Transcriptional profiling of belatacept and calcineurin inhibitor therapy in renal allograft recipients.

Calcineurin inhibitor (CNI) use may lead to allograft injury and compromised renal function. Gene expression profiles of 12-month kidney biopsies from a Phase 3 study of belatacept and a CNI comparator, cyclosporine (CsA), were compared with expression profiles of a set of historical, demographically matched, preimplantation control biopsies. Gene set enrichment analysis was used to test each set of differentially expressed genes (DEGs) for the enrichment of an in vitro-derived CNI toxicity (CNIT) gene set and published gene sets associated with chronic allograft injury (CAI), immune modulation and tissue remodeling.

Genetic resistance to diet-induced obesity in chromosome substitution strains of mice.

Discovery of genes that confer resistance to diseases such as diet-induced obesity could have tremendous therapeutic impact. We previously demonstrated that the C57BL/6J-Chr(A/J)/NaJ panel of chromosome substitution strains (CSSs) is a unique model for studying resistance to diet-induced obesity. In the present study, three replicate CSS surveys showed remarkable consistency, with 13 A/J-derived chromosomes reproducibly conferring resistance to high-fat-diet-induced obesity.

Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation.

Background: The selective inhibitor of T-cell costimulation, belatacept, blocks CD28-mediated T-cell activation by binding CD80 and CD86 on antigen-presenting cells. Understanding the extent to which belatacept binds to its targets in patients may enable correlation of belatacept exposure to receptor saturation as a pharmacodynamic measure of costimulation blockade.

Methods: Flow cytometry-based receptor competition assays were developed to monitor concentration-dependent occupancy of CD80 and CD86 receptors in whole blood and dendritic cell cultures in vitro.

Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis.

The genetic architecture of complex traits underlying physiology and disease in most organisms remains elusive. We still know little about the number of genes that underlie these traits, the magnitude of their effects, or the extent to which they interact. Chromosome substitution strains (CSSs) enable statistically powerful studies based on testing engineered inbred strains that have single, unique, and nonoverlapping genetic differences, thereby providing measures of phenotypic effects that are attributable to individual chromosomes.

Efficient mapping of mendelian traits in dogs through genome-wide association.

With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks.