Articles
Sharafshah, A.,
Bashi naeini, M.M.,
Blum, K.,
Lewandrowski, K.,
Gold, M.S.,
Keshavarz, P.,
Thanos, P.K. Cellular and Molecular Neurobiology (02724340)45(1)
This study aimed to integrate genome-wide association studies (GWAS) with pharmacogenomics data to develop personalized pain and inflammatory therapeutics. Despite recent developments in the clinical utilities of pharmacogenomics, it needs more investigations for uncovering the complicated mechanisms of drugs from a genetic standpoint. The research addresses the increasing misuse of opioids during recovery, emphasizing personalized interventions for opioid use disorder (OUD). Key pain-related pathways were analyzed to uncover their interactions. Five GWAS traits, including pain, inflammatory biomarkers, immune system abnormalities, and opioid-related traits, were examined. Candidate genes extracted from GWAS datasets were refined through in silico analyses, including protein–protein interactions (PPIs), TF-miRNA coregulatory interactions, enrichment analysis (EA), and clustering enrichment analysis (CEA). A network of 50 highly connected genes was identified, with APOE emerging as a top candidate due to its role in cholesterol metabolism and opioid-induced lipid effects. Pharmacogenomics analysis highlighted significant gene annotations, including OPRM1, DRD2, APOE, GRIN2B, and GPR98, linking them to opioid dependence, neurological disorders, and lipid traits. Protein interaction analyses further validated these connections, with implications for epigenetic repair. Our findings reveal a strong association between APOE, opioid use, and Alzheimer’s disease, suggesting potential for novel recovery strategies. Combining HDL-boosting drugs with pro-dopaminergic regulators like KB220 may help prevent relapse. This study underscores the importance of integrating genetic and pharmacogenomic data to advance personalized therapies. © The Author(s) 2025.
Iranian Journal Of Medical Sciences (17353688)50(7)pp. 472-480
Background: An incapacitating chronic inflammatory neurodegenerative illness, known as multiple sclerosis (MS), is characterized by lymphocyte infiltration into the central nervous system. We aimed to identify specific miRNAs whose altered expression correlates with MS diagnosis and therapy selection, which could be biomarkers for these aspects of the disease. Methods: The GSE21079 dataset was obtained for this study using Geoquery version 2.50.5 from the Gene Expression Omnibus database. The miRNAs exhibiting the highest variance were selected, and a miRNA-miRNA interaction network was constructed through a Bayesian network utilizing the bnlearn R package (version 4.7.1). The adjacency matrix generated from the learned network was subsequently analyzed in the Cytoscape environment. For the workbench lab, whole blood samples were collected from the MS Research Center and Al-Zahra Hospital in Isfahan, Iran, between June 2019 and October 2019. RNA extraction was conducted in the laboratory at Isfahan University. Real-time PCR (RT-PCR) was employed to validate the expression changes of the candidate mirRNAs (hsa-miR-520d-3p, hsa-miR449a). The results were analyzed using REST 2009 software. Results: The Notch1 signaling pathway was targeted by hsamiR-520d-3p and hsa-miR-449a in MS patients, which led to downregulation of critical genes, such as LIM and SH3 protein 1 (LASP1), Tubulin Alpha1c (TUBA1C), and S100 calcium binding protein A6 (S100A6). Furthermore, the results from RT-PCR among 50 whole blood samples, comprising 30 cases of MS and 20 control cases, indicated that the expression levels of miRNA in patients with MS exhibited a statistically significant difference compared to those in healthy individuals, with values of 0.324 for hsa-miR520d-3p and 0.075 for hsa-miR-449a. These values correspond to a downregulation of 3.1-fold and 13.3-fold, respectively. Conclusion: The findings indicate that MS patients have lower expression levels of hsa-miR-520d-3p and hsa-miR-449a. © Iranian Journal of Medical Sciences.
Background: Next-Generation Sequencing (NGS) methods specifically Whole-Exome Sequencing (WES) have demonstrated promising findings with a high accuracy of 91%-99% in Pharmacogenomics (PGx). A PGx-based panel can be utilized to minimize adverse drug reactions (ADRs) and maximize the treatment efficacy. Remarkably, Cancer Pain Management (CPM) is a cutting-edge concept in modern medicine. Thus, this study aimed to investigate the WES results by a PGx-based panel containing genes involved in Pain, Anti-inflammatory, and Immunomodulating agents (PAIma) signaling pathways. Methods: A total of 200 unrelated Iranians (100 western and 100 northern) were included. 100 WES results were analyzed through the PAIma panel. After DNA extraction, 100 samples were genotyped by Multiplex-Amplification-Refractory Mutation System (ARMS) PCR. A primary in silico investigation performed on 128 candidate genes through Protein-Protein Interactions (PPIs) and Gene-miRNA Interactions (GMIs) via the STRING database, and miRTargetLink2, respectively. Additionally, Enrichment Analysis (EA) was applied to find the unknown interplays among these three major pathways by Enrichr. Results: 55,590 annotations through 21 curated pathways were filtered, 900 variants were found, and 128 genes were refined. Finally, 54 candidate variants (48 non-synonymous single nucleotide variants (nsSNVs), 2 stop-gained, 1 frameshift, and 3 splicing) remained. Conclusion: Conclusively, six potentially actionable variants including rs1695 (GSTP1), rs628031 (SLC22A1), rs17863778 (UGT1A7), rs16947 (CYP2D6), rs2257401 (CYP3A7), and rs2515641 (CYP2E1) had the most deviations among Iranians, compared with the reference genome, which should be genotyped for drug prescribing. Remarkably, PPIs, GMIs, and EA revealed potential risks of carcinogenesis and cancer phenotypes resulting from PAIma pathways genes. © Iranian Journal of Medical Sciences.
