Open Access Research

The 372 T/C genetic polymorphism of TIMP-1 is associated with serum levels of TIMP-1 and survival in patients with severe sepsis

Leonardo Lorente1*, Mar Martín2, Fátima Plasencia3, Jordi Solé-Violán4, José Blanquer5, Lorenzo Labarta6, César Díaz7, Juan María Borreguero-León8, Alejandro Jiménez3, José Antonio Páramo9, Josune Orbe9, José A Rodríguez9 and Eduardo Salido3

Author Affiliations

1 Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n La Laguna 38320, Santa Cruz de Tenerife, Spain

2 Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Carretera Rosario s/n, Santa Cruz Tenerife 38010, Spain

3 Research Unit, Hospital Universitario de Canarias, La Laguna 38320, Santa Cruz de Tenerife, Spain

4 Intensive Care Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain

5 Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avenida Blasco Ibáñez nº17, Valencia 46004, Spain

6 Intensive Care Unit, Hospital San Jorge de Huesca, Avenida Martínez de Velasco nº36, Huesca 22004, Spain

7 Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain

8 Laboratory Deparment, Hospital Universitario de Canarias, Ofra s/n, La Laguna 38320, Santa Cruz de Tenerife, Spain

9 Atherosclerosis Research Laboratory, CIMA-University of Navarra, Avenida Pío XII nº55, Pamplona 31008, Spain

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Critical Care 2013, 17:R94  doi:10.1186/cc12739


See related commentary by Behnes et al., http://ccforum.com/content/17/4/170

Published: 25 May 2013

Abstract

Introduction

Previous studies have found higher circulating levels of tissue inhibitor of matrix metalloproteinase (TIMP)-1 in nonsurviving septic patients than in surviving septic patients, and an association between the 372 T/C genetic polymorphism of TIMP-1 and the risk of developing certain diseases. However, the relationship between genetic polymorphisms of TIMP-1, circulating TIMP-1 levels and survival in patients with severe sepsis has not been examined, and this was the objective of the study.

Methods

This multicentre, prospective, observational study was carried out in six Spanish ICUs. We determined the 372 T/C genetic polymorphism of TIMP-1 (rs4898), serum levels of TIMP-1, matrix metalloproteinase (MMP)-9, MMP-10, TNFα, IL-10 and plasma plasminogen activator inhibitor-1 (PAI-1). Survival at 30 days from ICU admission was the endpoint assessed. The association between continuous variables was carried out using Spearman's rank correlation coefficient or Spearman's rho coefficient. Multivariate logistic regression analysis was applied to determine the association between the 372 T/C genetic polymorphism and survival 30 days from ICU admission.

Results

Of 275 patients with severe sepsis, 80 had genotype CC, 55 had genotype CT and 140 had genotype TT of the 372 T/C genetic polymorphism of TIMP-1. Patients with the T allele showed higher serum levels of TIMP-1 than patients without the T allele (P = 0.004). Multiple logistic regression analysis showed that the T allele was associated with higher mortality at 30 days (odds ratio = 2.08; 95% confidence interval = 1.06 to 4.09; P = 0.03). Survival analysis showed that patients with the T allele presented lower 30-day survival than patients without the T allele (χ2 = 5.77; P = 0.016). We found an association between TIMP-1 levels and levels of MMP-9 (ρ = -0.19; P = 0.002), MMP-10 (ρ = 0.55; P <0.001), TNFα (ρ = 0.56; P <0.001), IL-10 (ρ = 0.48; P <0.001) and PAI-1 (ρ = 0.49; P <0.001).

Conclusion

The novel findings of our study are that septic patients with the T allele in the 372 T/C genetic polymorphism of TIMP-1 showed higher serum TIMP-1 levels and lower survival rate. The determination of the 372 T/C genetic polymorphism of TIMP-1 thus has prognostic implications and could help in the selection of patients who may benefit from modulation of the MMP/TIMP balance.

Keywords:
tissue inhibitor of matrix metalloproteinase-1; genetic; polymorphism; sepsis; mortality