Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients.

Guadalupe Martin,Eulalia Valle-Garay,Víctor Asensi,Francisco Taboada,Julio Collazos,A Hugo Montes,Victoria Alvarez,José A Carton

doi:10.1038/srep05002

Abstract

Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs), modulated by different single nucleotide polymorphisms (SNPs), are critical in sepsis development. Ninety ICU severely septic and 91 ICU uninfected patients were prospectively studied. MMP-1 (−1607 1G/2G), MMP-3 (−1612 5A/6A), MMP-8 (−799 C/T), MMP-9 (−1562 C/T), and MMP-13 (−77A/G) SNPs were genotyped. Plasma MMPs (-1, -2, -3, -8, -9, -10, -13) and TIMPs (-1,-2,-4) were measured. AA homozygotes and A allele carriers of MMP-13 (−77 A/G) and 1G2G carriers of the MMP-1 (−1607 1G/2G) SNPs frequencies were different between septic and uninfected patients (p < 0.05), as well as plasma MMP-3, -8, -9 -10 and TIMP-2 levels (p < 0.04). No differences in MMPs levels among MMP-13 or MMP-1 SNPs genotypes carriers were observed. The area under the ROC curve for MMP-8 in the diagnosis of sepsis was 0.87 (95% CI 0.82–0.92), and that of CRP was 0.98 (0.94–0.998), whereas the area of MMP-9 in the detection of non-septic state was 0.73 (0.65–0.80), p < 0.0001 for all curves. Sepsis associated with increased MMP-8 and decreased MMP-9 levels in multivariate analysis (p < 0.0002). We report for the first time an association between MMP-13 and MMP-1 SNPs and sepsis. An independent association of MMP-8 and MMP-9 levels with sepsis was also observed.

Highlights

Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in Intensive Care Units (ICU) patients
We report for the first time an association between matrix metalloproteases (MMPs)-13 and MMP-1 SNPs and sepsis
Of all the MMPs SNPs studied we only found that the AA genotype of the MMP-13 (277 A/G) SNP was significantly more frequent and the 1G2G genotype of the MMP1(21607 1G/2G) less frequent in septic patients compared to uninfected ICU controls

Summary

Introduction

Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients. AA homozygotes and A allele carriers of MMP-13 (277 A/G) and 1G2G carriers of the MMP-1 (21607 1G/2G) SNPs frequencies were different between septic and uninfected patients (p , 0.05), as well as plasma MMP-3, -8, -9 -10 and TIMP-2 levels (p , 0.04). MMPS are a family of zinc-dependent endoproteases that share amino-acid sequences, structural domains and substrates and can degrade the extracellular matrix (ECM) proteins Their activity depends on activation of MMPs zymogens and is influenced by tissue inhibitors (TIMPs). To investigate the baseline and time course plasma levels of MMPs and TIMPs in ICU septic and uninfected patients; 2. In order to answer these questions, plasma levels of different MMPs and TIMPs were measured and different SNPs of MMPs were genotyped in septic and uninfected control patients. The time course of MMPs and TIMPs at days 1, 3 and 7 of ICU admission in a subgroup of septic patients and uninfected controls was analyzed

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