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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

Protein structure of VPS9D1 showing approximate location of variants associated with sepsis survival.
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Fig4: Protein structure of VPS9D1 showing approximate location of variants associated with sepsis survival.

Mentions: We then looked for associations between sepsis outcome and mRNA variants likely to have functional effects, specifically 20,168 potentially phenotype-causing variants mapping to 6,793 coding domains. Our hypothesis was that common metabolomic, proteomic, or transcriptional phenotypes of sepsis non-survival might be causally related to multiple rare variants on a gene-by-gene basis. One gene, Vacuolar Protein Sorting 9 Domain-containing gene 1 (VPS9D1), showed significant associations between potentially functional mRNA variants and sepsis survival (FigureĀ 4).Figure 4


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)

Protein structure of VPS9D1 showing approximate location of variants associated with sepsis survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Protein structure of VPS9D1 showing approximate location of variants associated with sepsis survival.
Mentions: We then looked for associations between sepsis outcome and mRNA variants likely to have functional effects, specifically 20,168 potentially phenotype-causing variants mapping to 6,793 coding domains. Our hypothesis was that common metabolomic, proteomic, or transcriptional phenotypes of sepsis non-survival might be causally related to multiple rare variants on a gene-by-gene basis. One gene, Vacuolar Protein Sorting 9 Domain-containing gene 1 (VPS9D1), showed significant associations between potentially functional mRNA variants and sepsis survival (FigureĀ 4).Figure 4

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