You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1 Nicola Fiotti + 1744 word(s) 1744 2022-02-17 07:20:12 |
2 update layout and reference Rita Xu + 1 word(s) 1745 2022-02-22 03:34:39 | |
3 update layout Rita Xu Meta information modification 1745 2022-02-22 03:42:52 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Fiotti, N. Matrix Metalloproteinases Polymorphism. Encyclopedia. Available online: https://encyclopedia.pub/entry/19694 (accessed on 18 December 2025).
Fiotti N. Matrix Metalloproteinases Polymorphism. Encyclopedia. Available at: https://encyclopedia.pub/entry/19694. Accessed December 18, 2025.
Fiotti, Nicola. "Matrix Metalloproteinases Polymorphism" Encyclopedia, https://encyclopedia.pub/entry/19694 (accessed December 18, 2025).
Fiotti, N. (2022, February 21). Matrix Metalloproteinases Polymorphism. In Encyclopedia. https://encyclopedia.pub/entry/19694
Fiotti, Nicola. "Matrix Metalloproteinases Polymorphism." Encyclopedia. Web. 21 February, 2022.
Matrix Metalloproteinases Polymorphism
Edit
This entry is adapted from the peer-reviewed paper 10.3390/biom12020279

Matrix metalloproteinases (MMPs) are a family of Calcium and Zinc-dependent endoproteases able to degrade all extracellular matrix components and with a wide array of intracellular targets. They are involved in many physiologic processes (e.g. reproduction, tissue remodeling, cell migration, apoptosis) as well as in disease (cancer, cardiovascular and infective). Their biological activity is regulated with different mechanisms at expression, activation and neutralization levels. One of the earliest, is the occurrence of functional genetic polymorphisms (GP), i.e. DNA sequence variants of the gene or of its promoter (flanking region) accounting for a different expression. In some of these GP it has been demonstrated that one allelic variant ensures a different binding of transcription factors compared to the alternative allele. Another regulatory mechanism is neutralization, which is based on the expression of 4 different Tissue Inhibitors of MMPs (TIMPs) which undergo to the same regulation by GP. GPs of MMPs and TIMPs have been associated to susceptibility or complications of various diseases. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis.

matrix metalloproteinases polymorphism sepsis inflammation fever MMP8 intracellular pathogens virus MMP-1 MMP-3

1. Introduction

Sepsis, the invasion of microorganisms inducing a generalized inflammatory response, is a major cause of death and permanent disability in Western countries and worldwide [1]. Its occurrence and outcomes reflect the balance between, on one side, the invading capacities of the pathogen, and on the other, mechanical and immune (innate and acquired) mechanisms. Both defense mechanisms have key players in matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) [2]. MMPs are calcium and zinc-dependent proteolytic enzymes that can be membrane-bound or soluble (secreted), which are able to degrade all components of the extracellular matrix, thereby favoring cell migration within tissues and enhancing the availability of growth factors bound to the matrix. Over the years, many non-structural and intracellular targets of MMPs have been identified, thus expanding their potential role in immune modulation [3][4][5] and other cellular functions [6].
MMP activities are tightly regulated through epigenetic, transcriptional, and post-transcriptional modulation of gene expression, proteolytic activation, post-translational modifications, and extracellular inhibition [7]. Among these, functional polymorphisms influence gene expression and activity and might therefore control the pathogen invasion process, thus influencing susceptibility, clinical presentation, and likely the outcomes of sepsis. Inhibition and clearance of these MMPs are performed by specific inhibitors (tissue inhibitor of metalloprotease, TIMP 1–4), which, in turn, undergo regulation of its expression by genetic polymorphisms. At present, knowledge on the role of MMP/TIMP polymorphisms has been derived from small studies mainly focused on the prognostic value of these variants. Nonetheless, their differential expression might identify specific pathways for the susceptibility and presentation of sepsis compared to other inflammatory non-septic conditions.
The role of MMPs in sepsis has already been addressed in experimental and clinical conditions, although clinical investigation has mainly focused on plasma levels [8][9][10]. A major limitation of this type of approach is that plasma MMP or TIMP concentration fluctuates in sepsis according to the stage of the disease, and each MMP might have different timing in appearance, some being immediately released by activated neutrophils (e.g., MMP-8 and MMP-9) [11] while others are expressed and released by inflamed tissues over a different time period [12]. In this context, functional genetic variants would enable us to estimate the in vivo effects of a different expression of MMP or TIMP within tissues free from the timing of the sample collection. In the choice of MMP/TIMP and their genetic variants, the researchers started from MMPs with increased/decreased expression (or plasma levels) during sepsis [13], with functional genetic variants and adequate allelic frequency and, when available, connected with expression pathways known to be activated during sepsis, (e.g., ets or NF-kB) [14][15][16].

