Inflammatory bowel disease (IBD) is a chronic gastrointestinal tract inflammatory disorder affecting millions worldwide. Despite significant progress in understanding IBD’s molecular mechanisms, effective therapies targeting the disease remain limited. The proteome, which encompasses all the proteins expressed by an organism or tissue, has emerged as a promising source of therapeutic targets for IBD.
Researchers have conducted a proteome-wide Mendelian randomization (MR) analysis to identify potential targets for IBD. MR is a statistical method that leverages genetic variants as instrumental variables to investigate the causal relationships between exposures and outcomes. By using genetic variants associated with protein expression levels as instruments, MR can help identify proteins causally related to IBD.
A new study published in the eBioMedicine has identified potential drug targets for inflammatory bowel disease (IBD) and ulcerative colitis (UC) by conducting proteome-wide MR and colocalization analyses on over 4000 circulating proteins. The study identified three protein-IBD and five protein-UC associations and found strong evidence that genetically predicted higher levels of MST1 and HGFAC were inversely associated with IBD risks.
MST1 was identified as a potential target for both IBD and UC, and the study showed that MST1 was a negative regulator of TNF-induced inflammatory signaling. The study also found that genetically predicted higher levels of circulating STAT3 were associated with an increased risk of UC, whereas genetically predicted higher levels of circulating MST1, CXCL5, and ITPKA were associated with a reduced risk of UC. These findings suggest that STAT3 inhibitors have promising therapeutic potential as drug candidates for UC and that MST1 could be investigated for its pathological role in IBD and UC.
In addition to MR analysis, researchers also conducted colocalization analysis, a method for identifying whether a genetic variant associated with a protein expression level is associated with a disease phenotype in the same genomic region.
Colocalization analysis can help identify whether a protein is likely involved in the disease process. By combining MR and colocalization analyses, researchers have identified potential new drug targets for IBD from the proteome. These targets may offer new avenues for developing effective therapies for this debilitating disease.
Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases that affect the intestine, including Crohn’s disease and ulcerative colitis. IBD poses a significant caregiving burden for individuals, families, and society, and conventional therapies are not always practical. As a result, there is an urgent need to identify new drug targets for IBD. Circulating proteins have been identified as potential targets for IBD therapies because they play a crucial role in molecular pathways.
Previous studies have shown that proteins associated with the complement cascade, lysosomes, and the innate immune response may be involved in the development of IBD and could be potential therapeutic targets. However, these observational studies may be susceptible to confounding and reverse causation.
Mendelian randomization (MR) is a method that employs genetic variants as an instrumental variable to reinforce causal inference. MR is less prone to confounding because genetic variants are randomly assorted at conception and thus not related to environmental and self-adopted factors. A previous MR analysis examined the causal associations between 1300 serum metabolites and IBD, including 464 CD patients and 484 UC patients.
Recent studies on genetic associations with circulating protein levels in a large sample provide opportunities to investigate the causal effects of circulating proteins on IBD in a comprehensive way. This study conducted a proteome-wide MR analysis plus colocalization analysis to identify potential therapeutic targets for IBD and its subtypes, CD and UC.
The results of this study could provide crucial insights into the biological pathways involved in IBD. They could ultimately lead to the developing of new and effective therapies for this debilitating disease.
