Identification of potential drug targets for achalasia from genetic insights: a Mendelian randomization study

Achalasia (AC) is an esophageal dyskinetic disorder characterized by loss of function of ganglion cells of the intermuscular plexus of the distal esophagus and lower esophageal sphincter. Although there have been some advances in its diagnosis and treatment, the maintenance of pharmacologic therapy is very short-lived, the indications for surgical treatment are more limited, and postoperative complications have not been resolved. Therefore, targeted prediction of drugs for better treatment of AC is of great clinical interest.

In this study, we utilized a large number of drug-related databases to perform Mendelian randomization (MR) analysis and co-localization analysis of the data from the genome-wide association study (GWAS) of blood expression quantitative trait loci (eQTL) and AC, so as to identify genes that are highly associated with AC, and screened them in combination with differential genes analyzed by transcriptome sequencing data. In addition, phenotype-wide studies, enrichment analysis, protein network construction, drug prediction, and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic drugs.

We identified nine potential drug target genes for the treatment of AC (NOG, FGFBP3, BST2, IFIT1, CD28, QPCT, IGSF11 and CDK14), which are differentially expressed in AC with different subtypes and sites. These genes were predominantly enriched in virus-associated pathways. The optimal genes for distal esophagus of type 1 AC, distal esophagus of type 2 AC, proximal esophagus of type 1 AC and proximal esophagus of type 2 AC were BST2, FGFBP3, NOG and CDK14, respectively, and our predicted most likely effective potential drugs were puromycin, pictilisib, chlorpyrifos oxon, R547.

This study identifies potential drug targets for the treatment of different fractions and sites of AC, and these findings provide promising clues for more effective treatment of AC and have the potential to reduce drug development costs.