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Rare variant burden analysis from exomes of three consanguineous families reveals and as potential key proteins in inflammatory bowel disease pathogenesis. | LitMetric

AI Article Synopsis

  • Inflammatory bowel disease (IBD) is a chronic autoimmune condition causing severe intestinal inflammation, with unclear genetic causes, prompting this study to explore key genetic factors involved in its pathogenesis.
  • Researchers analyzed whole exome sequences from three Saudi families with multiple IBD cases and utilized AI-driven methods to identify potential IBD-related genes linked to immune pathways.
  • The study identified rare genetic variants that negatively affect protein structures important for the innate immune system, suggesting that defects in this system may contribute to the development of IBD.

Article Abstract

Background: Inflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and uncovering the role of key genetic factors in IBD.

Method: The whole exome sequences (WESs) of three consanguineous Saudi families having many siblings with IBD were analyzed to discover the causal genetic defect. Then, we used a combination of artificial intelligence approaches, such as functional enrichment analysis using immune pathways and a set of computational functional validation tools for gene expression, immune cell expression analyses, phenotype aggregation, and the system biology of innate immunity, to highlight potential IBD genes that play an important role in its pathobiology.

Results: Our findings have shown a causal group of extremely rare variants in the (Q53L, Y99N, W351G, D365A, and Q376H) and (F4L and V25I) genes in IBD-affected siblings. Findings from amino acids in conserved domains, tertiary-level structural deviations, and stability analysis have confirmed that these variants have a negative impact on structural features in the corresponding proteins. Intensive computational structural analysis shows that both genes have very high expression in the gastrointestinal tract and immune organs and are involved in a variety of innate immune system pathways. Since the innate immune system detects microbial infections, any defect in this system could lead to immune functional impairment contributing to IBD.

Conclusion: The present study proposes a novel strategy for unraveling the complex genetic architecture of IBD by integrating WES data of familial cases, with computational analysis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10196255PMC
http://dx.doi.org/10.3389/fmed.2023.1164305DOI Listing

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