TIMP-1 gene polymorphism: are genetics able to predict outcome of septic patients?

The multicenter study conducted by Lorente and coworkers - published in the previous issue of Critical Care - suggests that levels of tissue inhibitor of metalloproteinase (TIMP)-1 in association with the 372 T/C genetic polymorphism of TIMP-1 are promising markers to predict the clinical outcome of septic patients. TIMPs bind to active matrix metalloproteinases and, amongst other effects, inhibit their proteolytic activity of the extracellular matrix. Previous clinical studies showed increased plasma levels of TIMP-1 in nonsurvivors of sepsis, and showed associations between the 372 T/C genetic polymorphism of TIMP-1 and increased risk of developing certain diseases. In recent years, there has been great interest in understanding whether genetic determinants of the host response to systemic infections are associated with poor outcome. Furthermore, the pharmacogenomics of sepsis may allow us to target immune-modulating therapies. Measurement of TIMP-1 protein levels and TIMP-1 polymorphism 372 T/C in the intensive care setting could therefore be an attractive noninvasive tool to determine the outcome of septic patients, and might help to select patients potentially benefitting from a target-specific immune-modulatory therapy directed to matrix metalloproteinase/TIMP homeostasis.


Introduction
In the previous issue of Critical Care, the Spanish group of Lorente and colleagues reports results in which the role of the 372 T/C polymorphism of tissue inhibitor of metalloproteinase (TIMP)-1 (rs 4898) and serum levels of TIMP-1 were related to the outcome of 275 patients with severe sepsis [1]. Th ey found the T-allele in the 372 T/C genetic poly morphism of TIMP-1 and increased levels of TIMP-1 to be associated with lower survival rates, and suggest that this genetic polymorphism may have prognostic impli cations in severe septic patients.
Sepsis represents a systemic infl ammatory response to an infectious agent and may lead to multiple organ failure, increased mortality and costs. Genetic testing has been discussed as a strategy to identify septic patients with a poor prognosis. Advances in genetic sequence analysis and high-throughput platform analysis of gene expression improved the understanding of immunopathogenetics during sepsis [2].
TIMPs naturally occur as inhibitors of matrix metalloproteinases (MMPs), whilst additionally revealing growth factor functions [3]. TIMP-1 itself inhibits almost all of the diff erent MMP subtypes [3]. TIMP-1 activates human granulocytes, protecting them from apoptosis and blocking their transmigration during infl ammation [4]. Several studies showed increased protein levels of MMPs and TIMPs, and evaluated the prognostic value of TIMP-1 in patients with severe sepsis [5,6].
Increasing evidence suggests that diff erences of a specifi c disease manifestation and outcome may result from the patient's individual genetic disposition. A study by Skarmoutsou and colleagues demonstrated the prognostic impact of the 372 T/C TIMP-1 genetic polymorphism for the onset of systemic sclerosis in women [7]. An association of genetic polymorphisms of the X-linked TIMP-1 gene with the risk of developing certain other diseases has been reported, the 372 T/C TIMP-1 polymorphism being the most studied variant [7-9].

TIMP-1 as a biomarker in the ICU
Th e association between levels of TIMP-1 and the 372 T/C TIMP-1 polymorphism was previously evaluated in patients with acute heart failure, left ventricular dysfunction and ST-elevation myocardial infarction treated by primary percutaneous coronary intervention [10]. In this previous study, an independent relationship between an exon 5 TIMP-1 gene polymorphism, TIMP-1 levels and left ventricular dysfunction was not shown.

Abstract
The multicenter study conducted by Lorente and coworkers -published in the previous issue of Critical Caresuggests that levels of tissue inhibitor of metalloproteinase (TIMP)-1 in association with the 372 T/C genetic polymorphism of TIMP-1 are promising markers to predict the clinical outcome of septic patients. TIMPs bind to active matrix metalloproteinases and, amongst other eff ects, inhibit their proteolytic activity of the extracellular matrix. Previous clinical studies showed increased plasma levels of TIMP-1 in nonsurvivors of sepsis, and showed associations between the 372 T/C genetic polymorphism of TIMP-1 and increased risk of developing certain diseases. In recent years, there has been great interest in understanding whether genetic determinants of the host response to systemic infections are associated with poor outcome. Furthermore, the pharmacogenomics of sepsis may allow us to target immune-modulating therapies. Measurement of TIMP-1 protein levels and TIMP-1 polymorphism 372 T/C in the intensive care setting could therefore be an attractive noninvasive tool to determine the outcome of septic patients, and might help to select patients potentially benefi tting from a target-specifi c immune-modulatory therapy directed to matrix metalloproteinase/TIMP homeostasis.
Th e majority of sepsis studies evaluated other infl ammatory mediators, such as TNF and its polymorphisms being associated with increasing stages of sepsis [11,12]. A meta-analysis of two common Toll-like receptor 4 polymorphisms showed no strong correlation with the development of sepsis [13]. Lorente and coworkers demonstrated for the fi rst time the association of SNP 372 T/C of TIMP-1 and TIMP-1 levels with survival in septic patients [1].
While the 372 T/C genetic polymorphism of TIMP-1 is located on the X chromosome, the study by Lorente and colleagues showed no diff erences in survival between women with C/C, C/T and T/T alleles, but the T-allele was associated with higher mortality in men [1]. Nonsurvivors of sepsis showed higher TIMP-1 protein levels than survivors, but levels of TIMP-1 were notably lower as described in other series [5,14]. Septic animal models showed that modulators of MMP/TIMP activity reduce TIMP-1 and improve the prognosis [15].
Emergent is the question of whether determination of the 372 T/C polymorphism of TIMP-1 could help the intensive care physician in the selection of patients who may benefi t from therapeutic modulation of MMP/TIMP activity. However, as there is extensive diversity in infl ammatory pathways and immune response during sepsis, the functional and clinical signifi cance of one SNP may not be the only marker for prognosis assessment in the large puzzle of sepsis.

Limitations of this study
A limitation of the study by Lorente and colleagues is the small sample size, making prognostic implications by one SNP challenging. A second limitation is the fact that the study group only tested the rs 4898 SNP of TIMP-1, a tag SNP for the region of interest. Whether this SNP is linked to other SNPs associated with the same eff ect could be of interest. Th e susceptibility to sepsis is probably aff ected by multiple genes rather than one single mutation. Further more, measurement of one SNP as a tool for identi fying septic patients at high risk of mortality is time consuming and costly, and thus may not be practical in the clinical routine. Finally, an important limitation of any association in this study is that it cannot establish a cause-eff ect relationship, but may only represent an epiphenomenon.

Conclusion
Genetic approaches to patients with severe sepsis have grown over the last decade. Until now, none of these results have been translated directly to clinical therapy. Th e determination of the 372 T/C polymorphism of TIMP-1 -as a new genetic biomarker for the severity of sepsis and for mortality assessment in critically ill patients -may provide a future tool. Whether biomarker determination such as TIMP-1 levels and genotyping could optimize treatment and sepsis outcome requires further methodological comparable research to bridge the gap between laboratory and bedside. Th ere is still a long road ahead of us until the ideal marker is found and is readily available in clinical practice.