Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 18, Issue 1, 2021

Background: Nipah virus (NiV) is a zoonotic paramyxovirus that can cause severe respiratory illness and encephalitis in humans, with no effective targets and treatment. Objective: To investigate potential targets involved in the progression of NiV infection by bioinformatics studies. Methods: To identify the key gene involved in NiV infection, a microarray dataset (GSE32902) was downloaded from the National Centre of Biotechnology Information (NCBI). The differentially expressed genes were unraveled by using Geo2Enrichr, and the functional enrichment analysis was facilitated by using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Search Tool for the Retrieval of Interacting Genes (STRING) was used to construct the Protein-protein interaction (PPI) network and visualized by using Cytoscape. Results: A total of 500 genes (262 up-regulated and 238 down-regulated) were identified among NiV infected cells. Nineteen upregulated genes were found with a node degree of more than 10, Among which MX1, ISG15, and IFIT1 were found to have the highest node degree (degree=20), followed by RSAD2 and IRF7 with node degree 18 and MX2 and IFIT3 with node degree 17. Conclusion: The above results explicitly demonstrate that the expressed genes attribute to a defensive response against the virus. Henceforth finding agonists for these genes would help in the effective management of Niv infection.

Background: Antiretroviral treatment (ART) has been reported to make changes in the functioning of dopaminergic neurons by altering the expression of dopamine active transporter (DAT). ART containing efavirenz drug has been related to show the adverse reactions on the central nervous system (CNS). Reported literature indicates the correlation of DAT19/10 genotype with the risk of progression of human immunodeficiency virus (HIV) infection. Objective: The aim of this study was to assess the polymorphism in the human gene DAT1, including variable number tandem repeats (VNTR) from individuals having an infection of HIV. Methods: Genotyping was completed by performing a polymerase chain reaction (PCR) in a total of 165 HIV-positive patients on ART treatment (34 were HIV-infected patients with hepatotoxicity, 131 HIV-infected patients) and 160 healthy controls without HIV infection. Results: Incidence of DAT19/9, 8/9 genotypes, and allele with 9 repeats were higher in individuals having hepatotoxicity compared to those who do not have hepatotoxicity (5.9 vs. 0.8%, OR = 7.73; 2.9 vs. 0.8%, OR = 3.86; 20.58% vs. 14.12%, OR = 1.56). DAT19/10 genotype was related to severity of hepatotoxicity (OR = 1.86; P = 0.05). Upon comparison of genotype between individuals who do not have hepatotoxicity but had HIV infection and healthy controls without HIV infection, the dispersion of DAT1 10/11, 6/10 genotypes were greater in individuals with HIV infection (1.5% vs. 0.6%, OR = 2.73; 3.1% vs. 1.3%, OR = 2.73). DAT19/10 genotype was related to the people of advanced stage of HIV infection (OR = 2.05, P = 0.04). A higher incidence of DAT19/10 genotype was found in individuals with early stage of HIV infection than healthy controls (26.3 vs. 15.6%, OR = 1.93). In alcohol and tobacco consuming individuals with HIV infection and hepatotoxicity, DAT19/10 genotype has demonstrated hazard in the progression of HIV infection and an increased severity of hepatotoxic condition (OR = 1.40, P = 0.91, OR = 1.50; P = 0.91 and OR = 1.57, P = 0.39; OR = 2.70; P = 0.53). In patients with hepatotoxicity, nevirapine utilization with DAT19/10 genotype demonstrated an increase in severity of hepatotoxicity (OR = 4.00, P = 0.41). In individuals with HIV infection and hepatotoxicity, alcohol and nevirapine usage, along with DAT1 9/10 genotype, indicated a risk for progression of HIV infection and severity of hepatotoxicity (OR = 1.47, P = 0.85; OR = 1.73; P = 0.32). Conclusion: The genetic polymorphism with DAT19/10 genotype was linked with the progression of HIV infection and in the advancement of HIV-related illnesses.

Objective: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality worldwide and statins are frequently prescribed in the treatment of CAD to help lower blood cholesterol levels. Since the main enzyme involved in the metabolism of statins is CYP3A4, we aimed to investigate the effect of CYP3A4 * 1B genotypes on plasma lipid profile in Turkish cardiovascular disease subjects with and without obesity taking statin. Materials and Methods: The study group consisted of 85 cardiovascular disease patients who were prescribed statins and had routine biochemical analysis data. Polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) assay was performed for genotyping of CYP3A4 *1B (rs2740574) polymorphism. Results: Genotype distribution of CYP3A4 *1B polymorphism was found for homozygous wild (AA) and homozygous polymorphic (GG) genotypes as 94.1% and 5.9%, respectively. We did not detect patients with heterozygous genotype in our study group. We found that the mean LDL-c, TG and TC levels were higher in patients with CYP3A4 *1B GG compared to the AA genotype. The frequency of CYP3A4 *1B GG genotype frequency (9.5%) was detected higher in the obese patients compared to the non-obese patients (7.7%) (χ2=0.037, p=0.85). Conclusion: Our results demonstrate that CYP3A4 *1B homozygous polymorphic genotype distribution tends to be higher in obese patients compared to non-obese patients with cardiovascular disease which may point to *1B allele having a slight effect on serum lipids during statin therapy. Additional studies with higher samples are needed for evaluating the role of CYP3A4 *1B on lipids in patients under statin therapy.

