Common Variants on Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial.

Background: Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking.

Methods: The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507).

Genome-wide association study of abnormal elevation of ALT in patients exposed to atabecestat.

Background: Atabecestat, a potent brain penetrable BACE1 inhibitor that reduces CSF amyloid beta (Aβ), was developed as an oral treatment for Alzheimer's disease (AD). Elevated liver enzyme adverse events were reported in three studies although only one case met Hy's law criteria to predict serious hepatotoxicity.

Method: We performed a case-control genome-wide association study (GWAS) to identify genetic risk variants associated with liver enzyme elevation using 42 cases with alanine transaminase (ALT) above three times the upper limit of normal (ULN) and 141 controls below ULN.

Tramadol Hydrochloride at Steady State Lacks Clinically Relevant QTc Interval Increases in Healthy Adults.

We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18-55 years) in a randomized, phase I, double-blind, placebo- and positive-controlled, multiple-dose, 4-way crossover study. Participants were randomized to receive 1 of 4 treatments (A-D), 1 each in 4 treatment periods (1-4), separated by a washout period (7-15 days). Treatment A comprised tramadol 400 mg (therapeutic dose) on days 1 through 3, tramadol 100 mg and moxifloxacin-matched placebo on day 4, and placebo on all 4 days.

The role of ADME pharmacogenomics in early clinical trials: perspective of the Industry Pharmacogenomics Working Group (I-PWG).

Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significantly impact the exposure of drugs having a high dependence on a single mechanism for their absorption, distribution or clearance, such that genotyping can lead to actionable steps in disease treatment. Recently, global regulatory agencies have provided guidance for assessment of pharmacogenomics during early stages of drug development, both in the form of formal guidance and perspectives published in scientific journals. The Industry Pharmacogenomics Working Group (I-PWG), conducted a survey among member companies to assess the practices relating to absorption, distribution, metabolism, excretion pharmacogenomics) during early stages of clinical development, to assess the impact of the recent Regulatory Guidance issued by the US FDA and EMA on Industry practices.

A candidate-gene association study of topiramate-induced weight loss in obese patients with and without type 2 diabetes mellitus.

Objective: Clinical response to topiramate can vary greatly in obese patients. Identifying genetic variants associated with treatment response could help gain insight into the mechanism of action of topiramate. Little is known about the relationship between genetic variability and topiramate treatment response.

In vitro metabolism of canagliflozin in human liver, kidney, intestine microsomes, and recombinant uridine diphosphate glucuronosyltransferases (UGT) and the effect of genetic variability of UGT enzymes on the pharmacokinetics of canagliflozin in humans.

O-glucuronidation is the major metabolic elimination pathway for canagliflozin. The objective was to identify enzymes and tissues involved in the formation of 2 major glucuronidated metabolites (M7 and M5) of canagliflozin and subsequently to assess the impact of genetic variations in these uridine diphosphate glucuronosyltransferases (UGTs) on in vivo pharmacokinetics in humans. In vitro incubations with recombinant UGTs revealed involvement of UGT1A9 and UGT2B4 in the formation of M7 and M5, respectively.

The effect of UGT2B7*2 polymorphism on the pharmacokinetics of OROS® hydromorphone in Taiwanese subjects.

This open-label, single-center, phase I study (NCT1487564) investigated the effect of uridine diphosphate-glucuronosyltransferase2B7 (UGT2B7*2) genetic polymorphism (H268Y) on the pharmacokinetics (PK) and safety of a single, oral, 16-mg dose of OROS® hydromorphone and its metabolite in healthy Taiwanese subjects. Plasma concentrations of hydromorphone and hydromorphone-3-glucuronide were determined in 28 subjects. PK parameters calculated included maximum plasma concentration (Cmax); time to reach maximum plasma concentration (tmax); area under plasma concentration-time curve from 0-48 hours (AUC0-48 h) and 0-infinite time (AUC∞); and hydromorphone-3-glucuronide:hydromorphone metabolic ratio (RM).

Rare variant collapsing in conjunction with mean log p-value and gradient boosting approaches applied to Genetic Analysis Workshop 17 data.

In addition to methods that can identify common variants associated with susceptibility to common diseases, there has been increasing interest in approaches that can identify rare genetic variants. We use the simulated data provided to the participants of Genetic Analysis Workshop 17 (GAW17) to identify both rare and common single-nucleotide polymorphisms and pathways associated with disease status. We apply a rare variant collapsing approach and the usual association tests for common variants to identify candidates for further analysis using pathway-based and tree-based ensemble approaches.

Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta.

Background: The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability.

Case-control study of the association between select HLA genes and anti-erythropoietin antibody-positive pure red-cell aplasia.

Aims: Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele.

Effect of CYP2D6 genetic polymorphism on the population pharmacokinetics of tipifarnib.

Objective: Evaluate the effect of CYP2D6 genotype on the pharmacokinetics of tipifarnib.

Methods: A total of 268 subjects included in six clinical trials were treated orally with tablet formulation of tipifarnib, as a single dose or as multiple b.i.

A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2.

We conducted a genome-wide search for childhood obesity-associated traits, including BMI >/==" BORDER="0">95th percentile (PCT95), 97th percentile (PCT97), and 99th percentile (PCT99) as well as age of adiposity rebound (AAR), which corresponds to the beginning of the second rise in childhood adiposity. A set of 431 microsatellite markers was genotyped in 506 subjects from 115 multiplex French Caucasian families, with at least one child with a BMI >/==" BORDER="0">95th percentile. Among these 115 pedigrees, 97 had at least two sibs with a BMI >/==" BORDER="0">95th percentile.

TAK-677 (Dainippon/Takeda).

TAK-677 is a beta3-adrenergic agonist under development by Dainippon and Takeda for the potential treatment of non-insulin dependent diabetes and obesity. In March 2001, Takeda initiated a phase II trial in the US for Type II diabetes [411811], [416686], [423455]. By December 2001, the compound was also in phase II trials for obesity in the US, and Dainippon was conducting phase II studies in Japan for diabetes [458750].