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.
摘要：
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的。本研究旨在寻找GERD和Barrett食管（BE）的新药靶点。我们获得了GERD的遗传仪器，BE,和2004年来自最近发表的全基因组关联研究（GWAS）的血浆蛋白，孟德尔随机化(MR)用于探索潜在的药物靶点。我们通过复制进一步筛选了MR优先的蛋白质，反向因果关系检验，共定位分析，表型扫描，和全表型MR。此外，我们构建了一个蛋白质-蛋白质相互作用网络，揭示候选蛋白质之间的潜在关联。同时,我们从另一个包含4种不同组织的GWAS获得了mRNA表达数量性状位点(eQTL)数据,以确定其他药物靶点.同时,我们搜索了药物数据库以评估这些目标.在Bonferroni校正下(P<4.8×10-5)，我们鉴定了11种与GERD显著相关的血浆蛋白.其中,7是保护性蛋白质(MSP，GPX1、ERBB3、BT3A3、ANTR2、CCM2和DECR2），而4是有害蛋白质(TMEM106B，DUSP13,C1-INH,和LINGO1）。最终,C1-INH和DECR2成功通过了筛选过程，并对BE表现出相似的方向因果效应。对eQTL的进一步分析强调了4个潜在的药物靶标，包括EDEM3、PBX3、MEIS1-AS3和NME7。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的潜在药物靶标，保证进一步调查。
