Anthony Au

Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients

The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.

The Influence of OLR1 and PCSK9 Gene Polymorphisms on Ischemic Stroke: Evidence from a Meta-Analysis.

Both OLR1 and PCSK9 genes are associated with atherosclerosis, cardiovascular disease and ischemic stroke. The overall prevalence of PCSK9 rs505151 and OLR1 rs11053646 variants in ischemic stroke were 0.005 and 0.116, respectively. However, to date, association between these polymorphisms and ischemic stroke remains inconclusive. Therefore, this first meta-analysis was carried out to clarify the presumed influence of these polymorphisms on ischemic stroke. All eligible case-control and cohort studies that met the search terms were retrieved in multiple databases. Demographic and genotyping data were extracted from each study, and the meta-analysis was performed using RevMan 5.3 and Metafor R 3.2.1. The pooled odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed- and random-effect models. Seven case-control studies encompassing 1897 cases and 2119 controls were critically evaluated. Pooled results from the genetic models indicated that OLR1 rs11053646 dominant (OR = 1.33, 95%  CI:1.11–1.58) and co-dominant models (OR = 1.24, 95%  CI:1.02–1.51) were significantly associated with ischemic stroke. For the PCSK9 rs505151 polymorphism, the OR of co-dominant model (OR = 1.36, 95%  CI:1.01–1.58) was found to be higher among ischemic stroke patients. In conclusion, the current meta-analysis highlighted that variant allele of OLR1 rs11053646 G > C and PCSK9 rs505151 A > G may contribute to the susceptibility risk of ischemic stroke.

A Potential Epigenetic Marker Mediating Serum Folate and Vitamin B12 Levels Contributes to the Risk of Ischemic Stroke

Stroke is a multifactorial disease that may be associated with aberrant DNA methylation profiles. We investigated epigenetic dysregulation for the methylenetetrahydrofolate reductase (MTHFR) gene among ischemic stroke patients. Cases and controls were recruited after obtaining signed written informed consents following a screening process against the inclusion/exclusion criteria. Serum vitamin profiles (folate, vitamin B12, and homocysteine) were determined using immunoassays. Methylation profiles for CpGs A and B in the MTHFR gene were determined using a bisulfite-pyrosequencing method. Methylation of MTHFR significantly increased the susceptibility risk for ischemic stroke. In particular, CpG A outperformed CpG B in mediating serum folate and vitamin B12 levels to increase ischemic stroke susceptibility risks by 4.73-fold. However, both CpGs A and B were not associated with serum homocysteine levels or ischemic stroke severity. CpG A is a potential epigenetic marker in mediating serum folate and vitamin B12 to contribute to ischemic stroke.

Recent Advances in the Genetics of Hypertension

Hypertension is a silent killer worldwide, caused by both genetic and environmental factors. Until now, genetic and genomic association studies of hypertension are reporting different degree of association on hypertension. Hence, it is essential to gather all the available information on the reported genetic loci and to determine if any biomarker(s) is/are significantly associated with hypertension. Current review concluded the potential biomarkers for hypertension, with regards to electrolyte and fluid transports, as well as sodium/potassium ions homeostasis, which are supported by the results of case-controls and meta-analyses.

Clinical impact of ABCC1 and ABCC2 genotypes and haplotypes in mediating imatinib resistance among chronic myeloid leukaemia patients

The introduction and success of imatinib mesylate (IM) has brought about a paradigm shift in chronic myeloid leukaemia (CML) treatment. However, despite the high efficacy of IM, clinical resistance develops due to a heterogeneous array of mechanisms. Pharmacogenetic variability as a result of genetic polymorphisms could be one of the most important factors influencing resistance to IM. The aim of this study was to investigate the association between genetic variations in drug efflux transporter ABCC1 (MRP1) and ABCC2 (MRP2) genes and response to IM in patients with CML.

Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis

INTRODUCTION The association between ischemic stroke and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR; 677C>T and 1298A>C), endothelial nitric oxide synthase (eNOS; -786T>C, +894G>T, and variable number tandem repeat [VNTR]), phosphodiesterase 4D (PDE4D; SNPs 83 and 87), angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) 235M>T, paraoxonase 1 (PON1) 192Q>R, and apolipoprotein E (ApoE) ε2ε3ε4 remains inconclusive. Therefore, this updated meta-analysis aimed to clarify the presumed influence of genetic polymorphisms on ischemic stroke by meta-analyzing the comprehensive coverage of all individual association studies. METHODS All case-control studies published in different languages such as English, Japanese, Korean, Spanish, Chinese, Hungarian, Ukrainian, or Russian were identified from databases. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via fixed- and random-effect models. Sensitivity analysis, heterogeneity test, Hardy Weinberg Equilibrium, and Eggers regression analyses were performed in this study. RESULTS A total of 490 case-control studies with 138,592 cases and 159,314 controls were included in this meta-analysis. Pooled ORs from all the genetic models indicated that MTHFR 677TT and 1298CC, eNOS +894TT and VNTR, PDE4D SNP 83, ACE DD, AGT 235TT, PON1 192RR, and ApoE ε4 polymorphisms were increasing the risks of ischemic stroke. Nevertheless, PDE4D SNP 87 and eNOS -786T>C polymorphisms are not associated with ischemic stroke risks. CONCLUSIONS Hence, the evidence from this meta-analysis concluded that MTHFR (677C>T and 1298A>C), eNOS (+894G>T and VNTR), PDE4D SNP 83, ACE I/D, AGT 235M>T, PON1 192Q>R, and ApoE ε2ε3ε4 polymorphisms predispose individuals to ischemic stroke.

Metabolomics, Lipidomics and Pharmacometabolomics of Human Hypertension

Hypertension is a common but complex human disease, which can lead to a heart attack, stroke, kidney disease or other complications. Since the pathogenesis of hypertension is heterogeneous and multifactorial, it is crucial to establish a comprehensive metabolomic approach to elucidate the molecular mechanism of hypertension. Although there have been limited metabolomic, lipidomic and pharmacometabolomic studies investigating this disease to date, metabolomic studies on hypertension have provided greater insights into the identification of disease-specific biomarkers, predicting treatment outcome and monitor drug safety and efficacy. Therefore, we discuss recent updates on the applications of metabolomics technology in human hypertension with a focus on metabolic biomarker discovery.

Methylenetetrahydrofolate Reductase CpG Islands: Epigenotyping

Determination of the differential DNA methylation patterns of methylenetetrahydrofolate reductase (MTHFR) that are associated with differential MTHFR activity is important to understand the pathogenesis of ischemic stroke. However, to date, no data are available on the differential DNA methylation profiles of Kelantanese Malays. Therefore, we developed a rapid and efficient serial pyrosequencing assay to determine differential DNA methylation profiles of MTHFR, which help to further our understanding of the pathogenesis of ischemic stroke. The developed assay also served as the validation platform for our previous computational epigenetic research on MTHFR.

Metabolomics and Lipidomics of Ischemic Stroke

Ischemic stroke is a sudden loss of brain function due to the reduction of blood flow. Brain tissues cease to function with subsequent activation of the ischemic cascade. Metabolomics and lipidomics are modern disciplines that characterize the metabolites and lipid components of a biological system, respectively. Because the pathogenesis of ischemic stroke is heterogeneous and multifactorial, it is crucial to establish comprehensive metabolomic and lipidomic approaches to elucidate these alterations in this disease. Fortunately, metabolomic and lipidomic studies have the distinct advantages of identifying tissue/mechanism-specific biomarkers, predicting treatment and clinical outcome, and improving our understanding of the pathophysiologic basis of disease states. Therefore, recent applications of these analytical approaches in the early diagnosis of ischemic stroke were discussed. In addition, the emerging roles of metabolomics and lipidomics on ischemic stroke were summarized, in order to gain new insights into the mechanisms underlying ischemic stroke and in the search for novel metabolite biomarkers and their related pathways.

Chapter 12 – Computational Epigenetics

Epigenetics has emerged as a rapidly growing field for studying the heritable alterations involved in the regulation of gene expression patterns that are not due to changes in DNA sequence. To which, the epigenetic mechanisms, such as DNA methylation and histone modifications, can modulate chromatin structure and gene regulation, during cellular development and differentiation in higher organisms. Recent advancements in high-throughput epigenetic profiling technologies, including bisulfite microarray, bisulfite sequencing, affinity enrichment, ChIP-on-chip, and ChIP sequencing, have generated vast amounts of epigenomic data. In turn, the developments of bioinformatics databases and software tools have thus contributed significantly to the substantial, and growing, interest in epigenetic research. This chapter reviews the key aspects and techniques of computational epigenetics. In particular, the major computational tools, databases, and strategies for epigenetics analysis of DNA methylation and histone modifications have been summarized.