Introduction: Nitric Oxide (NO) is a diatomic free radical gaseous molecule that is formed from L-arginine through NOS (Nitric oxide synthase) catalyzed reaction. NO controls vascular tone (hence blood pressure), insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis (growth of new blood vessels) and development of the nervous system. In the CNS, NO is an important messenger molecule, which is involved in various major functions in the brain. NOS has been classified into three isoforms, including nNOS (neuronal NOS), eNOS (endothelial NOS) and iNOS (inducible NOS). NOS1 is localized on chromosome 12 consisting of 1434 amino acids and 161 KDa molecular weight. nNOS is involved in synaptic transmission, regulating the tone of smooth muscles and penile erection. We studied NOS1 gene and protein network analysis through in silico techniques as human nNOS sequence was fetched from GenBank and its homologous sequences were retrieved through BLAST search. Moreover, the results of this study exploit the role of NOS1 in various pathways, which provide ways to regulate it in various neurodegenerative diseases. Background: Previous research has revealed the role of Nitric Oxide (NO) formed from L-arginine through NOS (Nitric Oxide Synthase) as physiological inter/intra-cellular messenger in central as well as peripheral nervous systems. The diverse functions of NOS include insulin secretion, airway tone, vascular tone regulation, and in brain, it is involved in differentiation, development, synaptic plasticity and neurosecretion. Objective: The objective of this study is to unravel the role of neuronal Nitric Oxide Synthase (nNOS) in different pathways and its involvement as therapeutic target in various neurodegenerative disorders that can surely provide ways to regulate its activity in different aspects. Materials and Methods: In this study, we employed various bioinformatics tools and databases initiating the study by fetching the neuronal Nitric Oxide Synthase (nNOS) sequence (GenBank) to find its homologous sequences(BLAST) and then exploring its physical properties and post translational modifications, enhancing the research by network analysis (STRING), leading to its functional enrichment (Panther). Results: The results positively support the hypothesis of its role in various pathways related to neurodegeneration and its interacting partners are the probable therapeutic targets of various neurodegenerative diseases focusing on specifically multi-target analysis. Conclusion: This study considered evolutionary trend of physical, chemical and biological properties of NOS1 through different phyla. The neuronal Nitric Oxide Synthase (nNOS), being one of the three isoforms of NOS (Nitric Oxide Synthase), is found to be involved in more pathways than just forming Nitric Oxide. This research provides the base for further neurological research.

Background: Toll-like receptors (TLRs) act as mediators of an innate immune response to infectious agents. The risk for chronic infection and the development of cancer can be potentially influenced by the genetic variations in the TLR genes. TLR3 and TLR7 genes have been associated with susceptibility to several infections and immune diseases. Human populations are very diverse. There are significant variations in the TLR3 and TLR7 polymorphisms among ethnic groups. Variations within the population are associated with the disease outcome. Hence, we aimed to compare the occurrence of TLR3 (rs5743312 C/T, rs3775296 C/A, and rs3775291 C/T) and TLR7 (rs179009 and rs179008) polymorphisms among healthy individuals of various populations. Methods: Genotyping of TLR3 (rs5743312 C/T, rs3775296 C/A, and rs3775291 C/T) and TLR7 (rs179009 and rs179008) polymorphisms were done in 158 healthy controls from the Western India by utilization of PCR-RFLP. Results: In our study population, the prevalence of TLR3 rs5743312 CC, CT, and TT genotypes were found to be 67.1%, 31.0%, and 1.9%, respectively, whereas genotype distribution of rs3775296 C/A polymorphism was 65.2%, 31.6%, and 3.2%, respectively and rs3775291C/T was 59.5%, 32.3% and 8.2%, respectively. The occurrence of TLR7 rs179008AA, rs179008AT, rs179008TT genotypes and rs179008A, rs179008T alleles in the healthy individuals was found to be 81.0%, 16.5%, 2.5% and 89.24%, 10.75%, respectively. The prevalence of TLR7 rs179009AA, rs179009AG, rs179009GG genotypes and rs179009A, rs179009G alleles in healthy individuals was 63.3%, 29.1%, 7.6% and 63.3%, 36.7%, respectively. The frequency of TLR7 polymorphism was compared with Italian, Asian, European, African, German and France populations. The frequency of TLR3 polymorphism was compared with Asians, Caucasians, Taiwanese, Caucasians and Saudi Arabians, Poland, Taiwanese, Italy, Taiwan, Estonia, Asia and Caucasus. The inter-population differences were observed in the distribution of TLR3 and TLR7 polymorphisms. Conclusion: The prevalence of TLR3 and TLR7 polymorphisms suggested that genotype-phenotype studies should be conducted among populations to address the innate immune responses against pathogens.

Background: The impact of personalized medicine is potentially enormous, but the genetic results are often difficult to integrate into health settings. A number of research studies are emerging to aid in translating pharmacogenomics into clinical practice. Objective: We aimed to create a standardized process to guide the implementation of dose adjustment recommendations into the electronic health record (EHR). Materials and Methods: Monographs were created for selected drug-gene pairs, allowing for a standardized review of available evidence. A scoring template was developed to assess whether the evidence presented in the drug monograph qualified the mentioned drug-gene pair for Clinical Decision Support (CDS) within the EHR. Results: Of nine medications reviewed, only one drug-gene pair qualified for a CDS proposal to the institution’s governing pharmacogenomics committee. Conclusion: This project resulted in the development of a standard process for reviewing pharmacogenomics- related literature, allowing for more CDS proposals to be accepted.