Project description:Pharmacogenomics has employed candidate gene studies and, more recently, genome-wide association studies (GWAS) in efforts to identify loci associated with drug response and/or toxicity. The advantage of GWAS is the simultaneous, unbiased testing of millions of SNPs; the challenge is that functional information is absent for the vast majority of loci that are implicated. In the present study, we systematically evaluated SNPs associated with chemotherapeutic agent-induced cytotoxicity for six different anticancer agents and evaluated whether these SNPs were disproportionately likely to be within a functional class such as coding (consisting of missense, nonsense, or frameshift polymorphisms), noncoding (such as 3'UTRs or splice sites), or expression quantitative trait loci (eQTLs; indicating that a SNP genotype is associated with the transcript abundance level of a gene). We found that the chemotherapeutic drug susceptibility-associated SNPs are more likely to be eQTLs, and, in fact, more likely to be associated with the transcriptional expression level of multiple genes (n > or = 10) as potential master regulators, than a random set of SNPs in the genome, conditional on minor allele frequency. Furthermore, we observed that this enrichment compared with random expectation is not present for other traditionally important coding and noncoding SNP functional categories. This research therefore has significant implications as a general approach for the identification of genetic predictors of drug response and provides important insights into the likely function of SNPs identified in GWAS analysis of pharmacologic studies.

| S-EPMC2889115 | biostudies-literature

Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

Project description:We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

| S-EPMC3601550 | biostudies-literature

Upper gastrointestinal haemorrhage: an update.

Project description:Upper gastrointestinal (GI) haemorrhage is a common cause for admission to hospital and is associated with a mortality of around 10%. Prompt assessment and resuscitation are vital, as are risk stratification of the severity of bleeding, early involvement of the multidisciplinary team and timely access to endoscopy, preferably within 24 h. The majority of bleeds are due to peptic ulcers for which Helicobacter pylori and non-steroidal anti-inflammatory agents are the main risk factors. Although proton pump inhibitors (PPIs) are widely used before endoscopy, this is controversial. Pre-endoscopic risk stratification with the Glasgow Blatchford score is recommended as is the use of the Rockall score postendoscopy. Endoscopic therapy, with at least two haemostatic modalities, remains the mainstay of treating high-risk lesions and reduces rebleeding rates and mortality. High-dose PPI therapy after endoscopic haemostasis also reduces rebleeding rates and mortality. Variceal oesophageal haemorrhage is associated with a higher rebleeding rate and risk of death. Antibiotics and vasopressin analogues are advised in suspected variceal bleeding; however, endoscopic variceal band ligation remains the haemostatic treatment of choice. Balloon tamponade remains useful in the presence of torrential variceal haemorrhage or when endoscopy fails to secure haemostasis, and can be a bridge to further endoscopic attempts or placement of a transjugular intrahepatic portosystemic shunt. This review aims to provide an update on the latest evidence-based recommendations for the management of acute upper GI haemorrhage.

| S-EPMC5369541 | biostudies-other

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