2. Population and MMP/TIMP Polymorphism

In total, 1058 patients were analyzed in the present sub-study. Among these, a definite diagnosis was reached in 939 patients: 127 non infective SIRS (Ni-SIRS) and 812 sepsis, leaving debatable diagnosis (SIRS cases that could not be robustly characterized as infected) in the remaining 119. Clinical and laboratory data were complete in more than 99% of cases. Genotyping was successful in 99.5% of patients overall with few patients not fully genotyped (namely 6, 7, 3, 3, and 8 patients for MMP-1, -3, -8, -9, and TIMP-1, respectively). HW equilibrium was maintained for MMP1, -3, and -9 (p = 0.99, 0.354, 0.181, respectively) and for TIMP-1 female patients, (p = 0.857, T allelic frequency of 0.57 and 0.566 in the female and male sex, respectively). HW equilibrium for MMP8 was not demonstrated (p = 0.000029) with increased heterozygosity. Furthermore, HW equilibrium was reevaluated in patients with a definite diagnosis, with no remarkable differences from the whole population. Consistently, for MMP-8 rs11225395, HW was not confirmed in all groups of patients (p = 0.02, 0.0022, and 0.039 for non-infective SIRS, sepsis, and undefined patients, respectively). Linkage disequilibrium between MMP-1 rs1799750 and MMP-8 rs11225395 was demonstrated (D stat = 0.0241, D’ = 0.12 r = 0.0992 p =< 0.0001). No difference in genetic frequencies could be detected comparing the different centers contributing to the study (all p > 0.05). Patients’ general characteristics, SIRS criteria, clinical variables at presentation, and severity and comorbidity indexes are reported in Table 1 grouped according to the final diagnosis.
Table 1. Demographic, clinical presentation, comorbidities, and clinical severity of the patients, according to the final diagnosis. SIRS criteria and comorbidities are described as positive/negative finding for the condition, while continuous variables are the median and, in parentheses, interquartile range. p = p values of Kruskal–Wallis or χ2 square test, WBC = white blood cells.
  Ni-SIRS (127) Sepsis (812) Debatable (119) p
Male/female 66/61 426/386 52/67 0.201
Age 72 (59–84) 81 (72–87) 78 (71–87) 0.000
SIRS criteria        
Hyperthermia 20/107 389/423 33/86 0.0000
Hypothermia 4/123 33/779 3/116 0.658
Leukocytosis 55/72 459/353 77/42 0.002
Leukopenia 4/123 30/782 7/112 0.464
Tachycardia 112/15 608/204 95/24 0.003
Tachypnea 98/29 615/197 81/38 0.165
Immature leukocytes 0/127 3/809 0/119 0.634
Clinical presentation        
Breathing rate 22 (20–26) 24 (20–27) 22 (20–26) 0.301
Heart rate, 103 (96–110) 100 (90–110) 100 (90–108) 0.001
Temperature 36.5 (36–37.1) 37.6 (36.5–38.2) 36.7 (36–37.8) 0.000
WBC count 10.8(7.5–14.5) 12.8(9.2–16.7) 13 (9.4–15.8) 0.001
Comorbidities, severity and scores      
Charlson comorbidity index 2 (1–5) 3 (1–5) 3 (2–5) 0.008
SOFA Score 2 (1–3) 3 (2–4) 3 (2–4) 0.000
Apache II Score 10 (7–12) 12 (9–15) 11 (9–14) 0.000
SAPS Score 36 (27–40) 37 (34–43) 36 (34–42) 0.000
The association of MMP polymorphisms with features of presentation were examined independent of final diagnosis.

3. MMP/TIMP Genotype and Sepsis Susceptibility

The prevalence of different genotypes was compared only in patients with definite diagnosis (i.e., sepsis and non-infective SIRS). Allelic and genetic prevalence are reported in Figure 1. Cross tabulation of genetic prevalence was marginally significant only for MMP-8 (codominant model), although MMP-8 G/G genotype (recessive model) was more prevalent in sepsis patients than in non-infective SIRS patients (35.6 vs. 26%) with an increase in risk of 58% (95%CI 1.04–2.42).
Biomolecules 12 00279 g001
Figure 1. MMP/TIMP genetic variables and diagnosis.
Haplotype analysis was conducted to observe additive diagnostic efficacy of MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898 haplotype over the MMP-8 genotype. No advantage was demonstrated for haplotype analysis of MMP-8 and MMP-9 (global haplotype association p value = 0.24) and when TIMP-1 rs4898 was considered as a covariate (interaction p value = 0.2).

