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An Enrichment Strategy Yields Seven Novel Single Nucleotide Polymorphisms Associated With Mortality and Altered Th17 Responses Following Blunt Trauma.

ABSTRACT: Trauma is the leading cause of death worldwide for individuals under the age of 55. Interpatient genomic differences, in the form of candidate single-nucleotide polymorphisms (SNPs), have been associated previously with adverse outcomes after trauma. However, the utility of these SNPs to predict outcomes based on a meaningful endpoint such as survival is as yet undefined. We hypothesized that specific SNP haplotypes could segregate trauma survivors from non-survivors. Genomic DNA samples were obtained from 453 blunt trauma patients, for whom complete daily clinical and biomarker data were available for 397. Of these, 13 patients were non-survivors and the remaining 384 were survivors. All 397 DNA samples were amplified, fragmented, and examined for 551,839 SNPs using the Illumina Infinium CoreExome-24 v1.1 BeadChip (Illumina). To enrich for likely important SNPs, we initially compared SNPs of the 13 non-survivors versus 13 matched survivors, who were matched algorithmically for injury severity score (ISS), age, and gender ratio. This initial enrichment yielded 126 SNPs; a further comparison to the haplotypes of the remaining 371 survivors yielded a final total of 7 SNPs that distinguished survivors from non-survivors. Furthermore, severely injured survivors with the same seven SNPs as non-survivor exhibited distinct inflammatory responses from similarly injured survivors without those SNPs, and specifically had evidence of altered Th17 cell phenotypes based on computational modeling. These studies suggest an interaction among genetic polymorphism, injury severity, and initial inflammatory responses in driving trauma outcomes.

SUBMITTER: Schimunek L

PROVIDER: S-EPMC5809248 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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An Enrichment Strategy Yields Seven Novel Single Nucleotide Polymorphisms Associated With Mortality and Altered Th17 Responses Following Blunt Trauma.

Schimunek Lukas L Namas Rami A RA Yin Jinling J Liu Dongmei D Barclay Derek D El-Dehaibi Fayten F Abboud Andrew A Lindberg Haley H Zamora Ruben R Billiar Timothy R TR Vodovotz Yoram Y

Shock (Augusta, Ga.) 20180301 3

Trauma is the leading cause of death worldwide for individuals under the age of 55. Interpatient genomic differences, in the form of candidate single-nucleotide polymorphisms (SNPs), have been associated previously with adverse outcomes after trauma. However, the utility of these SNPs to predict outcomes based on a meaningful endpoint such as survival is as yet undefined. We hypothesized that specific SNP haplotypes could segregate trauma survivors from non-survivors. Genomic DNA samples were ob ...[more]

PMID: 28930911

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Project description:BACKGROUND:The risk of the acute respiratory distress syndrome (ARDS) is increased in passive and active smokers after blunt trauma. However, the mechanisms responsible, including the role of platelet aggregation, for this association are unknown. METHODS:We analyzed 215 patients with severe blunt trauma from a prospective observational cohort at a Level I trauma center between 2010 and 2015. Subjects underwent impedance-based platelet aggregometry in response to platelet agonists arachidonic acid, adenosine diphosphate, collagen, and thrombin receptor activating peptide-6. Acute respiratory distress syndrome within the first 8 days of admission was adjudicated using Berlin criteria. Plasma cotinine was measured to assess cigarette smoke exposure. Regression analyses were used to assess the relationship between (1) platelet aggregation and ARDS and (2) cigarette smoke exposure and platelet aggregation. RESULTS:At both 0 hour and 24 hours, impaired platelet aggregation was associated with increased odds of developing ARDS. Cigarette smoke exposure was associated with increased platelet aggregation upon arrival to the emergency department. However, at 24 hours, cigarette smoke exposure was associated with increased impairment in platelet aggregation, reflecting a statistically significant decline in platelet aggregation over the initial 24 hours after trauma. The relationship between this decline in platelet aggregation and ARDS differed by cigarette smoke exposure status, suggesting that impaired platelet activation differentially affects the risk of ARDS in those with cigarette smoke exposure (arachidonic acid, p for interaction: 0.005, collagen p for interaction: 0.02, adenosine diphosphate, p for interaction: 0.05). CONCLUSION:Impaired platelet aggregation at 0 hour and 24 hours is associated with an increased risk of developing ARDS after severe blunt trauma. Cigarette smoke-exposed patients are more likely to develop impaired platelet aggregation over the first 24 hours of admission, which may contribute to their increased risk of ARDS. LEVEL OF EVIDENCE:Prognostic/Epidemiological, level III.

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An Enrichment Strategy Yields Seven Novel Single Nucleotide Polymorphisms Associated With Mortality and Altered Th17 Responses Following Blunt Trauma.

Publications

An Enrichment Strategy Yields Seven Novel Single Nucleotide Polymorphisms Associated With Mortality and Altered Th17 Responses Following Blunt Trauma.

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