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An integrated transcriptome and expressed variant analysis of sepsis survival and death.

Tsalik EL, Langley RJ, Dinwiddie DL, Miller NA, Yoo B, van Velkinburgh JC, Smith LD, Thiffault I, Jaehne AK, Valente AM, Henao R, Yuan X, Glickman SW, Rice BJ, McClain MT, Carin L, Corey GR, Ginsburg GS, Cairns CB, Otero RM, Fowler VG, Rivers EP, Woods CW, Kingsmore SF - Genome Med (2014)

Bottom Line: Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes.The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

View Article: PubMed Central - PubMed

Affiliation: Emergency Medicine Service, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705 USA ; Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.

ABSTRACT

Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.

Methods: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes.

Results: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

Conclusions: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies.

Trial registration: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.

No MeSH data available.


Related in: MedlinePlus

Differentially expressed genes and pathways. (A) Number and overlap among the differentially expressed, annotated genes in each pairwise comparison. (B) Hierarchical clustering of 2,140 differentially expressed gene (including 314 unannotated loci) using Pearson’s moment correlations applied to subjects with SIRS, Sepsis Non-survivors, and Sepsis Survivors. ANOVA with 7.5% FDR correction; −log10 P value = 2.21. (C) Highly represented ToppGene pathways and processes among the annotated genes differentially expressed between SIRS and Sepsis Survivors as well as Sepsis Survivors and Sepsis Non-survivors.
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Fig3: Differentially expressed genes and pathways. (A) Number and overlap among the differentially expressed, annotated genes in each pairwise comparison. (B) Hierarchical clustering of 2,140 differentially expressed gene (including 314 unannotated loci) using Pearson’s moment correlations applied to subjects with SIRS, Sepsis Non-survivors, and Sepsis Survivors. ANOVA with 7.5% FDR correction; −log10 P value = 2.21. (C) Highly represented ToppGene pathways and processes among the annotated genes differentially expressed between SIRS and Sepsis Survivors as well as Sepsis Survivors and Sepsis Non-survivors.

Mentions: Differences in transcript abundance were measured between groups. There were 2,455 significant differences between all pairwise comparisons (Figure 3 and Additional file 2) based on ANOVA with a 7.5% false discovery rate (FDR), chosen to impart a greater degree of specificity. These 2,455 expression differences included 315 unannotated loci. The number of genes in each pairwise comparison is depicted in Figure 3A along with an expression heat map in Figure 3B. The first focus was to distinguish sepsis from SIRS, which is a particularly important diagnostic decision made at a patient’s first clinical contact. We therefore combined all sepsis survivors and sepsis non-survivors to create a Sepsis category, which was then compared to SIRS. There were 338 genes with significantly different expression, the majority of which (317/338; 94%) were upregulated in subjects with sepsis, indicating a robust increase in gene expression. Gene enrichment and pathway analysis was performed with the ToppFun algorithm [29]. The highly significant pathways differentiating sepsis and SIRS included response to wounding, defense response, and the immune or inflammatory response. Among the genes downregulated in sepsis, there were few significant pathways. One notable example of decreased gene expression in sepsis was PROC (Protein C), a key regulator of fibrin clot formation [37,38]. This plasma protein, often depleted in severe sepsis, was the basis for recombinant activated protein C as the only drug approved for the treatment of severe sepsis. Subsequent trials failed to replicate the beneficial effects, prompting its removal from the market [39]. PROC expression was decreased to a similar degree in sepsis survivors and sepsis non-survivors when compared to SIRS.Figure 3


An integrated transcriptome and expressed variant analysis of sepsis survival and death.

Tsalik EL, Langley RJ, Dinwiddie DL, Miller NA, Yoo B, van Velkinburgh JC, Smith LD, Thiffault I, Jaehne AK, Valente AM, Henao R, Yuan X, Glickman SW, Rice BJ, McClain MT, Carin L, Corey GR, Ginsburg GS, Cairns CB, Otero RM, Fowler VG, Rivers EP, Woods CW, Kingsmore SF - Genome Med (2014)

Differentially expressed genes and pathways. (A) Number and overlap among the differentially expressed, annotated genes in each pairwise comparison. (B) Hierarchical clustering of 2,140 differentially expressed gene (including 314 unannotated loci) using Pearson’s moment correlations applied to subjects with SIRS, Sepsis Non-survivors, and Sepsis Survivors. ANOVA with 7.5% FDR correction; −log10 P value = 2.21. (C) Highly represented ToppGene pathways and processes among the annotated genes differentially expressed between SIRS and Sepsis Survivors as well as Sepsis Survivors and Sepsis Non-survivors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4274761&req=5

Fig3: Differentially expressed genes and pathways. (A) Number and overlap among the differentially expressed, annotated genes in each pairwise comparison. (B) Hierarchical clustering of 2,140 differentially expressed gene (including 314 unannotated loci) using Pearson’s moment correlations applied to subjects with SIRS, Sepsis Non-survivors, and Sepsis Survivors. ANOVA with 7.5% FDR correction; −log10 P value = 2.21. (C) Highly represented ToppGene pathways and processes among the annotated genes differentially expressed between SIRS and Sepsis Survivors as well as Sepsis Survivors and Sepsis Non-survivors.
Mentions: Differences in transcript abundance were measured between groups. There were 2,455 significant differences between all pairwise comparisons (Figure 3 and Additional file 2) based on ANOVA with a 7.5% false discovery rate (FDR), chosen to impart a greater degree of specificity. These 2,455 expression differences included 315 unannotated loci. The number of genes in each pairwise comparison is depicted in Figure 3A along with an expression heat map in Figure 3B. The first focus was to distinguish sepsis from SIRS, which is a particularly important diagnostic decision made at a patient’s first clinical contact. We therefore combined all sepsis survivors and sepsis non-survivors to create a Sepsis category, which was then compared to SIRS. There were 338 genes with significantly different expression, the majority of which (317/338; 94%) were upregulated in subjects with sepsis, indicating a robust increase in gene expression. Gene enrichment and pathway analysis was performed with the ToppFun algorithm [29]. The highly significant pathways differentiating sepsis and SIRS included response to wounding, defense response, and the immune or inflammatory response. Among the genes downregulated in sepsis, there were few significant pathways. One notable example of decreased gene expression in sepsis was PROC (Protein C), a key regulator of fibrin clot formation [37,38]. This plasma protein, often depleted in severe sepsis, was the basis for recombinant activated protein C as the only drug approved for the treatment of severe sepsis. Subsequent trials failed to replicate the beneficial effects, prompting its removal from the market [39]. PROC expression was decreased to a similar degree in sepsis survivors and sepsis non-survivors when compared to SIRS.Figure 3

Bottom Line: Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes.The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

View Article: PubMed Central - PubMed

Affiliation: Emergency Medicine Service, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705 USA ; Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.

ABSTRACT

Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.

Methods: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes.

Results: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

Conclusions: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies.

Trial registration: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.

No MeSH data available.


Related in: MedlinePlus