The Affymetrix GeneChip Human Mapping 500K array is common for genome-wide association studies (GWASs). Recent findings highlight the importance of accurate genotype calling algorithms to reduce the inflation in Type I and Type II error rates. Differential results due to genotype calling errors can introduce severe bias in case–control association study results. Using data from...
Batch effects are the systematic non-biological differences between batches (groups) of samples in microarray experiments due to various causes such as differences in sample preparation and hybridization protocols. Previous work focused mainly on the development of methods for effective batch effects removal. However, their impact on cross-batch prediction performance, which is...
The Genome-Wide Association Working Group (GWAWG) is part of a large-scale effort by the MicroArray Quality Consortium (MAQC) to assess the quality of genomic experiments, technologies and analyses for genome-wide association studies (GWASs). One of the aims of the working group is to assess the variability of genotype calls within and between different genotype calling...
Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene...
Microarray-based classifiers and associated signature genes generated from various platforms are abundantly reported in the literature; however, the utility of the classifiers and signature genes in cross-platform prediction applications remains largely uncertain. As part of the MicroArray Quality Control Phase II (MAQC-II) project, we show in this study 80–90% cross-platform...
Genomic biomarkers for the detection of drug-induced liver injury (DILI) from blood are urgently needed for monitoring drug safety. We used a unique data set as part of the Food and Drug Administration led MicroArray Quality Control Phase-II (MAQC-II) project consisting of gene expression data from the two tissues (blood and liver) to test cross-tissue predictability of genomic...
Smokers (10 cigarettes per day, N=331) of European ancestry taking part in a double-blind placebo-controlled randomized trial of 12 weeks of treatment with bupropion along with counseling for smoking cessation were genotyped for a variable number of tandem repeats polymorphism in exon III of the dopamine D4 receptor gene. Generalized estimating equations predicting point...
Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E ɛ4 (APOE ɛ4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD...
MicroRNAs are non-coding RNAs that can block mRNA translation and influence mRNA stability. Recent evidence indicates that miRNA variations can affect drug resistance, efficacy, and metabolism, opening new avenues of pharmacogenomics research. We investigated associations between polymorphisms in both miRNA-containing genomic regions (primary and precursor miRNA) and in genes...
Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human...
Nonsteroidal anti-inflammatory drugs possess antiproliferative activities that can affect cancer cells. The aim of this study was to examine the antiproliferative effects of ibuprofen on the MKN-45 cell line. Cells were treated with ibuprofen for 24, 48 or 72 h, and cell proliferation was evaluated by cell counting and [3H]-thymidine incorporation. Using microarray technology, we...
The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n−3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and...
Single-nucleotide polymorphisms (SNPs) can be assayed using DNA isolated from archival formalin-fixed, paraffin-embedded (FFPE) samples, making retrospective pharmacogenetic studies possible. In this study, we describe methods that significantly increase the number of SNP determinations possible using FFPE samples. Quantifying the amount of DNA amenable to PCR (amplification...
Estrogen replacement therapy in women has shown a protective effect on the development of colonic carcinomas. Gender-related differences in the development of colonic carcinomas have also been reported. Estrogen receptor-β (ERβ) is expressed in colon carcinomas and has shown prognostic value in colon cancer patients. This study investigated an ERβ 3′ non-coding polymorphism...
Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been associated with variations in nitric oxide (NO) formation and response to drugs in white subjects. We examined whether genetic polymorphisms (T-786C, b/a intron 4 and Glu298Asp) and haplotypes of the eNOS gene affect NO formation in 179 healthy black subjects. To assess NO formation, we measured the...
β-Arrestin2 (ARRB2) is a component of the G-protein-coupled receptor complex and is involved in μ-opioid and dopamine D2 receptor signaling, two central processes in methadone signal transduction. We analyzed 238 patients in methadone maintenance treatment (MMT) and identified a haplotype block (rs34230287, rs3786047, rs1045280 and rs2036657) spanning almost the entire ARRB2...
The effects of leptin-replacement therapy on the plasma proteome of three unique adults with genetically based leptin deficiency were studied longitudinally during the course of recombinant human leptin-replacement treatment. Quantitative proteomics analysis was performed in plasma samples collected during four stages: before leptin treatment was initiated, after 1.5 and 6 years...
The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic...
Aurora kinases are conserved eukaryotic serine–threonine kinases, which serve as key regulators of mammalian mitosis. Several studies revealed a distinct correlation between inaccurate chromosome segregation, leading to chromosomal number instability, cancer progression and poor outcome. The aim of this study was to investigate the correlation of Aurora kinases A (AURKA) and B...
The discordance in results of independent genome-wide association studies (GWAS) indicates the potential for Type I and Type II errors. We assessed the repeatibility of current Affymetrix technologies that support GWAS. Reasonable reproducibility was observed for both raw intensity and the genotypes/copy number variants. We also assessed consistencies between different SNP arrays...
ABCC2 (MRP2) is an important export pump, expressed at tissue barriers. The genetic variants −24C>T, 1249G>A and 3972C>T are leading to inter-individual differences of bioavailability of various endogenous and exogenous compounds. Considering ABCC2 haplotypes, we investigated DNA–protein binding properties, mRNA secondary structure, mRNA stability, protein expression and...
Tetrahydrobiopterin (BH4) is an essential cofactor for synthesis of many neurotransmitters including serotonin. In serotonergic neurons, BH4 is tightly regulated by GTP-cyclohydrolase I feedback regulator (GFRP). Given the pivotal role of the serotonergic system in mood disorders and selective serotonin reuptake inhibitors (SSRIs) antidepressant function, we tested the hypothesis...
SLC30A8 encodes the β-cell-specific zinc transporter-8 (ZnT-8) expressed in insulin secretory granules. The single-nucleotide polymorphism rs13266634 of SLC30A8 is associated with susceptibility to post-transplantation diabetes mellitus (PTDM). We tested the hypothesis that the polymorphic residue at position 325 of ZnT-8 determines the susceptibility to cyclosporin A (CsA...