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

Abstract

IntroductionPrevious 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.MethodsThis 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.ResultsOf 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).ConclusionThe 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.

Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients

“…However other studies have reported that carriers of the 6A6A genotype of this MMP-3 SNP had higher plasma MMP-3 levels202122232425262728293031323334. Our results were similar to the latter studies although only in septic patients but not in the uninfected controls, which is intriguing and needs further exploration.…”

“…TIMP-1 has been proposed as a useful laboratory marker to predict the clinical outcome of septic patients1011. Furthermore, carriers of the T allele in the TIMP-1 (372 T/C) SNP (rs4898) showed higher serum TIMP-1 levels and lower survival rate among septic patients in one study27. The low death rate among septic patients in our cohort (7.8%) has limited the statistical significance of TIMP-1 and the rest of data analyzed.…”

Association of MMP-1, 9, 12 and TIMP-1 gene polymorphisms in Malaysian male hypertensive subjects

“…The TIMP-1 gene is located on the X chromosome. Due to the nature of the analysis in Xlinked gene polymorphisms, there might be larger or no difference seen in genotypic distribution of this variant regarding the gender [19,48]. In this study, the 372 T/C polymorphism of TIMP-1 was significantly associated with EH (p=0.000) among Malay males.…”

“…Circulating levels of TIMP-1 were associated with Left ventricular diastolic impairment in hypertensives [11]. The TIMP-1 372 T/C polymorphism (rs4898) resulted from T to C substitution at position 372, was shown to be associated with survival rate in sepsis [19] and crohn's disease [48]. However, the association between 372 T/C gene polymorphism of TIMP-1, was not determined in hypertensive subjects.…”

“…The study of ischemic patients showed this SNP effects the drug responsiveness to nitrates in men [18]. Furthermore, higher plasma concentration of TIMP-1 was associated with T allele [19] in septic patients. To the best of our knowledge there were no former data available in respect to p MMP-1, 9, 12 and TIMP-1 gene polymorphisms, in relation to EH in Malaysian population.…”