Exploring the causal relationship between constipation and ileus: Insights from bidirectional Mendelian randomization...

Constipation currently affects approximately 15% of the global population, and contemporary lifestyles are increasing its incidence every year. A significant number of individuals with constipation also experience ileus, a common surgical emergency known for its sudden onset and rapid progression. However, the intricate dynamics of the relationship between constipation and ileus are not well understood. This study aimed to elucidate the causal relationship and underlying mechanisms of constipation and ileus, thereby advancing our understanding of their interconnections. A bidirectional 2-sample Mendelian randomization (MR) analysis was performed using the IEU OpenGWAS database. Single nucleotide polymorphisms were used as instrumental variables to determine the causative association between constipation and ileus. Additionally, we utilized eQTL datasets to identify pertinent genes, conducted gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses, and constructed protein-protein interaction (PPI) networks via the GeneMANIA database to identify the possible molecular pathways involved. Bidirectional MR revealed a significantly elevated risk of ileus due to constipation (OR = 1.467, 95% CI = 1.217-1.770, P < .001). Our eQTL investigation revealed 6 genes that were co-expressed in both ailments. Enrichment analysis suggested potential roles of these genes in nucleic acid metabolism and ribosomal biosynthesis, with b-ureidopropionase 1 (UPB1) exhibiting the most pronounced enrichment. Furthermore, PPI network analysis highlighted several pivotal proteins and genes. The findings of this study indicate the existence of a causal nexus between constipation and ileus, underscoring the significant genetic susceptibility shared between these conditions. It has been postulated that constipation can perturb the incidence of ileus via biochemical pathways, including nucleic acid metabolism and ribosomal biosynthesis, with UPB1 possibly serving as a key molecular target. Our results elucidate the novel genetic basis of constipation and ileus and provide a foundation for future experimental studies and the development of customized preventive and therapeutic approaches.