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An Aging-Related Single-Nucleotide Polymorphism is Associated With Altered Clinical Outcomes and Distinct Inflammatory Profiles in Aged Blunt Trauma Patients.

ABSTRACT: The contribution of individual genetic determinants of aging to the adverse clinical outcomes and altered inflammation mediator networks characteristic of aged trauma patients is unknown. The AA genotype of the aging-related single-nucleotide polymorphism (SNP) rs2075650 in TOMM40 has been associated with longevity, while the AG and GG genotypes are associated with an increased risk of Alzheimer disease. Here, we studied the effect of rs2075650 on clinical outcomes and dynamic biomarker patterns after traumatic injury. Genomic DNA was obtained from blunt trauma patients admitted to the ICU and examined for 551,839 SNPs using an Illumina microarray kit. Plasma was sampled from each patient three times within the first 24?h and daily from day 1 to 7 then assayed for 31 biomarkers using Luminex. Aged patients (65-90 years) were segregated into AA (n?=?77) and AG/GG (n?=?17) genotypes. Additional comparisons were made with matched groups of young patients (18-30 years), controlling for injury severity score (ISS) and sex ratio, and also segregated into AA (n?=?56) and AG/GG (n?=?19) genotypes. Aged patients with the AA genotype had a significantly lower requirement for ventilation and fewer days on mechanical ventilation, as well as significantly higher levels of one mediator and lower levels of two mediators. Dynamic Bayesian Network inference revealed IL-23 as a central node in each network regardless of age or genotype, with MIG and IP-10 also as key mediators in the networks of the aged patients. These findings suggest that an aging-related SNP, rs2075650, may influence clinical outcomes and inflammation networks in aged patients following blunt trauma, and thus may serve as a predictive outcome biomarker in the setting of polytrauma.

SUBMITTER: Lamparello AJ

PROVIDER: S-EPMC6960334 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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An Aging-Related Single-Nucleotide Polymorphism is Associated With Altered Clinical Outcomes and Distinct Inflammatory Profiles in Aged Blunt Trauma Patients.

Lamparello Ashley J AJ Namas Rami A RA Schimunek Lukas L Cohen Maria M El-Dehaibi Fayten F Yin Jinling J Barclay Derek D Zamora Ruben R Billiar Timothy R TR Vodovotz Yoram Y

Shock (Augusta, Ga.) 20200201 2

The contribution of individual genetic determinants of aging to the adverse clinical outcomes and altered inflammation mediator networks characteristic of aged trauma patients is unknown. The AA genotype of the aging-related single-nucleotide polymorphism (SNP) rs2075650 in TOMM40 has been associated with longevity, while the AG and GG genotypes are associated with an increased risk of Alzheimer disease. Here, we studied the effect of rs2075650 on clinical outcomes and dynamic biomarker patterns ...[more]

PMID: 31318836

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Project description:BackgroundAging is accompanied by alterations in immune functions. How these changes translate into levels of circulating inflammatory mediators and network expression after severe trauma is not well characterized. To address this, we compared time-dependent changes in the levels of an extensive biomarker panel in cohorts of severely injured young and aged adults.Study designCohorts of young (18 to 30 years old, n = 115) and aged (65 to 90 years old, n = 101) blunt trauma patients admitted to the ICU with plasma sampled 3 times within the first 24 hours and daily from day 1 to day 7 were assayed for 30 inflammatory biomarkers using Luminex analyzer. Stringently matched groups controlling for sex ratio and Injury Severity Score (n = 56 young vs n = 56 aged) were generated. Data were analyzed using 2-way ANOVA, area under the curve analysis, Dynamic Bayesian Network inference, and Dynamic Network Analysis.ResultsIn the overall cohorts, the young group had a significantly higher Injury Severity Score, which was associated with higher circulating levels of 18 inflammatory mediators from admission to day 7. The aged group had higher levels of C-X-C motif chemokine ligand 10/interferon gamma-induced protein 10 and C-X-C motif chemokine ligand 9/monokine induced by gamma interferon. In groups that were matched for Injury Severity Score, the significantly higher levels of interferon gamma-induced protein 10 and monokine induced by gamma interferon persisted in the aged. Dynamic Bayesian Network revealed interferon gamma-induced protein 10 and monokine induced by gamma interferon as key mediators in the aged, and Dynamic Network Analysis revealed higher network complexity in the aged.ConclusionsThese findings indicate that differences in the early inflammatory networks between young and aged trauma patients are not simply a suppression of pro-inflammatory responses in the aged, but are characterized by a major shift in the mediator profile patterns with high levels of CXC chemokines in the aged.

Project description:BackgroundThe genomic/cytokine "storm" after severe trauma is well described. However, the differing composition, magnitude and resolution of this response, and its relationship to clinical outcomes remain unclear.MethodsThis is a secondary analysis of a prospective longitudinal cohort study of severely injured trauma patients in hemorrhagic shock. Peripheral blood sampling was performed at 0.5, 1, 4, 7, 14, and 28 days after injury for measurement of circulating immune biomarkers. K-means clustering using overall mean and trajectory slope of selected immunologic biomarkers were used to identify distinct temporal immunologic endotypes. Endotypes were compared with known clinical trajectories defined as early death (<14 days), chronic critical illness (CCI) (ICU length of stay of ≥14 days with persistent organ dysfunction), and rapid recovery (RAP) (ICU length of stay of <14 days with organ recovery).ResultsThe cohort included 102 subjects enrolled across 2 level 1 trauma centers. We identified three distinct immunologic endotypes (iA, iB, and iC), each with unique associations to clinical trajectory. Endotype iA (n = 47) exhibited a moderate initial proinflammatory response followed by a return to immunologic homeostasis, with a primary clinical trajectory of RAP (n = 44, 93.6%). Endotype iB (n = 44) exhibited an early hyperinflammatory response with persistent inflammation and immunosuppression, with the highest incidence of CCI (n = 10, 22.7%). Endotype iC (n = 11) exhibited a similar hyperinflammatory response, but with rapid return to immunologic homeostasis and a predominant trajectory of RAP (n = 9, 81.8%). Patients with endotype iB had the highest severity/duration of organ dysfunction and highest incidence of nosocomial infections (50%, p = 0.001), and endotype iB was the predominant endotype of patients who developed CCI (10 of 13 patients, 76.9%; p = 0.002).ConclusionWe identified three distinct immunologic endotypes after severe injury differing the magnitude and duration of the early response. The clinical trajectory of CCI is characterized by an endotype (iB) defined by persistent alteration in inflammation/immunosuppression and is associated with poor clinical outcomes.Level of evidencePrognostic, level III.

Dataset Information

An Aging-Related Single-Nucleotide Polymorphism is Associated With Altered Clinical Outcomes and Distinct Inflammatory Profiles in Aged Blunt Trauma Patients.

Publications

An Aging-Related Single-Nucleotide Polymorphism is Associated With Altered Clinical Outcomes and Distinct Inflammatory Profiles in Aged Blunt Trauma Patients.

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