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The 372 T/C genetic polymorphism of TIMP-1 as a biomarker of mortality in patients with sepsis

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In the previous issue of Critical Care, Behnes and colleagues [1] provide an interesting commentary on our study showing that septic patients with the T-allele in 372 T/C (rs4898) genetic polymorphism of the tissue inhibitor of metalloproteinase-1 (TIMP-1) had higher mortality and higher TIMP-1 serum levels than those without it [2].

As the authors state in their commentary, our study had some limitations. One limitation was the relatively small sample size to establish prognostic implications by only one single-nucleotide polymorphism (SNP) challenge. However, the sample size was large enough to find an association between polymorphism and survival.

Another limitation was that we tested only the rs4898 SNP, a tag SNP, for the region of interest. However, it may be that this SNP, which is in strong linkage disequilibrium with other TIMP-1 polymorphisms, is linked to other SNPs associated with the same effect.

Another possibility is that this association represents only an epiphenomenon since, in our study, a cause-effect relationship between polymorphism and mortality was not established. However, we found that patients with the T-allele had higher TIMP-1 serum levels and that patients with higher TIMP-1 circulating levels showed higher mortality [3, 4]. Besides, we found a positive association between TIMP-1 and plasminogen activator inhibitor-1 circulating levels, previously found in myocardial infarction patients [5], probably suggesting a prothrombotic state. In conclusion, we think that the determinations of 372 T/C genetic polymorphism and circulating levels of TIMP-1 could be used as mortality biomarkers in patients with sepsis.

Abbreviations

SNP:

Single-nucleotide polymorphism

TIMP:

Tissue inhibitor of matrix metalloproteinase.

References

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    Behnes M, Bertsch T, Hoffmann : TIMP-1 gene polymorphism: are genetics able to predict outcome of septic patients? Crit Care 2013, 17: 170. 10.1186/cc12799

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    Lorente L, Martín MM, Plasencia F, Solé-Violán J, Blanquer J, Labarta L, Díaz C, Borreguero-León JM, Jiménez A, Páramo JA, Orbe J, Rodríguez JA, Salido E: The 372 T/C genetic polymorphism of TIMP-1 is associated with serum levels of TIMP-1 and survival in patients with severe sepsis. Crit Care 2013, 17: R94. 10.1186/cc12739

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    Hoffmann U, Bertsch T, Dvortsak E, Liebetrau C, Lang S, Liebe V, Huhle G, Borggrefe M, Brueckmann M: Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. Scand J Infect Dis 2006, 38: 867-872. 10.1080/00365540600702058

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    Lorente L, Martín MM, Labarta L, Díaz C, Solé-Violán J, Blanquer J, Orbe J, Rodríguez JA, Jiménez A, Borreguero-León JM, Belmonte F, Medina JC, Llimiñana MC, Ferrer-Agüero JM, Ferreres J, Mora ML, Lubillo S, Sánchez M, Barrios Y, Sierra A, Páramo JA: Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis. Crit Care 2009, 13: R158. 10.1186/cc8115

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    Cavusoglu E, Ruwende C, Chopra V, Yanamadala S, Eng C, Clark LT, Pinsky DJ, Marmur JD: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction. Am Heart J 2006, 151: 1101. e1-8

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Acknowledgments

This study was supported, in part, by grants (FIS/PI-10-1572, I3SNS-INT-11-063, and I3SNS-INT-12-087) from Instituto de Salud Carlos III (Madrid, Spain).

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Correspondence to Leonardo Lorente.

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Competing interests

The authors declare that they have no competing interests.

Authors' contributions

LL drafted the manuscript and MMM reviewed it. Both authors read and approved the final manuscript.

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Keywords

  • Myocardial Infarction
  • Plasminogen
  • Plasminogen Activator
  • Genetic Polymorphism
  • Septic Patient