Abstract
BackgroundThe expression levels of many genes show wide natural variation among strains or populations. This study investigated the potential for animal strain-related genotypic differences to confound gene expression profiles in acute cellular rejection (ACR). Using a rat heart transplant model and 2 different rat strains (Dark Agouti, and Brown Norway), microarrays were performed on native hearts, transplanted hearts, and peripheral blood mononuclear cells (PBMC).ResultsIn heart tissue, strain alone affected the expression of only 33 probesets while rejection affected the expression of 1368 probesets (FDR 10% and FC ≥ 3). Only 13 genes were affected by both strain and rejection, which was < 1% (13/1368) of all probesets differentially expressed in ACR. However, for PBMC, strain alone affected 265 probesets (FDR 10% and FC ≥ 3) and the addition of ACR had little further effect. Pathway analysis of these differentially expressed strain effect genes connected them with immune response, cell motility and cell death, functional themes that overlap with those related to ACR. After accounting for animal strain, additional analysis identified 30 PBMC candidate genes potentially associated with ACR.ConclusionIn ACR, genetic background has a large impact on the transcriptome of immune cells, but not heart tissue. Gene expression studies of ACR should avoid study designs that require cross strain comparisons between leukocytes.
Highlights
The expression levels of many genes show wide natural variation among strains or populations
Strain differences in animals and heterogeneity across human populations may significantly influence the Animal Care The protocol described in the current study was approved by the Animal Care and Use Committee (ACUC) of the Clinical Center of the National Institutes of Health (NIH)
Allografts were characterized by diffuse inflammation and necrosis consistent with International Society for Heart and Lung Transplantation (ISHLT) grade 3 R
Summary
The expression levels of many genes show wide natural variation among strains or populations. This study investigated the potential for animal strain-related genotypic differences to confound gene expression profiles in acute cellular rejection (ACR). Acute cellular rejection (ACR) is a major cause of morbidity and mortality among cardiac transplant patients [1,2,3]. Noninvasive, sensitive, and specific tests that reliably detect ACR in its earliest stages would greatly simplify the management of cardiac transplant patients, increase graft survival, and improve clinical outcomes. These issues combined with the advent of high-throughput functional genomic and proteomic methodologies have fueled a search for ACR biomarkers, as well as new therapeutic targets
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