Plasma proteins and irritable bowel syndrome: A proteome-wide Mendelian randomization study

Irritable bowel syndrome (IBS) is a complex disorder with unclear etiology and underlying mechanisms. This research aimed to identify possible plasma proteins linked to IBS using a proteome-wide Mendelian randomization (MR) analysis. We performed a bidirectional two-sample MR analysis to investigate the causal relationship between 4907 plasma proteins and IBS. Genetic data from 35,559 Icelanders and IBS genome-wide association study data from 329,381 individuals in the FinnGen consortium were used to select instrumental variables meeting stringent criteria. Several MR methods such as inverse variance weighted, MR-Egger, and Weighted Median, along with sensitivity analyses, were utilized to confirm the robustness of the findings. Enrichment analyses and gene interaction studies were also conducted to investigate biological pathways related to the significant findings. MR analysis identified 20 plasma proteins significantly associated with IBS. Of these, Scavenger Receptor Class A Member 5 and Fibroblast Growth Factor Binding Protein-1 were negatively associated with IBS, indicating a protective effect. The other 18 plasma proteins associated with IBS onset include but are not limited to Leucine-rich repeat kinase 2, Ras and Rab interactor 3, and Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, all of which showed a positive correlation with increased IBS risk. Reverse MR analysis revealed no evidence that IBS influences plasma protein expression, suggesting that these proteins may play a causal role in the development of IBS. Enrichment analyses highlighted significant involvement in mitochondrial processes, synaptic vesicle recycling, and endosomal transport. In summary, this study identified 20 plasma proteins as potential causal factors in the development of IBS. The findings suggest that these proteins could serve as therapeutic targets, offering new insights into the underlying mechanisms of IBS.