Impact of nitric oxide synthase 2 gene variant on risk of anti-tuberculosis drug- induced liver injury in the Malaysian population

Liver injury is a great threat associated with anti-tuberculosis (anti-TB) medication. Genetic variations in genes encoding drug-metabolising enzymes further enhance this threat. We aimed to explore genetic contributions by evaluating the impact of single nucleotide polymorphisms (SNPs) within the anti-tuberculosis (AT) metabolism pathway genes and within their respective chromosomes on anti-tuberculosis drug- induced liver injury (AT-DILI). Patients (n= 90) were recruited and 170 SNPs were genotyped using Illumina array and validated using Sanger Sequencing. The well-studied N-acetyltransferase 2 (NAT2*6) rs1799930 and cytochrome P450 2E1 (CYP2E1) C1/C1 were not significantly associated with AT-DILI in our cohort but nitric oxide synthase (NOS2A) rs11080344-C was found to be significantly higher in the cases than the controls (OR 2.73, 95% CI 1.12-6.64, P= 0.027). Association studies on all other SNPs within the anti-tuberculosis metabolism pathway genes and within their respective chromosomes also found no significant report. Our study suggests that genetic variation in NOS2A could influence the occurrence of AT-DILI

Prevalence of HLA-DQ Alleles and Haplotypes in Patients with Hepatitis B Infection

Objective: This study aimed to investigate whether HLA-DQA1 and HLA–DQB1 alleles and haplotypes are associated with progression of HBV infection to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in HBV infected patients. Methods: Genotyping of the HLA-DQ variants were carried out in 121 HBV patients (including 52 HBV without LC/HCC and 69 HBV with LC/HCC), using a polymerase chain reaction amplification with sequence specific oligonucleotide (PCR-SSO) technique and Luminex profiling system. Results: The two highest allele frequencies were seen for HLA-DQA1*01 and HLA-DQB1*03. A total of 66% of the HBV patients with LC/HCC and 62% of HBV patients without LC/HCC are carriers of HLA-DQA1*01 (p value= 0.908, OR= 0.95, CI= 0.41 - 2.10). As for HLA-DQB1*03, 73% of the HBV patients with LC/HCC and 60% of HBV patients without LC /HCC are carriers of this allele (p value= 0.320, OR= 1.56, CI= 0.65 - 3.72). In addition, 62% of HBV patients with LC/HCC (n=32) and 48% of HBV patients without LC/HCC (n=25) were carriers of haplotype DQA1*01-DQB1*05 (p value= 0.495, OR= 0.76, CI= 0.34 - 1.68). Conclusion: no association was seen between the HLA-DQA1 and the HLA–DQB1 alleles and haplotypes with HBV disease progression in the Malaysian population.

Success stories in genomic medicine from resource-limited countries

In recent years, the translation of genomic discoveries into mainstream medical practice and public health has gained momentum, facilitated by the advent of new technologies. However, there are often major discrepancies in the pace of implementation of genomic medicine between developed and developing/resource-limited countries. The main reason does not only lie in the limitation of resources but also in the slow pace of adoption of the new findings and the poor understanding of the potential that this new discipline offers to rationalize medical diagnosis and treatment. Here, we present and critically discuss examples from the successful implementation of genomic medicine in resource-limited countries, focusing on pharmacogenomics, genome informatics, and public health genomics, emphasizing in the latter case genomic education, stakeholder analysis, and economics in pharmacogenomics. These examples can be considered as model cases and be readily replicated for the wide implementation of pharmacogenomics and genomic medicine in other resource-limited environments

A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease

The adiponutrin (PNPLA3) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non-alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C>G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69–3.24, p < 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12–3.37, p = 0.018; OR 3.51, 95% CI 1.69–7.26, p = 0.001 and OR 2.05, 95% CI 1.25–3.35, p = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85–3.75, p < 0.0001), with NASH severity (OR 1.85, 95% CI 1.05–3.26, p = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17–3.26, p = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides (p = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurence of fibrosis in patients with NAFLD

The first Malay database toward the ethnic-specific target molecular variation

BACKGROUND:The Malaysian Node of the Human Variome Project (MyHVP) is one of the eighteen official Human Variome Project (HVP) country-specific nodes. Since its inception in 9(th) October 2010, MyHVP has attracted the significant number of Malaysian clinicians and researchers to participate and contribute their data to this project. MyHVP also act as the center of coordination for genotypic and phenotypic variation studies of the Malaysian population. A specialized database was developed to store and manage the data based on genetic variations which also associated with health and disease of Malaysian ethnic groups. This ethnic-specific database is called the Malaysian Node of the Human Variome Project database (MyHVPDb). FINDINGS:Currently, MyHVPDb provides only information about the genetic variations and mutations found in the Malays. In the near future, it will expand for the other Malaysian ethnics as well. The data sets are specified based on diseases or genetic mutation types which have three main subcategories: Single Nucleotide Polymorphism (SNP), Copy Number Variation (CNV) followed by the mutations which code for the common diseases among Malaysians. MyHVPDb has been open to the local researchers, academicians and students through the registration at the portal of MyHVP ( http://hvpmalaysia.kk.usm.my/mhgvc/index.php?id=register ). CONCLUSIONS:This database would be useful for clinicians and researchers who are interested in doing a study on genomics population and genetic diseases in order to obtain up-to-date and accurate information regarding the population-specific variations and also useful for those in countries with similar ethnic background