4. Clinical Presentation and MMP-8 rs11225395

Further investigation was carried out on MMP-8 polymorphism and its association with clinical presentation. SIRS criteria between Ni-SIRS and sepsis are summarized in Table 1 and their comparison according to MMP-8 genotype for Ni-SIRS and sepsis is reported in Table 2.
Table 2. Clinical presentation of sepsis and MMP8 rs11225935 (unstandardized). Comparisons were carried out with χ2 test or Mann–Whitney, according to the variable considered, and p values are reported on the right columns. p values legend: Ni-SIRS and Seps = comparison of SIRS criteria according to MMP-8 genotypes within each group (Ni-SIRS and Sepsis, respectively), GG and A* = comparison of SIRS criteria within a specific genotype (GG or A carrier) across the different groups of patients.
  Ni-SIRS Sepsis p values
  GG (n = 33) A* (n = 94) GG (n = 289) A* (n = 520) Ni-SIRS Seps GG A*
Hyperthermia 5/28 15/79 124/165 262/258 0.913 0.041 0.002 0.000
Hypothermia 1/32 3/91 13/276 20/500 0.964 0.653 0.695 0.758
Temperature 36.5 (36–37) 36.5 (36–37) 37.5 (36.5–38) 37.7 (36.6–38) 0.981 0.247 0.000 0.000
Leukocytosis 13/20 42/52 165/124 293/227 0.598 0.837 0.053 0.037
Leukopenia 1/32 3/91 10/279 19/501 0.964 0.887 0.898 0.824
WBC count 10.9 (7.9–13.6) 10.7 (7.2–14.9) 12.7 (8.9–16.7) 12.9 (9.4–16.8) 0.606 0.677 0.19 0.002
Tachycardia 30/3 82/12 229/60 377/143 0.574 0.034 0.109 0.002
Heart rate 107 (99.113) 101 (96–110) 100 (92–110) 100 (90–110) 0.359 0.576 0.017 0.011
Tachypnea 26/7 72/22 227/62 387/133 0.796 0.189 0.974 0.655
Breath rate 22 (20–26) 22 (20–26) 24 (20–26) 24 (20–26) 0.408 0.854 0.617 0.33
Immat. WBC 0 0 2/287 1/519 n.a. 0.262 0.632 0.67
In order to rule out the effect of possible confounders in the comparison between Ni-SIRS and septic patients, the same comparisons were carried out after stratification for age and disease severity (SOFA, Charlson, Apache II, and SAPS score). This yielded a group of 91 patients, whose results are reported in Figure 2. After standardization, body temperature at admission was the only SIRS criteria remaining higher in septic patients and different according to MMP8 genotype. Compared to the G/G genotype, A carriers had an increased risk for hyperthermia across the whole group and in the stratified septic patients (HR 4.4, 95%CI 1.7–11.4, p = 0.0024 and 5.8, 95%CI 1.9–18.2, p = 0.0024, respectively). Breathing rate showed a statistically weak paradoxical pattern, particularly with a higher rate of A carriers in Ni-SIRS patients.
Biomolecules 12 00279 g002
Figure 2. SIRS criteria according to MMP8 rs11225395 polymorphism in patients with Ni-SIRS (A) and sepsis (B) standardized for diabetes, age, and severity (SOFA score). ** = p < 0.01, * = p < 0.05.

