MPPED2 Polymorphism Is Associated With Altered Systemic Inflammation and Adverse Trauma Outcomes

Abstract

Trauma is a leading cause of morbidity and mortality. It is unclear why some trauma victims follow a complicated clinical course and die, while others, with apparently similar injury characteristics, do not. Interpatient genomic differences, in the form of single nucleotide polymorphisms (SNPs), have been associated previously with adverse outcomes after trauma. Recently, we identified seven novel SNPs associated with mortality following trauma. The aim of the present study was to determine if one or more of these SNPs was also associated with worse clinical outcomes and altered inflammatory trajectories in trauma survivors. Accordingly, of 413 trauma survivors, DNA samples, full blood samples, and clinical data were collected at multiple time points in the first 24 h and then daily over 7 days following hospital admission. Subsequently, single-SNP groups were created and outcomes, such as hospital length of stay (LOS), ICU LOS, and requirement for mechanical ventilation, were compared. Across a broad range of Injury Severity Scores (ISS), patients carrying the rs2065418 TT SNP in the metallophosphoesterase domain-containing 2 (MPPED2) gene exhibited higher Marshall MODScores vs. the control group of rs2065418 TG/GG patients. In patients with high-severity trauma (ISS ≥ 25, n = 94), those carrying the rs2065418 TT SNP in MPPED2 exhibited higher Marshall MODScores, longer hospital LOS (21.8 ± 2 days), a greater requirement for mechanical ventilation (9.2 ± 1.4 days on ventilator, DOV), and higher creatinine plasma levels over 7 days vs. the control group of rs2065418 TG/GG high-severity trauma patients (LOS: 15.9 ± 1.2 days, p = 0.03; DOV: 5.7 ± 1 days, p = 0.04; plasma creatinine; p < 0.0001 MODScore: p = 0.0003). Furthermore, rs2065418 TT patients with ISS ≥ 25 had significantly different plasma levels of nine circulating inflammatory mediators and elevated dynamic network complexity. These studies suggest that the rs2065418 TT genotype in the MPPED2 gene is associated with altered systemic inflammation, increased organ dysfunction, and greater hospital resource utilization. A screening for this specific SNP at admission might stratify severely injured patients regarding their lung and kidney function and clinical complications.

Keywords: SNP; genomics; inflammation; outcomes; systems biology; trauma; ventilation.

Figure 1

Significantly elevated Marshall MODScores in rs2065418 TT patients with a broad range of ISS vs. control. Rs2065418 TT patients with a broad range of ISS (n = 168) exhibited significantly higher Marshall MODScore values over 7 days (p = 0.01) compared to the control group of rs2065418 TG/GG patients (n = 245).

Figure 2

Severely injured rs2065418 TT patients exhibit worse clinical outcomes vs. control. High-severity rs2065418 TT patients (n = 42) and control rs2065418 TG/GG patients (n = 52) were assessed for clinical outcomes as described in the Materials and Methods. High-ISS rs2065418 TT patients exhibited longer total LOS (p = 0.03) (A) longer DOV (p = 0.04) (B) elevated plasma creatinine levels (p 0.0001) (C), and higher Marshall MODScore over 7 days (p = 0.0003) (D) compared to the control group of high-ISS rs2065418 TG/GG patients. Total LOS and DOV were not normally distributed and therefore were tested by Mann–Whitney U test.

Figure 3

Analysis of network complexity shows an initially elevated inflammatory response in severely injured rs2065418 TT patients. DyNA of inflammatory mediators was carried out using data from admission to 7 days following injury, as described in the Materials and Methods. This analysis revealed that severely injured rs2065418 TT patients (n = 42) exhibited elevated inflammatory network complexity score (NCS) values in the first 24 h relative to controls (n = 52). rs2065418 TT and control TG/GG patients reached comparable NCS values at days 2 and 3. During days 4 to 6, rs2065418 TT patients again showed higher NCS values vs. controls. At day 7, control patients exhibited an elevated NCS compared to rs2065418 TT patients.

Figure 4

Putative interactions among injury severity, inherent tissue resilience, and the systemic inflammatory response. Based on the results presented in this study, we suggest an intertwined interaction among injury severity, inherent (genetically determined) tissue resilience, and the systemic inflammatory response driving outcomes after trauma as a novel paradigm for understanding the response to traumatic injury.