The 372 T/C genetic polymorphism of TIMP-1 as a biomarker of mortality in patients with sepsis
Critical Care volume 17, Article number: 456 (2013)
In the previous issue of Critical Care, Behnes and colleagues  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 .
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 , 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.
Tissue inhibitor of matrix metalloproteinase.
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
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
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
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
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
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).
The authors declare that they have no competing interests.
LL drafted the manuscript and MMM reviewed it. Both authors read and approved the final manuscript.
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Lorente, L., Martín, M.M. The 372 T/C genetic polymorphism of TIMP-1 as a biomarker of mortality in patients with sepsis. Crit Care 17, 456 (2013). https://doi.org/10.1186/cc13037
- Myocardial Infarction
- Plasminogen Activator
- Genetic Polymorphism
- Septic Patient