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microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.

Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of pore-forming &alpha, subunits and two auxiliary &beta, subunits, several of which have been well studied in epileptic conditions. However, despite the &beta, 4-subunits&rsquo, role having been reported in some neurological conditions, there is little research investigating its potential significance in epilepsy. Therefore, the purpose of this work was to assess the role of SCN4&beta, in epilepsy by using a combination of molecular and bioinformatics approaches. We first demonstrated that there was a reduction in the relative expression of SCN4B in the drug-resistant TLE patients compared to non-epileptic control specimens, both at the mRNA and protein levels. By analyzing a co-expression network in the neighborhood of SCN4B we then discovered a linkage between the expression of this gene and K+ channels activated by Ca2+, or K+ two-pore domain channels. Our approach also inferred several potential effector functions linked to variation in the expression of SCN4B. These observations support the hypothesis that SCN4B is a key factor in AED-resistant TLE, which could help direct both the drug selection of TLE treatments and the development of future AEDs.

The Allele Frequency Net Database (AFND, www.allelefrequencies.net) provides the scientific community with a freely available repository for the storage of frequency data (alleles, genes, haplotypes and genotypes) related to human leukocyte antigens (HLA), killer-cell immunoglobulin-like receptors (KIR), major histocompatibility complex Class I chain related genes (MIC) and a number of cytokine gene polymorphisms in worldwide populations. In the last five years, AFND has become more popular in terms of clinical and scientific usage, with a recent increase in genotyping data as a necessary component of Short Population Report article submissions to another scientific journal. In addition, we have developed a user-friendly desktop application for HLA and KIR genotype/population data submissions. We have also focused on classification of existing and new data into ‘gold–silver–bronze’ criteria, allowing users to filter and query depending on their needs. Moreover, we have also continued to expand other features, for example focussed on HLA associations with adverse drug reactions. At present, AFND contains >1600 populations from >10 million healthy individuals, making AFND a valuable resource for the analysis of some of the most polymorphic regions in the human genome.

The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the system contains data from 1505 populations in more than ten million individuals on the frequency of genes from different polymorphic regions including data for the human leukocyte antigens (HLA) system. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, and population genetics, among many others. In this chapter, we present some of the more commonly used searching mechanisms and some of the most recent developments included in AFND.

BACKGROUND: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity. METHODS: A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults. Replication of signals was determined in a cohort of 116 cases and 68 controls obtained from Malawi, Uganda and Mozambique. Interaction with ERAP genes was determined in patients positive for HLA-C*04:01 In silico docking studies were also performed for HLA-C*04:01 RESULTS: Fifteen SNPs demonstrated nominal significance (P

This review describes a database for the collection, archiving, sorting, searching and display of gene and allele frequencies for immunogenetic genes.

Tupí linguistic groups display a wide geographical dispersion in South America, probably originated, as pointed by linguistic, from Madeira-Guaporé Region (MGR) in Brazil. The present study reviewed genetic data on Tupians for autosomal and uniparental (Y-chromosome and mtDNA) markers, using it to evaluate Tupians geographic origin as well as the demographic dynamics of their dispersion from a genetic point of view. Comparison of genetic variability and mtDNA haplogroups D frequencies suggests a scenario where MGR is the Tupí homeland. The relationship between five estimators of genetic variability (Thetas-S, -Pi, -m2, -H and -k) shows that Tupí groups from MGR and non-MGR experienced different patterns of demographic dynamics, with an ancient Tupí expansion in MGR, followed by dispersion to other South America regions, probably associated to depopulation/founder effect events. Furthermore, other recent depopulation events could also be detected in both regions. Finally, the dispersion seems to be related to patrilocality, as suggested by comparison of uniparental markers genetic differentiation. This genetic model of dispersion dynamics may have an important impact in the interpretation of archeological and linguistic data, allowing to test if female associated technologies, like ceramic, are more extensively shared between dispersed populations than those which are not female-exclusive. Resumo: Grupos linguísticos Tupí exibem uma grande dispersão geográfica na América do Sul, provavelmente originadas, conforme apontada pela linguistica, na Região Madeira-Guaporé (MGR), Brasil. O presente estudo revisou dados geneticos de populacoes Tupí para marcadores autossomicos e uniparentais (Y-cromossomo and mtDNA), delineando abordagens para avaliar origem geográfica, bem como a dinâmica demográfica de sua dispersão, de um ponto de vista genético. Comparação da variabilidade genetica e das frequencias do haplogrupo D do mtDNA sugere um cenário onde MGR é o local de origem Tupí. A relação entre cinco estimadores de variabilidade genetica Thetas-S, -Pi, -m2, -H e -k) mostram que grupos Tupí da MGR não MGR experienciaram diferentes padrões de dinâmica demográfica, com uma antiga expansão Tupí em MGR, seguida de dispersão para outras regiões da América do Sul, provavelmente associada a eventos de depopulação/efeito fundador. Além disso, outros eventos recentes de depopulação também puderam ser detectados em ambas as regiões. Finalmente, a dispersão parece estar relacionada com práticas de patrilocalidade, como sugerido pela comparação de marcadores uniparentais. Este modelo genético de dinâmica de dispersão Tupí pode ter um impacto importante na interpretação dos dados arqueológicos e linguísticos, permitindo testar se tecnologias associadas ao sexo feminino, como a cerâmica, são mais amplamente compartilhadas entre populações dispersas do que tecnologias 1não exclusivas do sexo feminino.