A study on solution of matrix riccati differential equations using ant colony programming and simulink / Mohd Zahurin Mohamed Kamali

Swarm intelligence is a modern artificial intelligence discipline that is concerned with the design and optimization of multiagent systems with applications in robotics. This non-traditional approach is fundamentally different from the traditional approaches. In- stead of a sophisticated controller that governs the global behavior of the system, the swarm intelligence principle is based on many unsophisticated entities (for example such as ants, termites, bees etc.) that cooperate and interact in order to exhibit a desired behav- ior. In this thesis, we implement the modified ant colony programming (ACP) algorithm for solving the matrix Riccati differential equation (MRDE). Solving MRDE, especially nonlinear MRDE is the central issue in optimal control theory. It has been found that by implementing the ACP algorithm, the solution predicted is approximately close or similar to the exact solution. Besides that, we compared our present work with numerical solution obtained by Runge-Kutta fourth order (RK4) and a non-traditional method such as the ge- netic programming (GP). Furthermore, in this work, we also showed the implementation of the Simulink, for solving the MRDE in order to get the optimal solutions. This add-on Simulink package in the Matlab software can be used to create a block of diagrams which can be translated into a system of ordinary differential equations. Illustrative examples are shown to prove the effectiveness of the proposed algorithm. Moreover, the proposed method have been well applied to biological and engineering problems such as linear and nonlinear singular systems, human immunodeficiency virus (HIV) models, microbial growth model and ethanol fermentation process. ii

Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery

A common variant in the glucokinase regulatory gene rs780094 and risk of nonalcoholic fatty liver disease: A meta-analysis

Background and Aim: Although studies have suggested that rs780094, a common variant in the glucokinase regulatory (GCKR) gene to be associated with type 2 diabetes, obesity, and their related traits, the genetic basis of the association between GCKR rs780094 and nonalcoholic fatty liver disease (NAFLD) is still being examined. This meta-analysis was performed to evaluate the effect strength caused by GCKR rs780094 on NAFLD. Methods: We searched Medline, PubMed, Scopus, and Embase for relevant articles published up to April 2014. Data were extracted, and summary estimates of the association between GCKR rs780094 and NAFLD were examined. Heterogeneity and publication bias were also examined. Results: This meta-analysis incorporated a total of 2091 NAFLD cases and 3003 controls from five studies. Overall, the pooled result indicated that the GCKR rs780094 was significantly associated with increased risk of NAFLD (additive: odds ratio (OR) 1.25, 95% confidence interval (CI) 1.14-1.36, P<0.00001). Analysis also revealed significant associations with different alternative genetic models for the inheritance: dominant, recessive, and homozygote (OR 1.40, 95%CI 1.23-1.61, P<0.00001; OR 0.79, 95% CI 0.68-0.91, P=0.001, and (OR 1.27, 95% CI 1.10-1.47, P=0.001, respectively), but not the heterozygote model. Population subgroup analysis demonstrated similar effect size in both Asians and non-Asians (OR 1.27, 95%CI 1.12-1.45, P=0.0003 and OR 1.22, 95%CI 1.10-1.37, P=0.0003, respectively). Conclusions: Our meta-analysis provides evidence of significant association between GCKR rs780094 and risk of NAFLD. Similar effect size was demonstrated in both Asian and non-Asian populations

Alpha-asarone attenuates depression-like behavior in nicotine-withdrawn mice: Evidence for the modulation of hippocampal pCREB levels during nicotine-withdrawal

In the present study, the effect α-asarone on nicotine withdrawal-induced depression-like behavior in mice was investigated. In this study, mice were exposed to drinking water or nicotine solution (10–200 µg/ml) as a source of drinking for forty days. During this period, daily fluid consumption, food intake and body weight were recorded. The serum cotinine level was estimated before nicotine withdrawal. Naïve mice or nicotine-withdrawn mice were treated with α-asarone (5, 10 and 20 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) for eight consecutive days and the forced swim test (FST) or locomotor activity test was conducted. In addition, the effect of α-asarone or bupropion on the hippocampal pCREB, CREB and BDNF levels during nicotine-withdrawal were measured. Results indicated that α-asarone (5, 10 and 20 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) pretreatment did not significantly alter the immobility time in the FST or spontaneous locomotor activity in naïve mice. However, the immobility time of nicotine-withdrawn mice was significantly attenuated with α-asarone (5, 10 and 20 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) pretreatment in the FST. Besides, α-asarone (5, 10 and 20 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) pretreatment significantly attenuated the hippocampal pCREB levels in nicotine-withdrawn mice. Overall, the present results indicate that α-asarone treatment attenuated the depression-like behavior through the modulation of hippocampal pCREB levels during nicotine-withdrawal in mice