5. Pathogens and Genetic Variants

Evaluation of MMP polymorphisms have also been reported when grouping the pathogens according to Gram staining properties (Gram positive or negative), intracellular (atypical) bacteria, viruses, and fungi, amongst others, is reported in Table 3. Hazard ratios associated with diagnosis of a specific class of pathogens is reported as a forest plot in Figure 3. p = χ2 test for all diagnoses.
Biomolecules 12 00279 g003
Figure 3. Forest plot of HR and 95%CI of MMP genotype variants and diagnosis of some classes of pathogens. Legend: MMP1 = rs1799750, MMP3 = rs3025058.
Table 3. Genetic variants and groups of pathogens. Legend: a = codominant (− vs. −G vs. GG), p = 0.004. b = dominant (−/−G vs. GG) H.R. 6.2 95% C.I. 1.5–25.3, p = 0.004. c = codominant (− vs. −G vs. GG) p = 0.004. d = dominant (−/−G vs. GG), H.R. 7.7 95%CI 1.5–40.4, p = 0.005. e = dominant (−/−A vs. AA), H.R. 0.47 95% CI 0.23-.94, p = 0.032. f = T vs. Non-T H.R. 0.21, 95% C.I. 0.04–1.1 p = 0.041.
  MMP-1 MMP-3 MMP-8 MMP-9 TIMP-1
  rs1799750 rs3025058 rs11225395 rs2234681 rs4898
  −/−G/GG −/−A/AA AA/AG/GG SS/SL/LL Non-T/T
All 106/214/107 123/194/113 48/230/150 179/187/62 148/279
Gram+ 37/73/30 46/59/35 15/75/50 51/67/22 48/92
Gram− 59/121/54 66/114/57 28/129/78 104/102/29 83/152
Intracell 3/0/6 a b 1/4/4 1/5/3 4/2/3 1/8
Virus 6/19/12 9/13/15 e 4/18/15 15/14/8 11/25
Fungus 1/1/5 c d 1/4/2 0/3/4 5/2/0 5/2 f
p 0.004 0.346 0.942 0.239 0.152

6. Binary Logistic Regression

To integrate the predictive role of MMP polymorphisms in the diagnosis of sepsis, binary logistic regression considered as the dependent variable the diagnosis of sepsis, sepsis due to virus, or intracellular pathogens and as independent variables, those available at admission (detailed in the Materials and Methods). The results are reported in Table 4.
Table 4. Results of the last step of binary logistic regression for the inference of variables associated with all sepsis or sepsis caused by viruses or intracellular atypical bacteria.
  B Value (E.S). Wald Sig. Exp(B) 95% CI EXP(B)
All sepsis
TIMP-1 rs4898 T carrier −0.590 (0.265) 4.937 0.026 0.555 0.330 0.933
SOFA Score 0.227 (0.066) 11.908 0.001 1.255 1.103 1.427
Age 0.045 (0.007) 38.445 0.000 1.046 1.031 1.061
Hyperthermia 2.079 (0.315) 43.496 0.000 7.997 4.311 14.834
C Reactive Protein 0.013 (0.002) 41.767 0.000 1.014 1.009 1.018
MMP-8 11,225,395 Dominant −0.720 (0.254) 8.032 0.005 0.487 0.296 0.801
Antimicrobial at home 0.706 (0.306) 5.317 0.021 2.025 1.112 3.690
Constant −2.182 (0.706) 9.563 0.002 0.113    
Virus
MMP-3 rs3025058 5A carrier −0.838 (0.390) 4.613 0.032 0.433 0.201 0.929
COPD 1.086 (0.401) 7.352 0.007 2.963 1.351 6.498
Moderate/severe kidney disease −2.467 (1.034) 5.692 0.017 0.085 0.011 0.644
Constant −1.779 (0.325) 29.905 0.000 0.169    
Intracellular atypical bacteria
TIMP-1 rs4898 C carrier 2.362 (0.906) 6.800 0.009 10.617 1.798 62.681
Previous myocardial infarction 2.263 (0.816) 7.699 0.006 9.613 1.943 47.545
Dementia −2.607 (1.247) 4.373 0.037 0.074 0.006 0.849
MMP-1 rs1799750 2.638 (0.842) 9.819 0.002 13.982 2.686 72.795
Constant −9.255 (1.985) 21.736 0.000 0.000
Gram positive or negative bacteria as well as fungus sepsis did not show any association with MMP genetic variants as well as having a sepsis by more than one pathogen (data not shown).

