Boro, Ryan
(2024)
Use of Functional Genomics to Investigate Clinically Significant DILI GWAS SNPs in the Non-Coding Genome.
Master's Thesis, University of Pittsburgh.
(Unpublished)
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Abstract
Drug-induced liver injury (DILI) has become a significant contributor to patient morbidity and mortality and to drug market withdrawals and development discontinuation. Additionally, single nucleotide polymorphisms (SNPs) have become an interest in identifying genetic influences on disease and treatment outcomes. We will use functional genomics in the context of genome wide association studies (GWAS) and pharmacogenomics (PGx) to attempt to confirm the underlying mechanisms of how SNPs impact DILI. We will focus on the underexplored non-coding regulatory region of the genome and the ability of the SNPs to disrupt transcription factor binding sites (TFBS) motifs, the small DNA sequences transcription factors (TFs) bind to and initiate the transcription process. DILI associated SNPs were gathered from the GWAS Catalog to be annotated. Then, the bioinformatic tool MotifMap was used to predict potential nuclear receptor TFBS physically local to or overlapping with the gathered SNPs. We chose 3 SNPs as our focus, with rs12693892 containing the most significant false discovery rate (FDR) value from our gathered SNPs (7x10-8), and rs78098983 and rs73044680 due to their proximity being the closest in our searched TFBS motif, 260bps and 60 bps, respectively. By chance, these SNPs were from a GWAS study regarding associated DILI involving methotrexate (MTX) use. While our initial search did not give rise to any SNPs disrupting TFBS, after updating our annotations on the UCSC Genome Browser with the most recent JASPAR TFBS motif database track and its own computed TRANSAC track, discoveries were made. We found TFBS motif disruption in rs78098983, as well as additional TFBS motifs found adjacent to rs73044680 and rs12693892. Results with rs12693892 showed it being located in an intron of LINC01877 with FTCDNL1 genomically adjacent, the latter associated with the MTX protective folic acid and its metabolism. rs78098983 disrupted predicted TFBS motifs POU6F2 and HOXC11 and was found within the intronic region of ENSG00000287367 near SNX18 and CSPG4BP, with SNX18 associated with endosomal sorting. Finally, rs73044680 resided in the intronic region of RBMS3 which is associated with epithelial–mesenchymal transition. These discoveries provide a foundation to further explore SNP clinical association to causation of DILI, especially in the context of MTX induced DILI.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
6 December 2024 |
| Date Type: |
Publication |
| Defense Date: |
17 October 2024 |
| Approval Date: |
6 December 2024 |
| Submission Date: |
19 November 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
49 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Genomics, DILI, GWAS, SNPs, Non-Coding |
| Date Deposited: |
06 Dec 2024 15:56 |
| Last Modified: |
10 Apr 2025 13:20 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/47108 |
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