Biological and Pharmacogenomics Bases of Gastrointestinal and Some Long-Term Selective Serotonin Reuptake Inhibitors-Induced Adverse Effects

Background: Patients being treated with SSRIs who experience intolerable Adverse Effects (AEs) have a penchant for discontinuing treatment, inevitably jeopardizing any probability for treatment response. Aim: This study aims to identify the Single Nucleotide Polymorphisms (SNPs) that are associated with certain AEs of SSRI treatment in Major Depression Disorder (MDD). Results: Patients with the short (SS) genotype (44 base pair deletion) and those with the long along with guanine substitution (LgLg - 44 base pair insertion with rs25531- guanine substitution variant) of the serotonin transporter gene (STG) have substantially been reported with a higher incidence of AEs to SSRI. While variants of glutamate receptor ionotropic genes have been found to be linked with different domains of sexual dysfunction, polymorphisms of 5-HT2A gene - rs6311 (G > A), the long allele (L) of STG, rs6295 (C > G) polymorphism of HTR1A and polymorphism rs1160351 (A > C) of MAM domain-containing glycosyl-phosphatidyl inositol anchor 2 (MDGA2) gene have also been found to be associated with sexual dysfunction. The rs4680 (G>A; Val > Met) polymorphism of catechol-O-methyltransferase (COMT), AA genotype of rs18532 polymorphism of tryptophan hydroxylase, the rs6318 (C > G) polymorphism of the serotonin receptor 2C (HTR2C), and S allele of STG were found to be associated with weight gain following SSRI treatment. The sanctity of these results is limited by the inability of some researchers to replicate these association findings. Conclusion: This review highlights a number of polymorphisms associated with some of the key AEs encountered in SSRI treatments. Standardized study designs in pharmacogenomic evaluations hold great promise for replication of association findings.

Association of N-acetyltransferase-2 Polymorphism with Antituberculosis Induced Hepatotoxicity: A meta-analysis

Background: N-acetyltransferase (NAT2) polymorphisms were reported to play important roles in antituberculosis-induced hepatotoxicity (ATDIH). However, the allelic types with increased risks for ATDIH were inconsistent as most studies are of a small sample size. Objective: The objective of the study was to conduct a meta-analysis to identify NAT2 alleles associated with increased risks of ATDIH. Methods: Studies reported on NAT2 polymorphism with the risk of ATDIH were searched systematically in PubMed, Scopus, and the World of Sciences. Studies were included if they fulfilled the inclusion criteria and excluded accordingly. Quality assessments were done using Newcastle-Ottawa Score. Statistical analysis was performed using Review Manager version 5.3. Cochrane Q-statistic test and I2 statistic were used to assess and quantify heterogeneity. Results: A total of 12 studies involving 580 cases and 3129 controls were included. NAT2 polymorphism was significantly associated with the risk of ATDIH with an odd ratio (OR) of 2.76 (1.86 – 4.10, 95% CI). Among the slow acetylators genotypes, NAT2*5/*7 carry the highest risk associated with ATDIH. Conclusion: NAT2 polymorphism was significantly associated with ATDIH.

The Effect of Phytochemical Extracts on Cytokine Gene Expression

Background: In the last century, nutritional supplements have shown a wide spectrum of biochemical effects, most notably about immunomodulation and countering inflammation. Objective: This study investigates the impact of phytochemical compounds that are present in different quantities of pomegranate, grape seeds and garlic extracts on the expression of inflammatory (IL1β and IL6) and anti-inflammatory (IL10) genes, the effects of polymorphisms in these genes on this response. Methods: Human peripheral blood leukocyte cultures were treated with pomegranate (1.2% or 2.4%), garlic (0.5% or 1.2%), or grape seed (1.2% or 2.4%) extracts. Gene expression was assessed with real-time polymerase chain reaction (PCR). Polymorphisms of the cytokine genes were analyzed using allele-specific PCR. Results: Pomegranate extract (2.4%) reduced the transcription of IL1β by 16-fold in comparison to control. The expression of IL6 relative to the control after the addition of grape seed extract (1.2%) was reduced by 100-fold. The grape seeds extract (1.2%) showed the effect of increasing transcription for IL10 compared to the control. The level of IL1β transcription in culture with garlic extract depends on the genotype of the cell for -31T>C polymorphism (r = 0.67 p = 0.03). There is correlation between polymorphism -174G>C and level gene expression IL6 (r=-0.66, p = 0.04) after adding grape seeds extract. Conclusion: The phytochemical compounds in pomegranate extracts and grape seed extracts play the role of anti-inflammatory by decreasing the gene expression of IL1β, IL6 and increasing the transcription of IL10.

