Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

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.

Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study.

Introduction: Nephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD.

PBDE levels in breast milk are decreasing in California.

To assess the efficacy of the bans in reducing PBDE levels, we recruited 67 California first time mothers (sampled during 2009-2012) and collected cord blood at birth (n = 31), breast milk (n = 66) and maternal blood (n = 65) at 3-8 weeks postpartum. Using the same sample extraction procedures and analytical instrumentation method (GC-HRMS), we compared PBDE as well as PCB levels in these breast milk samples to those from our previous study (n = 82, sampled during 2003-2005) and found that the sum of PBDEs over the ∼7 year course declined by 39% (GeoMean = 67.8 ng/g lipid in 2003-2005; 41.

Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease.

Background And Aims: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients.

Methods: Inflammatory bowel disease patients were recruited from 89 sites around the world.

Phenotype standardization for drug-induced kidney disease.

Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease.

The international serious adverse events consortium.

The International Serious Adverse Events Consortium is generating novel insights into the genetics and biology of drug-induced serious adverse events, and thereby improving pharmaceutical product development and decision-making.

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world.

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing.

High postnatal exposures to polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) via breast milk in California: does BDE-209 transfer to breast milk?

Breast milk samples collected during 2003-2005 from 82 first-time mothers in 24 communities located throughout California contained levels of polybrominated diphenyl ethers (∑(tri-hexa (8))PBDEs; median = 53.3 ng/g lw, range = 9.60-1291) and polychlorinated biphenyls (∑(12)PCBs; median = 73.

Polybrominated diphenyl ether (PBDE) levels in peregrine falcon (Falco peregrinus) eggs from California correlate with diet and human population density.

Peregrine falcons are now considered a conservation success story due in part to the phasing out of harmful contaminants that adversely affected reproduction. Recent studies have shown that peregrine eggs collected from California cities, however, have high levels of the higher-brominated polybrominated diphenyl ethers (SigmaPBDE(183-209)), a class of industrial flame retardants, in comparison to published data for other wildlife. Sources of these high PBDE levels and unusual PBDE profiles are unknown.

Prey species as possible sources of PBDE exposures for peregrine falcons (Falco peregrinus) nesting in major California cities.

Our earlier findings indicate that (1) peregrine falcons (Falco peregrinus anatum Bonaparte) nesting in major California cities have among the highest polybrominated diphenyl ether (PBDE) levels in the world (max ∑PBDEs=100 ppm), and (2) Big City peregrines have higher levels and proportions of the higher-brominated congeners (hepta- to deca-BDEs) than do their Coastal counterparts. In this study we classified the prey species (n =185) from the remains of prey (feathers) at 38 peregrine nest sites over 25 years (1974-1998). We grouped the prey species into 15 categories based on diet and found distinctly different prey patterns for Big City vs.

Time-trends and congener profiles of PBDEs and PCBs in California peregrine falcons (Falco peregrinus).

High levels (microg/g lw) of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in peregrine falcon eggs from California (n = 90 eggs from 52 birds, 38 nest sites, collected 1986-2007, SigmaPBDEs median = 4.53, range = 0.08-53.

Unusual hepta- and octabrominated diphenyl ethers and nonabrominated diphenyl ether profile in California, USA, peregrine falcons (Falco peregrinus): more evidence for brominated diphenyl ether-209 debromination.

High (maximum of 4.1 ppm lipid weight) levels of BDE-209 and other higher brominated diphenyl ethers (BDEs) found in California, USA, peregrine falcon (Falco peregrinus) eggs (n = 95) provided an opportunity to examine homolog profiles of nona-, octa-, and hepta-BDEs as possible evidence for biological debromination of BDE-209. We found two congeners in eggs, an unidentified hepta-BDE (BDE-heptaUNK) and BDE-202 (octa-BDE) that are not present in commercial mixtures.

Concentrations and time trends of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in aquatic bird eggs from San Francisco Bay, CA 2000-2003.

Concentrations of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in 169 avian eggs. We analyzed randomly collected eggs of two species of piscivorous birds: Caspian tern (Sterna caspia) (n=78) and Forster's tern (Sterna forsteri) (n=76). We also analyzed fail-to-hatch eggs from two species protected under the Federal Endangered Species Act of 1973, that breed in the San Francisco Bay region: the piscivorous California Least tern (Sterna antillarum brownii) (n=11) and the omnivorous California Clapper rail (Rallus longirostris obsoletus) (n=4).

A second generation human haplotype map of over 3.1 million SNPs.

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.

Depuration of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in breast milk from California first-time mothers (primiparae).

Background: Little is known about the rates of loss (depuration) of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) from mothers during lactation. Depuration rates affect infant exposure to chemicals during breast-feeding, and fetal and lactational transfers during subsequent pregnancies.

Objective: Our objective in this study was to estimate depuration rates of PBDEs and PCBs using serial samples of breast milk.

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in breast milk from the Pacific Northwest.

Breast milk samples from 40 first-time mothers from the Pacific Northwest of the US and Canada were analyzed for polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs). Total PBDEs (summation operator PBDEs), calculated by summing values for the 12 PBDEs congeners analyzed, ranged from 6 to 321 ppb (lipid weight) (mean=96 ppb; median=50 ppb). In approximately 40% of the women (15/40), summation operator PBDEs>100 ppb lw in their milk, and four samples had levels >250 ppb lw.

The innovative use of a large-scale industry biomedical consortium to research the genetic basis of drug induced serious adverse events.

The International Serious Adverse Event Consortium (SAEC) is a pharmaceutical industry and FDA led international (501 c3 non-profit) consortium, focused on identifying and validating DNA-variants useful in predicting the risk of drug induced, rare serious adverse events (SAEs). As such, it functions with the explicit purpose of enhancing the 'public good'. Its members are (i) organizations engaged principally in the business of discovering, developing and marketing pharmaceutical products, or (ii) a charitable, governmental, or other non-profit organization with an interest in researching the molecular basis of drug response.

Linkage disequilibrium and inference of ancestral recombination in 538 single-nucleotide polymorphism clusters across the human genome.

The prospect of using linkage disequilibrium (LD) for fine-scale mapping in humans has attracted considerable attention, and, during the validation of a set of single-nucleotide polymorphisms (SNPs) for linkage analysis, a set of data for 4,833 SNPs in 538 clusters was produced that provides a rich picture of local attributes of LD across the genome. LD estimates may be biased depending on the means by which SNPs are first identified, and a particular problem of ascertainment bias arises when SNPs identified in small heterogeneous panels are subsequently typed in larger population samples. Understanding and correcting ascertainment bias is essential for a useful quantitative assessment of the landscape of LD across the human genome.

A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set.

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)-based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes.