The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Diabetes mellitus: pathophysiological changes and therap

Proline induces oxidative stress in cerebral cortex of rats

In the present study we investigated the in vivo and in vitro effects of proline on some parameters of oxidative stress, such as chemiluminescence, total radical-trapping antioxidant potential (TRAP) and the activity of the antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase in rat cerebral cortex. Ten-day-old rats received one subcutaneous injection of proline (12.8 μmol/g body weight), while control rats received saline in the same volumes. The animals were killed 1 h after injection, the cerebral cortex was isolated and the assays immediately carried out. For the in vitro studies, homogenates from cerebral cortex of 10-day-old untreated rats were incubated for 1 h at 37 °C with various concentrations of proline (3.0 μM–1.0 mM). Results showed that proline-treated rats presented a decrease of TRAP (30%) and an increase of chemiluminescence (78%). In contrast, the activities of catalase, glutathione peroxidase and superoxide dismutase were not modified by proline acute treatment. Furthermore, the presence of proline in the medium increased chemiluminescence, decreased TRAP and the activity of superoxide dismutase at proline concentrations similar to those observed in tissues of hyperprolinemic patients (0.5–1.0 mM). However, catalase and glutathione peroxidase activities were not affected by the presence of proline in the medium. The results indicate that proline induces oxidative stress in the brain, which may be related, at least in part, to the neurological dysfunction observed in hyperprolinemia

Aspectos dinámicos de la bioquímica

Global expression profiling of neurologic or psychiatric disorders has been confounded by variability among laboratories, animal models, tissues sampled, and experimental platforms, with the result being that few genes demonstrate consistent expression changes. We attempted to minimize these confounds by pooling dentate granule cell transcriptional profiles from 164 rats in seven laboratories, using three status epilepticus (SE) epilepsy models (pilocarpine, kainate, self-sustained SE), plus amygdala kindling. In each epilepsy model, RNA was harvested from laser-captured dentate granule cells from six rats at four time points early in the process of developing epilepsy, and data were collected from two independent laboratories in each rodent model except SSSE. Hierarchical clustering of differentially-expressed transcripts in the three SE models revealed complete separation between controls and SE rats isolated 1 day after SE. However, concordance of gene expression changes in the SE models was only 26-38% between laboratories, and 4.5% among models, validating the consortium approach. Transcripts with unusually highly variable control expression across laboratories provide a 'red herring' list for low-powered studies