References

  1. Nunnally, M.E.; Ferrer, R.; Martin, G.S.; Martin-Loeches, I.; Machado, F.R.; De Backer, D.; Coopersmith, C.M.; Deutschman, C.S.; Antonelli, M.; Hellman, J.; et al. The Surviving Sepsis Campaign: Research priorities for the administration, epidemiology, scoring and identification of sepsis. Intensiv. Care Med. Exp. 2021, 9, 1–26.
  2. Elkington, P.T.; O’Kane, C.M.; Friedland, J.S. The paradox of matrix metalloproteinases in infectious disease. Clin. Exp. Immunol. 2005, 142, 12–20.
  3. Chen, Y.-L.; Li, W.-Y.; Hu, J.-J.; Li, Y.; Liu, G.-M.; Jin, T.-C.; Cao, M.-J. Nucleus-translocated matrix metalloprotease 1 regulates innate immune response in Pacific abalone (Haliotis discus hannai). Fish Shellfish Immunol. 2018, 84, 290–298.
  4. Nascimento, G.G.; Baelum, V.; Sorsa, T.; Tervahartiala, T.; Skottrup, P.D.; López, R. Salivary levels of MPO, MMP-8 and TIMP-1 are associated with gingival inflammation response patterns during experimental gingivitis. Cytokine 2019, 115, 135–141.
  5. Ceron, C.S.; Baligand, C.; Joshi, S.; Wanga, S.; Cowley, P.M.; Walker, J.P.; Song, S.H.; Mahimkar, R.; Baker, A.J.; Raffai, R.L.; et al. An intracellular matrix metalloproteinase-2 isoform induces tubular regulated necrosis: Implications for acute kidney injury. Am. J. Physiol. Physiol. 2017, 312, F1166–F1183.
  6. Bassiouni, W.; Ali, M.A.M.; Schulz, R. Multifunctional intracellular matrix metalloproteinases: Implications in disease. FEBS J. 2021, 288, 7162–7182.
  7. Madzharova, E.; Kastl, P.; Sabino, F.; Keller, U.A.D. Post-Translational Modification-Dependent Activity of Matrix Metalloproteinases. Int. J. Mol. Sci. 2019, 20, 3077.
  8. Ricarte-Bratti, J.P.; Brizuela, N.Y.; Jaime-Albarran, N.; Montrull, H.L. IL-6, MMP 3 and prognosis in previously healthy sepsis patients. Rev. Fac. Cien. Med. Univ. Nac. Cordoba 2017, 74, 99–106.
  9. Lauhio, A.; Hästbacka, J.; Pettilä, V.; Tervahartiala, T.; Karlsson, S.; Varpula, T.; Varpula, M.; Ruokonen, E.; Sorsa, T.; Kolho, E. Serum MMP-8, -9 and TIMP-1 in sepsis: High serum levels of MMP-8 and TIMP-1 are associated with fatal outcome in a multicentre, prospective cohort study. Hypothetical impact of tetracyclines. Pharmacol. Res. 2011, 64, 590–594.
  10. Martin, G.; Asensi, V.; Montes, A.H.; Collazos, J.; Álvarez, V.A.; Carton, J.A.; Taboada, F.; Valle-Garay, E. Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients. Sci. Rep. 2014, 4, 5002.
  11. Fiotti, N.; Altamura, N.; Moretti, M.; Wassermann, S.; Zacchigna, S.; Farra, R.; Dapas, B.; Consoloni, L.; Giacca, M.; Grassi, G.; et al. Short Term Effects of Doxycycline on Matrix Metalloproteinases 2 and 9. Cardiovasc. Drugs Ther. 2008, 23, 153–159.
  12. Maitra, S.R.; Jacob, A.; Zhou, M.; Wang, P. Modulation of matrix metalloproteinase-9 and tissue inhibitor of matrix metallopro-teinase-1 in sepsis. Int. J. Clin. Exp. Med. 2010, 3, 180–185.
  13. Fingleton, B. Matrix metalloproteinases as regulators of inflammatory processes. Biochim. Biophys. Acta BBA Bioenerg. 2017, 1864, 2036–2042.
  14. Rutter, J.; Mitchell, T.I.; Butticè, G.; Meyers, J.; Gusella, J.F.; Ozelius, L.J.; Brinckerhoff, C.E. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res. 1998, 58, 5321–5325.
  15. Ong, C.; Elkington, P.; Brilha, S.; Ugarte-Gil, C.; Esteban, M.T.T.; Tezera, L.B.; Pabisiak, P.J.; Moores, R.C.; Sathyamoorthy, T.; Patel, V.; et al. Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. PLoS Pathog. 2015, 11, e1004917.
  16. Borghaei, R.C.; Gorski, G.; Javadi, M. NF-κB and ZBP-89 regulate MMP-3 expression via a polymorphic site in the promoter. Biochem. Biophys. Res. Commun. 2009, 382, 269–273.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Medicine, Research & Experimental
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Nicola Fiotti
View Times: 649
Revisions: 3 times (View History)
Update Date: 22 Feb 2022
Table of Contents
    Notice
    You are not a member of the advisory board for this topic. If you want to update advisory board member profile, please contact office@encyclopedia.pub.
    OK
    Confirm
    Only members of the Encyclopedia advisory board for this topic are allowed to note entries. Would you like to become an advisory board member of the Encyclopedia?
    Yes
    No
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    There is no comment~
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    ${ selectedItem.replyTextCharacter }/${ selectedItem.replyMaxCharacter }
    Submit
    Cancel
    Confirm
    Are you sure to Delete?
    Yes No
    Academic Video Service
    Feedback