Limits...
Longitudinal analysis of whole blood transcriptomes to explore molecular signatures associated with acute renal allograft rejection.

Shin H, Günther O, Hollander Z, Wilson-McManus JE, Ng RT, Balshaw R, Keown PA, McMaster R, McManus BM, Isbel NM, Knoll G, Tebbutt SJ - Bioinform Biol Insights (2014)

Bottom Line: We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors.Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ.This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature.

View Article: PubMed Central - PubMed

Affiliation: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; University of British Columbia (UBC) Department of Medicine, Vancouver, BC. ; Institute for HEART + LUNG Health, Vancouver, BC.

ABSTRACT
In this study, we explored a time course of peripheral whole blood transcriptomes from kidney transplantation patients who either experienced an acute rejection episode or did not in order to better delineate the immunological and biological processes measureable in blood leukocytes that are associated with acute renal allograft rejection. Using microarrays, we generated gene expression data from 24 acute rejectors and 24 nonrejectors. We filtered the data to obtain the most unambiguous and robustly expressing probe sets and selected a subset of patients with the clearest phenotype. We then performed a data-driven exploratory analysis using data reduction and differential gene expression analysis tools in order to reveal gene expression signatures associated with acute allograft rejection. Using a template-matching algorithm, we then expanded our analysis to include time course data, identifying genes whose expression is modulated leading up to acute rejection. We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors. Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ. In addition, we describe an expression signature characteristic of lymphocyte activity and proliferation. This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature.

No MeSH data available.


Related in: MedlinePlus

Pattern matching of gene expression changes over time reveals a molecular signature associated with AR. A. PTM analysis showing genes matching the expression signature of upregulation from pretransplant to posttransplant in AR patients only. Five AR patients and 5 matched NR patients with the precisely matched time points were used for the analysis. The 3 time points used (plotted consecutively for each patient) are pretransplant (BL), 7 days prerejection (−7), and at rejection (RJ). B. PCA plot visualizing the expression signature described in A. The AR patients (red squares, with week [W] posttransplant data indicated) are moving away from their pretransplant time point (BL) as well as from control patients (green circles) and NR patients (blue triangles) as they are approaching rejection.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3921155&req=5

f5-bbi-8-2014-017: Pattern matching of gene expression changes over time reveals a molecular signature associated with AR. A. PTM analysis showing genes matching the expression signature of upregulation from pretransplant to posttransplant in AR patients only. Five AR patients and 5 matched NR patients with the precisely matched time points were used for the analysis. The 3 time points used (plotted consecutively for each patient) are pretransplant (BL), 7 days prerejection (−7), and at rejection (RJ). B. PCA plot visualizing the expression signature described in A. The AR patients (red squares, with week [W] posttransplant data indicated) are moving away from their pretransplant time point (BL) as well as from control patients (green circles) and NR patients (blue triangles) as they are approaching rejection.

Mentions: We have described differential gene expression signatures in peripheral blood leukocytes that are associated with acute allograft rejection. In particular, the increasing gene expression changes described by the neutrophil associated signature have potential utility for predicting transplant patient outcome. To refine this expression signature, we interrogated patient time course data for genes whose expression was specifically upregulated in AR patients as they approached rejection using an artificially defined pattern of increasing expression. For this analysis, we selected time point data that encompassed samples collected from pretransplant up to and including confirmation of rejection. For consistency, we selected precisely matched time points, which limited this analysis to a small cohort of 5 AR patients and their matched NR samples. Three time points—at pretransplant baseline (BL), at 7 days prior to rejection (−7), and at the time of rejection (RJ) (ie, biopsy confirmation)—were selected within this patient group. We then performed pattern matching analysis using PTM to identify genes that were upregulated specifically in AR patients from pretransplant levels and maintained at a high expression level as they approached the rejection time point (Fig. 5A). Twenty-nine genes followed this pattern with an R greater than 0.5 (Table 7). A PCA plot using these data confirmed that the AR patients were increasingly separating from their matched NR patients and control patients as they approached rejection (Fig. 5B). Consistent with the findings described above, the genes that most closely followed this pattern of expression were related to activated neutrophils and known neutrophil granule protein genes.37–40


Longitudinal analysis of whole blood transcriptomes to explore molecular signatures associated with acute renal allograft rejection.

