Limits...
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

Expression ofVPS9D1.VPS9D1 is represented by two different genetic loci: XLOC_011354 (Cufflinks Transcript ID TCONS_00032132; RefSeq ID NM_004913) and XLOC_010886 (Cufflinks Transcript ID TCONS_00030416; RefSeq ID NM_004913). The former demonstrated greater sequencing coverage and is presented here. Results for XLOC_010886 were similar (data not shown). (A) Level of VPS9D1 expression in sepsis survivors (n = 74) and sepsis non-survivors (n = 26). (B) Level of VPS9D1 expression as a function of the VPS9D1 reference (n = 64) or variant sequence (n = 36) among subjects with adequate coverage. (C) Volcano plot depicting differentially expressed genes as a function of the VPS9D1 reference or variant allele.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Expression ofVPS9D1.VPS9D1 is represented by two different genetic loci: XLOC_011354 (Cufflinks Transcript ID TCONS_00032132; RefSeq ID NM_004913) and XLOC_010886 (Cufflinks Transcript ID TCONS_00030416; RefSeq ID NM_004913). The former demonstrated greater sequencing coverage and is presented here. Results for XLOC_010886 were similar (data not shown). (A) Level of VPS9D1 expression in sepsis survivors (n = 74) and sepsis non-survivors (n = 26). (B) Level of VPS9D1 expression as a function of the VPS9D1 reference (n = 64) or variant sequence (n = 36) among subjects with adequate coverage. (C) Volcano plot depicting differentially expressed genes as a function of the VPS9D1 reference or variant allele.

Mentions: The biological consequences of these variants are unknown. To determine if these variants were associated with gene expression changes, we defined two new analysis populations: subjects with and without a variant in VPS9D1. Genes with differential expression in these groups were identified followed by pathway analysis. Individuals with variants in VPS9D1 differed in expression of 3,799 genes, representing many different pathways (Figure 5; Additional file 4). Among the most highly significant were those related to the Golgi, endosome, nucleoside processing, and protein conjugation including ubiquitination, consistent with the role of VPS9-domain containing proteins in Rab5 activation [40]. VPS9D1 expression was itself higher in subjects with the variant than those without but failed to reach the FDR threshold. As noted above, VPS9D1 expression was significantly higher in sepsis survivors than in sepsis non-survivors. This was also true of many RAS oncogene family members, including RAB5C (Additional file 2). The association of VPS9D1 variants with differential gene expression and pathways which this gene is itself associated with supports the biological relevance of these variants.Figure 5


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)

Expression ofVPS9D1.VPS9D1 is represented by two different genetic loci: XLOC_011354 (Cufflinks Transcript ID TCONS_00032132; RefSeq ID NM_004913) and XLOC_010886 (Cufflinks Transcript ID TCONS_00030416; RefSeq ID NM_004913). The former demonstrated greater sequencing coverage and is presented here. Results for XLOC_010886 were similar (data not shown). (A) Level of VPS9D1 expression in sepsis survivors (n = 74) and sepsis non-survivors (n = 26). (B) Level of VPS9D1 expression as a function of the VPS9D1 reference (n = 64) or variant sequence (n = 36) among subjects with adequate coverage. (C) Volcano plot depicting differentially expressed genes as a function of the VPS9D1 reference or variant allele.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Expression ofVPS9D1.VPS9D1 is represented by two different genetic loci: XLOC_011354 (Cufflinks Transcript ID TCONS_00032132; RefSeq ID NM_004913) and XLOC_010886 (Cufflinks Transcript ID TCONS_00030416; RefSeq ID NM_004913). The former demonstrated greater sequencing coverage and is presented here. Results for XLOC_010886 were similar (data not shown). (A) Level of VPS9D1 expression in sepsis survivors (n = 74) and sepsis non-survivors (n = 26). (B) Level of VPS9D1 expression as a function of the VPS9D1 reference (n = 64) or variant sequence (n = 36) among subjects with adequate coverage. (C) Volcano plot depicting differentially expressed genes as a function of the VPS9D1 reference or variant allele.
Mentions: The biological consequences of these variants are unknown. To determine if these variants were associated with gene expression changes, we defined two new analysis populations: subjects with and without a variant in VPS9D1. Genes with differential expression in these groups were identified followed by pathway analysis. Individuals with variants in VPS9D1 differed in expression of 3,799 genes, representing many different pathways (Figure 5; Additional file 4). Among the most highly significant were those related to the Golgi, endosome, nucleoside processing, and protein conjugation including ubiquitination, consistent with the role of VPS9-domain containing proteins in Rab5 activation [40]. VPS9D1 expression was itself higher in subjects with the variant than those without but failed to reach the FDR threshold. As noted above, VPS9D1 expression was significantly higher in sepsis survivors than in sepsis non-survivors. This was also true of many RAS oncogene family members, including RAB5C (Additional file 2). The association of VPS9D1 variants with differential gene expression and pathways which this gene is itself associated with supports the biological relevance of these variants.Figure 5

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