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Potential drug targets for gastroesophageal reflux disease and Barrett’s esophagus identified through Mendelian randomization analysis

Journal of Human Genetics (2024)Cite this article

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Abstract

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett’s esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10−5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

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Acknowledgements

We thank the authors for providing GWAS data and making the GWAS summary data publicly available. We acknowledge the participants and investigators of the ARIC cohort, deCODE cohort, IEU Open GWAS, The Genotype-Tissue Expression Consortium and the study of Ong et al.

Funding

This work was funded by the National Natural Science Foundation of China [grantnumbers82070333]; and the Zhejiang Provincial Natural Science Foundation [grantnumbersLY21H020011].

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  1. These authors contributed equally: Yun-Lu Lin, Tao Yao.

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  1. The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

    Yun-Lu Lin, Tao Yao, Ying-Wei Wang, Zhi-Xiang Zhou, Ze-Chao Hong, Yu Shen, Yu Yan, Yue-Chun Li & Jia-Feng Lin

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Yun-Lu Lin, Tao Yao, and Jia-Feng Lin designed the study and drafted the article; Ying-Wei Wang and Zhi-Xiang Zhou conducted data acquisition, and Ze-Chao Hong, Yu Shen, and Yu Yan performed data analysis and manuscript revision. All authors contributed to the article and approved the submitted version.

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Correspondence to Yue-Chun Li or Jia-Feng Lin.

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Lin, YL., Yao, T., Wang, YW. et al. Potential drug targets for gastroesophageal reflux disease and Barrett’s esophagus identified through Mendelian randomization analysis. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01234-9

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