Genetic Variants of Matrix Metalloproteinase and Sepsis: The Need Speed Study

Abstract

Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis. Prevalence of MMP8 rs11225395 G/G genotype was higher in sepsis patients than in those with non-infective Systemic Inflammatory Reaction Syndrome (35.6 vs. 26%, hazard ratio, HR 1.56, 95% C.I. 1.04–2.42, p = 0.032). G/G patients developed less hyperthermia (p = 0.041), even after stratification for disease severity (p = 0.003). Patients carrying the 6A allele in MMP3 rs3025058 had a higher probability of microbiologically-proven sepsis (HR 1.4. 95%C.I. 1.01–1.94, p = 0.044), particularly when due to virus (H.R. 2.14, 95% C.I. 1.06–4.31, p = 0.046), while MMP-1 G/G genotype patients carried a higher risk for intracellular bacteria (Chlamydia, Mycoplasma, and Legionella, H.R. 6.46, 95% C.I. 1.58–26.41, p = 0.003). Neither severity of sepsis at presentation, nor 30-day mortality were influenced by the investigated variants or their haplotype. MMP8 rs11225395 G/G carriers have lower temperature at presentation and a more than 50% increased susceptibility to sepsis. Among patients with sepsis, carriers of MMP1 rs1799750 G/G have an increased susceptibility for intracellular pathogen infections, while virus serology is more often positive in those with the MMP3 rs3025058 A/A genotype.

Identifying Six Chromatin Remodeling-related Genes As Diagnostic Biomarkers in Sepsis Using Bioinformatic Analyses

“…Thus, the vascular wall gets damaged and the microvessels become more permeable, increasing the likelihood of sepsis [23] . Previous research shows that Intracellular pathogens, viruses, and fungi have been shown to induce the expression of host MMPs, implying that MMPs may be a potential therapeutic target in sepsis, which is consistent with our results [24] . The diagnostic value of MMP9 in sepsis has also been previously reported [25,26] .…”

Identification and Internal Validation of a Novel Pre-Transplant Biomarker Panel to Predict Mortality Following Liver Transplantation: The Liver Immune Frailty Index

“…59,60 Dysregulation of MMP3 contributes to the pathogenesis of liver disease, 61 and similar to Fractalkine, MMP3 is implicated as a critical regulator of infection. [62][63][64][65] Inappropriately elevated MMP3 has both prognostic implications as a biomarker of sepsisrelated mortality and mechanistic importance in the pathogenesis of sepsis-related acute respiratory distress syndrome (ARDS) and multi-system organ failure. 66,67 The immunologic consequences of chronic HCV infection have been well studied, and it is known to not only induce chronic in ammation, but also signi cantly impact immune function.…”

Development and Internal Validation of a Novel Pre-Transplant Biomarker Panel to Predict Post-Liver Transplant Mortality

“…71,72 Dysregulation of MMP3 contributes to liver disease pathogenesis, 73 and similar to Fractalkine, MMP3 is a critical regulator of infection. [74][75][76][77] Inappropriately elevated MMP3 is both a biomarker of sepsis-related mortality and a mediator of damage in sepsis-related multi-system organ failure. 78,79 The immunologic consequences of chronic HCV infection have been well studied.…”