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

Critical Care

Eduardo Salido⁴  José A Rodríguez⁶  Josune Orbe⁶  José Antonio Páramo⁶  Alejandro Jiménez⁴  Juan María Borreguero-León¹  César Díaz²  Lorenzo Labarta⁷  José Blanquer⁸  Jordi Solé-Violán³  Fátima Plasencia⁴  Mar Martín⁹  Leonardo Lorente⁵ 

[1] Laboratory Deparment, Hospital Universitario de Canarias, Ofra s/n, La Laguna 38320, Santa Cruz de Tenerife, Spain;Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain;Intensive Care Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain;Research Unit, Hospital Universitario de Canarias, La Laguna 38320, Santa Cruz de Tenerife, Spain;Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n La Laguna 38320, Santa Cruz de Tenerife, Spain;Atherosclerosis Research Laboratory, CIMA-University of Navarra, Avenida Pío XII nº55, Pamplona 31008, Spain;Intensive Care Unit, Hospital San Jorge de Huesca, Avenida Martínez de Velasco nº36, Huesca 22004, Spain;Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avenida Blasco Ibáñez nº17, Valencia 46004, Spain;Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Carretera Rosario s/n, Santa Cruz Tenerife 38010, Spain

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

Others  :  818141
DOI  :  10.1186/cc12739

 received in 2013-01-30, accepted in 2013-05-25,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Lorente et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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