👤 Saima Ajaz

Pharmacogenomics (PGx), forming the basis of precision medicine, has revolutionized traditional medical practice. Currently, drug responses such as drug efficacy, drug dosage, and drug adverse reactions can be anticipated based on the genetic makeup of the patients. The pharmacogenomic data of Pakistani populations are limited. This study investigates the frequencies of pharmacogenetic variants and their clinical relevance among ethnic groups in Pakistan. The Pharmacogenomics Knowledge Base (PharmGKB) database was used to extract pharmacogenetic variants that are involved in medical conditions with high (1A + 1B) to moderate (2A + 2B) clinical evidence. Subsequently, the allele frequencies of these variants were searched among multiethnic groups of Pakistan (Balochi, Brahui, Burusho, Hazara, Kalash, Pashtun, Punjabi, and Sindhi) using the 1000 Genomes Project (1KGP) and ALlele FREquency Database (ALFRED). Furthermore, the published Pharmacogenomics literature on the Pakistani population was reviewed in PubMed and Google Scholar. Our search retrieved (n = 29) pharmacogenetic genes and their (n = 44) variants with high to moderate evidence of clinical association. These pharmacogenetic variants correspond to drug-metabolizing enzymes (n = 22), drug-metabolizing transporters (n = 8), and PGx gene regulators, etc. (n = 14). We found 5 pharmacogenetic variants present at >50% among 8 ethnic groups of Pakistan. These pharmacogenetic variants include This study highlights the frequency of important clinical pharmacogenetic variants (1A, 1B, 2A, and 2B) among multi-ethnic Pakistani populations. The high prevalence (>50%) of single nucleotide pharmacogenetic variants may contribute to the drug response/diseases outcome. These PGx data could be used as pharmacogenetic markers in the selection of appropriate therapeutic regimens for specific ethnic groups of Pakistan. Show less

Dysfunctional metabolism lies at the centre of the pathogenesis for Non-Alcoholic Fatty Liver Disease (NAFLD) and involves mitochondrial dysfunction, lipid dysmetabolism and oxidative stress. This study, for the first time, explores real-time energy changes in peripheral blood and corresponding metabolite changes, to investigate whether mitochondria-related immunometabolic biomarkers can predict progression in NAFLD. Thirty subjects divided into 3 groups were assessed: NAFLD with biopsy-proven mild fibrosis (n = 10), severe fibrosis (n = 10) and healthy controls (HC, n = 10). Mitochondrial functional analysis was performed in a Seahorse XFp analyzer in live peripheral blood mononuclear cells (PBMCs). Global metabolomics quantified a broad range of human plasma metabolites. Mitochondrial carbamoyl phosphate synthase 1(CPS-1), Ornithine transcarbamoylase (OTC), Fibroblast growth factor-21 (FGF-21) and a range of cytokines in plasma were measured by ELISA. NAFLD patients with severe fibrosis demonstrated reduced maximal respiration (106 ± 25 versus 242 ± 62, p < 0.05) and reserve capacity (56 ± 16 versus 184 ± 42, p = 0.006) compared to mild/moderate fibrosis. Comparing mild/moderate vs severe liver fibrosis in patients with NAFLD, 14 out of 493 quantified metabolites were significantly changed (p < 0.05). Most of the amino acids modulated were the urea cycle (UC) components which included citrulline/ornithine ratio, arginine and glutamate. Plasma levels of CPS-1 and FGF-21 were significantly higher mild versus severe fibrosis in NAFLD patients. This novel panel generated an area under the ROC of 0.95, sensitivity of 100% and specificity 80% and p = 0.0007 (F1-F2 versus F3-F4). Progression in NAFLD is associated with mitochondrial dysfunction and changes in metabolites associated with the urea cycle. We demonstrate a unique panel of mitochondrial-based, signatures which differentiate between stages of NAFLD. Mitochondrial dysfunction in peripheral cells along with alterations in metabolites of urea cycle act as a sensor of hepatocyte mitochondrial damage. These changes can be measured in blood and together represent a unique panel of biomarkers for progression of fibrosis in NAFLD. Show less