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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.
Highlights
We investigated the association of five functional polymorphisms of matrix metalloproteinases (MMPs)-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1
A definite diagnosis was reached in 939 patients: 127 non infective Systemic Inflammatory Response Syndrome (SIRS) (Ni-SIRS) and 812 sepsis, leaving debatable diagnosis (SIRS cases that could not be robustly characterized as infected) in the remaining 119
For MMP-8 rs11225395, HW was not confirmed in all groups of patients (p = 0.02, 0.0022, and 0.039 for non-infective SIRS, sepsis, and undefined patients, respectively)
Summary
Both defense mechanisms have key players in matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) [2]. Functional polymorphisms influence gene expression and activity and might control the pathogen invasion process, influencing susceptibility, clinical presentation, and likely the outcomes of sepsis. Knowledge on the role of MMP/TIMP polymorphisms has been derived from small studies mainly focused on the prognostic value of these variants. Their differential expression might identify specific pathways for the susceptibility and presentation of sepsis compared to other inflammatory non-septic conditions
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