Genetic association study of NOD2 and IL23R amino acid substitution polymorphisms in Saudi Inflammatory Bowel Disease patients

Al-Harbi, Raneem; Shaik, Noor Ahmad; Almahdi, Hadiah; ElSokary, Hanan Abdelhalim; Jamalalail, Bassam Adnan; Mosli, Mahmoud; Alsufyani, Hadeel A.; Al‐Aama, Jumana Y.; Elango, Ramu; Saadah, Omar I.; Banganapalli, Babajan

doi:10.1016/j.jksus.2021.101726

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…Most IBD genome-wide association studies (GWAS) have been conducted in Caucasian or Asian populations, leaving a gap in understanding population-specific variations in the Middle East [ 74 ]. When NOD2 (P268S and R702W) and IL23R (G149R and R381Q) variations, identified from GWAS in Caucasian populations, were assessed as potential genetic indicators for IBD in Saudi patients [ 9 ], it was found that of the four SNPs, IL23 [rs76418789, rs11209026] and NOD2 [rs2066842, rs2066844], three [rs2066844, rs76418789, rs11209026] were uncommon among IBD patients and controls in the Arabian population. The rs2066842 variation minor allele frequency (MAF) was higher in the Saudi population than globally, but there was no significant difference in MAF between those with and without IBD.…”

Section: Factors Affecting the Middle Eastern Microbiomementioning

confidence: 99%

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The Role of the Gut Microbiome in Inflammatory Bowel Disease: The Middle East Perspective

El-Sayed,

Kapila,

Taha

et al. 2024

JPM

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The gut microbiome is of paramount importance in preserving internal balance in the gastrointestinal tract; therefore, disruptions in its regulation have been linked to the development of inflammatory bowel disease (IBD). This article explores the intricate details of the gastrointestinal microbiome as it pertains to inflammatory bowel disease (IBD), with an emphasis on the Middle East. The study reviews the typical gut microbiome, modifications in inflammatory bowel disease (IBD), determinants impacting the gut microbiome of the Middle East, and prospective therapeutic interventions.

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Section: Factors Affecting the Middle Eastern Microbiomementioning

confidence: 99%

“…As the Middle East has industrialised, its diet has changed, along with an increased incidence of IBD [ 2 ]. Moreover, genetic markers, which seem to be prevalent indicators in Caucasian populations, have been found to not necessarily correlate with Middle Eastern populations [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of the Gut Microbiome in Inflammatory Bowel Disease: The Middle East Perspective

El-Sayed,

Kapila,

Taha

et al. 2024

JPM

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“…In recent years, the International IBD Genetics Consortium (IIBDGC), has pooled up all the GWAS findings and identified a total of 201 IBD susceptibility loci (4,5). Among these loci, NOD2 and IL23R still represent the strongest predictors for IBD susceptibility and clinical phenotypes (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Genotype-protein phenotype characterization of NOD2 and IL23R missense variants associated with inflammatory bowel disease: A paradigm from molecular modelling, dynamics, and docking simulations

Nasser

Shinawi²

2023

Front. Med.

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Inflammatory bowel disease (IBD) is a gastrointestinal disease with an underlying contribution of genetic, microbial, environment, immunity factors. The coding region risk markers identified by IBD genome wide association studies have not been well characterized at protein phenotype level. Therefore, this study is conducted to characterize the role of NOD2 (Arg675Trp and Gly908Arg) and IL23R (Gly149Arg and Arg381Gln) missense variants on the structural and functional features of corresponding proteins. Thus, we used different variant pathogenicity assays, molecular modelling, secondary structure, stability, molecular dynamics, and molecular docking analysis methods. Our findings suggest that SIFT, Polyphen, GREP++, PhyloP, SiPhy and REVEL methods are very sensitive in determining pathogenicity of NOD2 and IL23R missense variants. We have also noticed that all the tested missense variants could potentially alter secondary (α-helices, β-strands, and coils) and tertiary (residue level deviations) structural features. Moreover, our molecular dynamics (MD) simulation findings have simulated that NOD2 (Arg675Trp and Gly908Arg) and IL23R (Gly149Arg and Arg381Gln) variants creates rigid local structures comprising the protein flexibility and conformations. These predictions are corroborated by molecular docking results, where we noticed that NOD2 and IL23R missense variants induce molecular interaction deformities with RIPK2 and JAK2 ligand molecules, respectively. These functional alterations could potentially alter the signal transduction pathway cascade involved in inflammation and autoimmunity. Drug library searches and findings from docking studies have identified the inhibitory effects of Tacrolimus and Celecoxib drugs on NOD2 and IL23R variant forms, underlining their potential to contribute to personalized medicine for IBD. The present study supports the utilization of computational methods as primary filters (pre-in vitro and in vivo) in studying the disease potential mutations in the context of genptype-protein phenotype characteristics.

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“…However, genome-wide association studies (GWAS) have uncovered more than 200 common risk loci in IBD pathogenesis (8)(9)(10)(11)(12). Some of these risk alleles are missense variants that have been mapped to genes such as Interleukin 23 Receptor (IL23R), Nucleotide Binding Oligomerization Domain containing 2 (NOD2), and Autophagyrelated 16 like 1 (ATG16L1) (13). Majority of these risk markers are intronic variants (14).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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BackgroundInflammatory 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.MethodThe 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.ResultsOur findings have shown a causal group of extremely rare variants in the 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 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.ConclusionThe 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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Genetic association study of NOD2 and IL23R amino acid substitution polymorphisms in Saudi Inflammatory Bowel Disease patients

Cited by 5 publications

References 37 publications

The Role of the Gut Microbiome in Inflammatory Bowel Disease: The Middle East Perspective

The Role of the Gut Microbiome in Inflammatory Bowel Disease: The Middle East Perspective

Genotype-protein phenotype characterization of NOD2 and IL23R missense variants associated with inflammatory bowel disease: A paradigm from molecular modelling, dynamics, and docking simulations

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

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