Search

We tested over 267,000 SNPs in 1,005 Northern Europeans and 248,000 in 1,006 Indian Asians for association with triglycerides and HDL cholesterol, with replication in 10,536 subjects. We found association of a nonsynonymous SNP (rs3812316, G771C, Gln241His) in MLXIPL with plasma triglyceride levels (combined P = 1.4 x 10(-10)). MLXIPL coordinates transcriptional regulation of enzymes that channel glycolytic end-products into lipogenesis and energy storage, making MLXIPL a plausible 'thrifty gene'.

The usefulness of Bayesian statistical methods for the modelling of biochemical reactions is examined. With simulated data, it is shown that these methods can effectively fit mechanistic models of sequences of enzymatic reactions to experimental data. These methods have the advantages of being relatively easy to use and producing probability distributions for the model parameters rather than point estimates, allowing more informative inferences to be drawn. Three Markov Chain Monte Carlo algorithms are used to fit models to data from a sequence of four enzymatic reactions. The algorithms are evaluated with respect to the goodness-of-fit of the fitted models and the time to completion. It is shown that the algorithms produce essentially the same parameter distributions, but the time to completion varies.

Background: Reduction of drug-induced adverse events may be achievable through a better understanding of the underlying causes of such events. Identifying phenotypes and genotypes that allow event prediction would provide greater safety margins for new therapeutics. Torsades de pointes (TdP) is one such life-threatening adverse event and can arise from excessive lengthening of the QT interval. This study was designed to better understand the role of genetics in the development of TdP and to determine whether genotypes can be used to predict susceptibility and thus reduce adverse events., Methods: Seven known familial long QT syndrome genes were scanned for sequence variations in 34 patients with TdP. This group of patients is the largest such cohort ever assembled for this type of analysis. The allele frequencies for novel and known polymorphisms in these patients were compared with those in healthy control subjects., Results: Six novel mutations--4 in ANK2, 1 in KCNQ1, and 1 in SCN5A--were found in the patients with TdP. Two mutations were also found in 595 healthy control subjects, whereas the others were unique to patients with TdP. Two common single nucleotide polymorphisms may be associated with the risk of TdP. The entire ANK2 gene had not been screened in a population this large previously., Conclusions: Genotypes alone could not be used to completely predict susceptibility to TdP, even when used with phenotypes. The best model using genotypic and phenotypic variables was unable to predict all events. It is unclear what other risk genes or environmental effects might be necessary to predict such cases.

Genotoxic stress triggers a variety of biological responses including the transcriptional activation of genes regulating DNA repair, cell survival and cell death. Genomic approaches, which monitor gene expressions across large numbers of genes, can serve as a powerful tool for exploring mechanisms of toxicity. Here, using five different agents, we investigated whether the analysis of genome-wide expression profiles in Saccharomyces cerevisiae could provide insights into mechanisms of genotoxicity versus cytotoxicity. To differentiate the genotoxic stress-associated expression signatures from that of a general cytotoxic stress, we compared gene expression profiles following the treatment with DNA-reactive (cisplatin, MMS, bleomycin) and DNA non-reactive (ethanol and sodium chloride) compounds. Although each of the tested chemicals produced a distinct gene expression profile, we were able to identify a gene expression signature consisting of a relatively small number of biologically relevant genes capable of differentiating genotoxic and cytotoxic stress. The gene set includes such upregulated genes as HUG1, ECM4 and previously uncharacterized gene, YLR297W in the genotoxic and GAP1, CGR1 in the cytotoxic group. Our results indicate the potential of gene expression profile analysis for elucidating mechanism of action of genotoxic agents.

Genotoxic stress triggers a variety of biological responses including the transcriptional activation of genes regulating DNA repair, cell survival and cell death. Here, we investigated whether gene expression profiles can differentiate between DNA reactive and DNA non-reactive mechanisms of genotoxicity. We analyzed gene expression profiles and micronucleus levels in L5178Y cells treated with cisplatin and sodium chloride. The assessment of cisplatin genotoxicity (up to six-fold increase in the number of micronuclei) and gene expression profile (increased expression of genotoxic stress-associated genes) was in agreement with cisplatin mode of action as a DNA adduct-forming agent. The gene expression profile analysis of cisplatin-treated cells identified a number of genes with robust up regulation of mRNA expression including genes associated with DNA damage (i.e. members of GADD45 family), early response (i.e. cFOS), and heat shock protein (i.e. HSP40 homologue). The gene expression changes correlated well with DNA damage as measured by DNA-protein crosslinks and platinum-DNA binding. To differentiate the genotoxic stress-associated expression profile of cisplatin from a general toxic stress, we have compared the gene expression profile of cisplatin-treated cells to cells treated with sodium chloride, which causes osmotic shock and cell lysis. Although the sodium chloride treatment caused a two-fold induction of micronuclei, the gene expression profile at equitoxic concentrations was remarkably distinct from the profile observed with cisplatin. The profile of sodium chloride featured a complete lack of expression changes in genes associated with DNA damage and repair. In summary, the gene expression profiles clearly distinguished between DNA reactive and non-reactive genotoxic mechanisms of cisplatin and sodium chloride. Our results suggest the potential utility of gene expression profile analysis for elucidating mechanism of action of genotoxic agents.