The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
J Hum Genet. 2024 Jun;69(6):245-253. doi: 10.1038/s10038-024-01234-9. Epub 2024 Mar 1.
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), 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.
胃食管反流病（GERD）是一种常见的慢性疾病，目前的治疗方法并不总是有效。本研究旨在为 GERD 和 Barrett 食管（BE）寻找新的药物靶点。我们从最近发表的全基因组关联研究（GWAS）中获得了 GERD、BE 和 2004 种血浆蛋白的遗传工具，并利用孟德尔随机化（MR）来探索潜在的药物靶点。我们通过复制、反向因果关系测试、共定位分析、表型扫描和全表型 MR 进一步筛选了 MR 优先的蛋白质。此外，我们构建了一个蛋白质-蛋白质相互作用网络，揭示了候选蛋白质之间的潜在关联。同时，我们从另一个包含四个不同组织的 GWAS 中获取了 mRNA 表达数量性状基因座（eQTL）数据，以确定其他药物靶点。同时，我们搜索了药物数据库来评估这些靶点。在 Bonferroni 校正（P < 4.8 × 10）下，我们确定了 11 种与 GERD 显著相关的血浆蛋白。其中，7 种是保护蛋白（MSP、GPX1、ERBB3、BT3A3、ANTR2、CCM2 和 DECR2），而 4 种是有害蛋白（TMEM106B、DUSP13、C1-INH 和 LINGO1）。最终，C1-INH 和 DECR2 成功通过筛选过程，对 BE 表现出相似的定向因果效应。进一步对 eQTLs 的分析突出了 4 个潜在的药物靶点，包括 EDEM3、PBX3、MEIS1-AS3 和 NME7。对药物数据库的搜索进一步支持了我们的结论。我们的研究表明，血浆蛋白 C1-INH 和 DECR2 以及 4 个基因（EDEM3、PBX3、MEIS1-AS3 和 NME7）可能代表 GERD 和 BE 的潜在药物靶点，值得进一步研究。
