AUTHOR=Jan Rana Mohammed , Al-Numan Huda Husain , Al-Twaty Nada Hassan , Alrayes Nuha , Alsufyani Hadeel A. , Alaifan Meshari A. , Alhussaini Bakr H. , Shaik Noor Ahmad , Awan Zuhier , Qari Yousef , Saadah Omar I. , Banaganapalli Babajan , Mosli Mahmoud Hisham , Elango Ramu 

TITLE=Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis

JOURNAL=Frontiers in Medicine

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1164305

DOI=10.3389/fmed.2023.1164305

ISSN=2296-858X

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 (WES) 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 LILRB1 (Q53L, Y99N, W351G, D365A, and Q376H) and PRSS3 (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, involved in different a variety of innate immune system pathways. Since the innate immune system detects microbial infections, any defect in this system could lead to immune system functional defects contributing to IBD.
Conclusion: The current study proposes a novel strategy for unraveling the complex genetic architecture of IBD by integrating WES data of familial cases, with computational analysis.