|
Document Type |
: |
Thesis |
|
Document Title |
: |
Genetic and Metabolomic Dissection of CeD Disease for the Discovery of Molecular Markers in Arab Families. تحليل جيني وأيضي لمرض الداء الزلاقي لتحديد العلامات البيلوجية في العوائل العربية |
|
Subject |
: |
Faculty of Science |
|
Document Language |
: |
Arabic |
|
Abstract |
: |
Background: Celiac disease (CeD) is a multifactorial autoimmune enteropathy characterized by the over-activation of the immune system against the epithelial cells of the small intestine in response to dietary gluten. The molecular etiology of CeD is still unknown. Therefore, the current study was aimed to identify the integrated genetic and metabolic markers, that contribute to CeD in Arab familial cases.
Methods: Three Arab families having CeD individuals were screened by whole-exome sequencing (WES) and metabolomic fingerprinting. The variants’ (mutations) functional characterization was performed by a series of systems biology assays. The CeD variants were further screened using whole-exome data of one hundred control cases to ensure its rare prevalence in the population. The metabolomic fingerprinting data were generated by utilizing plasma samples from CeD patients and controls. Furthermore, LC-MS with tandem mass spectrophotometry-based untargeted metabolomic profiling was done to study the fluctuation in plasma metabolites which are relevant to the disease activities by a robust quality analysis and statistical approaches.
Result: A complex inheritance pattern of PAK2 (V43A), TAP2 (F468Y), and PLCL1 (V473I) genetic variants was observed in family A. The PAK2 variant (V43A) is a novel one, but TAP2 (F468Y) and PLCL1 (V473I) variants are extremely rare locally according to Saudi Human Genome (SGHP) and the Greater Middle East (GME) and globally based on gnomAD databases. All these variants were localized in genes’ functional domains, except for the PAK2 variant (V43A), and were predicted to alter the protein structural and functional features. Science the classical mode of inheritance failed to find any CeD-associated genes for all families (A, B and C), rare variants burden was applied, and 13 genes found to be associated with CeD based on a series of computational validation analyses like pathway enrichment, gene expression, phenotype analysis of and knockout mouse models. Metabolomics analysis in this study shed the light on lipid metabolism pathways, which significantly enriched in the plasma sample of CeD patient families with (p>0.05).
Conclusion: Our findings highlight the importance of exploring the alternate inheritance patterns in families presenting complex autoimmune diseases, where classical mode of inheritance often fails to explain their molecular basis. These findings may have potential implications for developing new therapeutic drugs for such complex disease patients.
Keywords: CeD disease- whole exome sequencing- autoimmune disease- metabolomics analysis- Arab families. |
|
Supervisor |
: |
Dr. Sabah Hassan |
|
Thesis Type |
: |
Doctorate Thesis |
|
Publishing Year |
: |
1444 AH
2022 AD |
|
Added Date |
: |
Sunday, February 19, 2023 |
|
Researchers
| أروى مستور الحارثي | Alharthi, Arwa Mastoor | Researcher | Doctorate | |
|