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Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes.

Grigoryev DN, Cheranova DI, Heruth DP, Huang P, Zhang LQ, Rabb H, Ye SQ - BMC Nephrol (2013)

Bottom Line: The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach.Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri School of Medicine, Kansas City, MO, USA. dgrigoryev@cmh.edu.

ABSTRACT

Background: Accumulated to-date microarray data on ischemia reperfusion injury (IRI) of kidney represent a powerful source for identifying new targets and mechanisms of kidney IRI. In this study, we conducted a meta-analysis of gene expression profiles of kidney IRI in human, pig, rat, and mouse models, using a new scoring method to correct for the bias of overrepresented species. The gene expression profiles were obtained from the public repositories for 24 different models. After filtering against inclusion criteria 21 experimental settings were selected for meta-analysis and were represented by 11 rat models, 6 mouse models, and 2 models each for pig and human, with a total of 150 samples. Meta-analysis was conducted using expression-based genome-wide association study (eGWAS). The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.

Results: Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach. Pathway analysis of our candidates identified "Acute renal failure panel" as the most implicated pathway, which further validates our new method. Among new IRI candidates were 10 novel (<5 published reports related to kidney IRI) and 11 new candidates (0 reports related to kidney IRI) including the most prominent candidates ANXA2, CLDN4, and TYROBP. The cross-species expression pattern of these genes allowed us to generate three workable hypotheses of kidney IRI, one of which was confirmed by an additional study.

Conclusions: Our first in the field kidney IRI meta-analysis of 150 microarray samples, corrected for a species bias, identified 10 novel and 11 new candidate genes. Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

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Ischemia time related pathway analysis of universal interspecies IRI genes. Genes that were significantly affected by IRI in more than one species at each selected time-point were analyzed by Ingenuity pathway tool. The top three significant pathways from each time-point were identified, and those that were present among top pathways at least twice were plotted against time-course of the IRI. The y axis represents negative log of p-value assigned by Ingenuity algorithm (Fisher Exact test) to a pathway. The p-value that corresponds to numeric 0.05 is depicted by the dashed line. The x axis represents time course in log10 format. The position of each depicted pathway in the list of pathways is shown in the insert table.
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Figure 3: Ischemia time related pathway analysis of universal interspecies IRI genes. Genes that were significantly affected by IRI in more than one species at each selected time-point were analyzed by Ingenuity pathway tool. The top three significant pathways from each time-point were identified, and those that were present among top pathways at least twice were plotted against time-course of the IRI. The y axis represents negative log of p-value assigned by Ingenuity algorithm (Fisher Exact test) to a pathway. The p-value that corresponds to numeric 0.05 is depicted by the dashed line. The x axis represents time course in log10 format. The position of each depicted pathway in the list of pathways is shown in the insert table.

Mentions: To evaluate, whether our tight filtering affected biological relevance of retained 47 gene candidates, we conducted Ingenuity Pathway Analysis (IPA). The IPA of 47 candidates identified Acute Renal Failure Panel as the top IRI affected pathway (P < 0.000001, Additional file 4). The pathway analysis for each time-point was conducted using significant candidates, identified by W-scoring: 430, 684, 1069, 369, and 93 genes for 1-2 hours, 4-8 hours, 24-36 hours, 3-10 days; 3-5 month after IRI, respectively. The five sets of pathways were generated. The pathways, which were among the top three pathways in at least two consecutive time points are reported in Figure 3 by their significance: “Acute Renal Failure Panel”, “Liver Necrosis/Cell Death, Renal Necrosis/Cell Death”, “Persistent Renal IRI”, and “Hepatic Fibrosis”. This result further validated our findings and addressed concern that our algorithm puts a strong filter on candidate gene selection, which might inappropriately restrict the biological relevance of the results.


Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes.

Grigoryev DN, Cheranova DI, Heruth DP, Huang P, Zhang LQ, Rabb H, Ye SQ - BMC Nephrol (2013)

Ischemia time related pathway analysis of universal interspecies IRI genes. Genes that were significantly affected by IRI in more than one species at each selected time-point were analyzed by Ingenuity pathway tool. The top three significant pathways from each time-point were identified, and those that were present among top pathways at least twice were plotted against time-course of the IRI. The y axis represents negative log of p-value assigned by Ingenuity algorithm (Fisher Exact test) to a pathway. The p-value that corresponds to numeric 0.05 is depicted by the dashed line. The x axis represents time course in log10 format. The position of each depicted pathway in the list of pathways is shown in the insert table.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016589&req=5

Figure 3: Ischemia time related pathway analysis of universal interspecies IRI genes. Genes that were significantly affected by IRI in more than one species at each selected time-point were analyzed by Ingenuity pathway tool. The top three significant pathways from each time-point were identified, and those that were present among top pathways at least twice were plotted against time-course of the IRI. The y axis represents negative log of p-value assigned by Ingenuity algorithm (Fisher Exact test) to a pathway. The p-value that corresponds to numeric 0.05 is depicted by the dashed line. The x axis represents time course in log10 format. The position of each depicted pathway in the list of pathways is shown in the insert table.
Mentions: To evaluate, whether our tight filtering affected biological relevance of retained 47 gene candidates, we conducted Ingenuity Pathway Analysis (IPA). The IPA of 47 candidates identified Acute Renal Failure Panel as the top IRI affected pathway (P < 0.000001, Additional file 4). The pathway analysis for each time-point was conducted using significant candidates, identified by W-scoring: 430, 684, 1069, 369, and 93 genes for 1-2 hours, 4-8 hours, 24-36 hours, 3-10 days; 3-5 month after IRI, respectively. The five sets of pathways were generated. The pathways, which were among the top three pathways in at least two consecutive time points are reported in Figure 3 by their significance: “Acute Renal Failure Panel”, “Liver Necrosis/Cell Death, Renal Necrosis/Cell Death”, “Persistent Renal IRI”, and “Hepatic Fibrosis”. This result further validated our findings and addressed concern that our algorithm puts a strong filter on candidate gene selection, which might inappropriately restrict the biological relevance of the results.

Bottom Line: The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach.Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri School of Medicine, Kansas City, MO, USA. dgrigoryev@cmh.edu.

ABSTRACT

Background: Accumulated to-date microarray data on ischemia reperfusion injury (IRI) of kidney represent a powerful source for identifying new targets and mechanisms of kidney IRI. In this study, we conducted a meta-analysis of gene expression profiles of kidney IRI in human, pig, rat, and mouse models, using a new scoring method to correct for the bias of overrepresented species. The gene expression profiles were obtained from the public repositories for 24 different models. After filtering against inclusion criteria 21 experimental settings were selected for meta-analysis and were represented by 11 rat models, 6 mouse models, and 2 models each for pig and human, with a total of 150 samples. Meta-analysis was conducted using expression-based genome-wide association study (eGWAS). The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species.

Results: Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach. Pathway analysis of our candidates identified "Acute renal failure panel" as the most implicated pathway, which further validates our new method. Among new IRI candidates were 10 novel (<5 published reports related to kidney IRI) and 11 new candidates (0 reports related to kidney IRI) including the most prominent candidates ANXA2, CLDN4, and TYROBP. The cross-species expression pattern of these genes allowed us to generate three workable hypotheses of kidney IRI, one of which was confirmed by an additional study.

Conclusions: Our first in the field kidney IRI meta-analysis of 150 microarray samples, corrected for a species bias, identified 10 novel and 11 new candidate genes. Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.

Show MeSH
Related in: MedlinePlus