment effect of cyclophosphamide, a current clinical treatment for RA-ILD. This study employed MR and colocalization analysis to identify 33 potential drug-target genes for RA-ILD, including three genes associated with the mechanism of action of cyclophosphamide. These findings offer a promising roadmap for developing targeted therapies, potentially shifting treatment strategies from broad immunosuppression to precise molecular interventions.