Shin H, Günther O, Hollander Z, Wilson-McManus JE, Ng RT, Balshaw R, Keown PA, McMaster R, McManus BM, Isbel NM, Knoll G, Tebbutt SJ - Bioinform Biol Insights (2014)

Pattern matching of gene expression changes over time reveals a molecular signature associated with AR. A. PTM analysis showing genes matching the expression signature of upregulation from pretransplant to posttransplant in AR patients only. Five AR patients and 5 matched NR patients with the precisely matched time points were used for the analysis. The 3 time points used (plotted consecutively for each patient) are pretransplant (BL), 7 days prerejection (−7), and at rejection (RJ). B. PCA plot visualizing the expression signature described in A. The AR patients (red squares, with week [W] posttransplant data indicated) are moving away from their pretransplant time point (BL) as well as from control patients (green circles) and NR patients (blue triangles) as they are approaching rejection.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3921155&req=5

f5-bbi-8-2014-017: Pattern matching of gene expression changes over time reveals a molecular signature associated with AR. A. PTM analysis showing genes matching the expression signature of upregulation from pretransplant to posttransplant in AR patients only. Five AR patients and 5 matched NR patients with the precisely matched time points were used for the analysis. The 3 time points used (plotted consecutively for each patient) are pretransplant (BL), 7 days prerejection (−7), and at rejection (RJ). B. PCA plot visualizing the expression signature described in A. The AR patients (red squares, with week [W] posttransplant data indicated) are moving away from their pretransplant time point (BL) as well as from control patients (green circles) and NR patients (blue triangles) as they are approaching rejection.
Mentions: We have described differential gene expression signatures in peripheral blood leukocytes that are associated with acute allograft rejection. In particular, the increasing gene expression changes described by the neutrophil associated signature have potential utility for predicting transplant patient outcome. To refine this expression signature, we interrogated patient time course data for genes whose expression was specifically upregulated in AR patients as they approached rejection using an artificially defined pattern of increasing expression. For this analysis, we selected time point data that encompassed samples collected from pretransplant up to and including confirmation of rejection. For consistency, we selected precisely matched time points, which limited this analysis to a small cohort of 5 AR patients and their matched NR samples. Three time points—at pretransplant baseline (BL), at 7 days prior to rejection (−7), and at the time of rejection (RJ) (ie, biopsy confirmation)—were selected within this patient group. We then performed pattern matching analysis using PTM to identify genes that were upregulated specifically in AR patients from pretransplant levels and maintained at a high expression level as they approached the rejection time point (Fig. 5A). Twenty-nine genes followed this pattern with an R greater than 0.5 (Table 7). A PCA plot using these data confirmed that the AR patients were increasingly separating from their matched NR patients and control patients as they approached rejection (Fig. 5B). Consistent with the findings described above, the genes that most closely followed this pattern of expression were related to activated neutrophils and known neutrophil granule protein genes.37–40

Bottom Line: We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors.Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ.This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature.

View Article: PubMed Central - PubMed

Affiliation: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; University of British Columbia (UBC) Department of Medicine, Vancouver, BC. ; Institute for HEART + LUNG Health, Vancouver, BC.

ABSTRACT
In this study, we explored a time course of peripheral whole blood transcriptomes from kidney transplantation patients who either experienced an acute rejection episode or did not in order to better delineate the immunological and biological processes measureable in blood leukocytes that are associated with acute renal allograft rejection. Using microarrays, we generated gene expression data from 24 acute rejectors and 24 nonrejectors. We filtered the data to obtain the most unambiguous and robustly expressing probe sets and selected a subset of patients with the clearest phenotype. We then performed a data-driven exploratory analysis using data reduction and differential gene expression analysis tools in order to reveal gene expression signatures associated with acute allograft rejection. Using a template-matching algorithm, we then expanded our analysis to include time course data, identifying genes whose expression is modulated leading up to acute rejection. We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors. Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ. In addition, we describe an expression signature characteristic of lymphocyte activity and proliferation. This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature.

No MeSH data available.


Related in: MedlinePlus