Genomics and Pharmacogenomics of Age-Related Hearing Loss

: Age-related hearing loss (ARHL) or presbycusis shares common features with conditions related to senescence and neurodegeneration. In this review, we explore the linking of genes involved in such processes with presbycusis, that has been proven to share important relationships with genes involved in dementia (APOE and MTHFR), ototoxicity (the GST group), and pharmacogenetics (NAT2). In this regard, we propose the construction of pharmacogenetics for the presbycusis database that could help better control side effects in this particularly vulnerable population susceptible to neurodegenerative disorders. Moreover, preliminary epigenetics studies have recently identified links in human genes involved in ARHL, which could serve as biomarkers or as therapeutic targets.

Prevalence of CYP2C19 Polymorphisms in Clopidogrel Treated Turkish Patients: Preliminary Results, 2017

Background: Clopidogrel is one of the most frequently prescribed antiplatelet agents to reduce the risk of atherosclerotic symptoms. CYP2C19 enzyme is involved in clopidogrel metabolism, and several genetic variations of CYP2C19gene are able to affect the clinical response of clopidogrel. Despite the lack of a fully accepted guideline for CYP2C19 pharmacogenetic testing before clopidogrel treatment by relevant communities, we believe that determination of the variant frequencies is important to predict the efficiency and possible clopidogrel related risks before the initiation of treatment on the basis of populations. Our aim was to determine the distribution of gene polymorphisms affecting the enzyme activity in Turkish cardiac patients prescribed clopidogrel. Methods: 54 clopidogrel prescribed patients were included in the study. The presence of CYP2C19*2, *3, *4, *5, *6, *7, *8, *9, *10 and *17 polymorphisms were investigated using a microarray platform. Results : No variant allele was detected for *4, *5, *6, *7, *8, *9 and *10 polymorphisms. The genotype frequencies were detected as 38.89% for *1/*1, 16.67% for *1/*2, 11.11% for *2/*17, 1.85% for *1/*3, 1.85% for *2/*3, 27.78% for *1/*17 and 1.85% for *17/*17. According to genotype analysis, 1.85% of the patients were recorded as poor and 29.63% intermediate; whereas 27.78% as rapid and 1.85% ultra-rapid metabolizers. Conclusion: Although our study population does not consist of a high number of patients, since the high frequency of intermediate, rapid and ultra-rapid metabolizer patients were detected in relatively high frequencies, CYP2C19 polymorphisms should be taken into account for efficiency and possible clopidogrel related risks in Turkish cardiac patients.

Comparative Occurrence of TLR3 and TLR7 Polymorphisms among Healthy Individual of Various Population

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 population is 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. Method: Genotyping TLR3 (rs5743312 C/T, rs3775296 C/A, and rs3775291 C/T) and TLR7 (rs179009 and rs179008) polymorphisms were done in 158 healthy controls from Western India by utilization of PCR-RFLP. Result: 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 were 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 were 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 the 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 population to address the innate immune responses against pathogens.

Comparative Genomic and Network Analysis of nNOS by Using Different Bioinformatics Approaches

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 in the 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 which include 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, 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 a physiological inter/intracellular messenger in the central as well as the peripheral nervous system. The diverse functions of NOS include insulin secretion, airway tone, vascular tone regulation, and in the 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 a therapeutic target in various neurodegenerative disorders, which 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., Its interacting partners are the probable therapeutic targets of various neurodegenerative diseases focusing on specifically multi-target analysis. Conclusion: This study considered the 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.