Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Dec 1.
Published in final edited form as: Circ Cardiovasc Genet. 2017 Dec;10(6):e001958. doi: 10.1161/CIRCGENETICS.117.001958

Cardiovascular Risk and Matrix Metalloproteinase Polymorphisms: Not Just A Simple Substitution

Francis G Spinale 1, Ashley A Sapp 1
PMCID: PMC5726789  NIHMSID: NIHMS917797  PMID: 29212903

Cardiovascular remodeling is a process by which structural changes occur within the vascular compartment and/or the myocardium and are hallmark events in the development and progression of cardiovascular disease. This remodeling process is multifactorial entailing biological shifts in molecular, cellular, and extracellular matrix (ECM) structure and function. The ECM, for example, plays a critical role in maintaining normal vascular and myocardial architecture, and proteolytic turnover of the ECM, driven in large part by the induction and activation of matrix metalloproteinases (MMPs), is a major determinant of ECM structure and function. The MMPs are tightly regulated by transcriptional, post-transcriptional, and post-translational checkpoints. Transcriptional regulation of MMPs is primarily determined by upstream gene promoter activity whereby a number of intracellular signaling factors bind to specific sequences within the MMP promoter sequence. As such, there has been considerable interest in nucleic acid substitutions (i.e. polymorphisms) that occur within the MMP promoter regions and relation to overall MMP levels, and most importantly, relation to cardiovascular outcomes.1,2

There have been a number of MMP polymorphisms identified in key MMP types, which include the collagenases (MMP-1, -8), the gelatinases (MMP-2, MMP-9), and stromelysins (MMP-3). A brief synopsis of MMP polymorphisms with respect to cardiovascular remodeling processes and selected citations is provided in Table 1.219 This summary table is by no means exhaustive but underscores the fact that several polymorphisms, primarily within the MMP promoter regions, have been identified and associated with subsets of patients at risk for cardiovascular events. Several of the MMP types identified in Table 1 are associated with acute/chronic inflammation in that these proteases are expressed by inflammatory cells as well as induced by mediators of inflammation, such as through cytokine signaling. For example, MMP-8 and MMP-9 are highly expressed by neutrophils and macrophages, and rapid induction of these MMP types through inflammatory signaling pathways has been well established. Coronary artery disease, and more specifically vulnerable coronary plaques, has been associated with inflammation and local activation of MMP-9 and MMP-8. Precisely, increased local MMP-8 levels and polymorphisms within the MMP-8 promoter region have been identified with coronary plaque progression and acute events.17,18 In this issue of Circulation: Cardiovascular Genetics, Salminen and colleagues performed a genome-wide association study (GWAS) to that of plasma MMP-8 levels as well as overall cardiovascular events in a large cohort of patients.18 These investigators identified that in certain subsets of patients, polymorphisms within the MMP-8 promoter region were associated with different plasma MMP-8 levels. Past studies have identified that polymorphisms within the MMP-9 promoter region would also result in higher plasma MMP-9 levels and in turn impart increased risk for cardiovascular events.7,8

Table 1.

Examples of MMP polymorphisms and association with risk of cardiovascular disease

Polymorphism Clinical Association Reference
MMP-9 CVD, Post-MI Remodeling, DCM 24, 68, 19
TAA / AAA 15
MMP-2 CAD, HF, CVD, HTN, TAA 12, 14
MMP-3 Post-MI Remodeling, DCM, CAD, HTN 9, 10, 5, 15, 16
MMP-1 Post-MI Remodeling, HF, CVA 5, 11, 3, 13
MMP-8 CVD 17, 18
MMP-12 CVD 4

MI – myocardial infarction, DCM – dilated cardiomyopathy, CVD – cardiovascular disease, TAA – thoracic aortic aneurysm, CAD – coronary artery disease, HTN – hypertension, AAA – abdominal aortic aneurysm, CVA – cerebrovascular accident

More importantly, however, Salminen and colleagues identified several important polymorphisms distal to that of MMP-8 itself using a GWAS approach: that of complement factor-H (CFH) and in a specific member of the S100A family, both of which directly or indirectly may have influenced MMP-8 levels.18 For example, the minor allele of S100A9 (rs1560833) was associated with differences in steady-state plasma MMP-8 levels. An association between plasma S100 protein levels, inflammatory signaling, and cardiovascular risk has been identified.20 While an oversimplification, the findings by Salminen et al18 add to the body of evidence regarding an inter-relationship between inflammatory signaling pathways, MMP induction, and cardiovascular risk. With respect to CFH polymorphisms, Salminen and colleagues demonstrated that a CFH polymorphism (rs800292) was associated with reduced MMP-8 release in a neutrophil functional assay.18 In this case, it is likely that the CFH polymorphism interferes in the release of preformed MMP-8 from neutrophils. These findings underscore how gene mutations, in what initially would appear to be unrelated pathways, can hold biological relevance, and in this case, alter a downsream MMP-8 post-translational regulatory step.

In the study by Salminen and colleagues, the minor allele of S100A9 (rs1560833) was not only associated with changes in MMP-8 plasma levels but also associated with overall cardiovascular events.18 Specifically, the S100A9 minor allele A of rs1560833 was associated with lower plasma MMP-8 levels and an inverse relative risk of cardiovascular events. Interestingly, the association with this S100A9 polymorphism and cardiovascular events was identified in men but not women. Past studies of MMP polymorphisms and cardiovascular risk have identified both gender and ethnicity as important independent confounding variables in predictive cardiovascular risk models.17, 2124 Indeed, a past study reported that polymorphisms contained within the MMP-8 promoter region conferred increased risk for the progression of carotid artery disease, specifically in women.17 In another study, the severity of carotid artery disease was most strongly associated with a common MMP-9 polymorphism (-1562T) in women.24 With respect to ethnicity, specific MMP polymorphisms have been identified to confer increased risk of cardiovascular disease progression and cardiovascular events in Asians and in blacks of African descent.21,22,23 In addition, specific MMP polymorphisms confer additive risk for cardiovascular events in subjects with other risk factors, such as diabetes and obesity.2,19 Thus, assessment of polymorphisms associated with MMP induction in at risk subpopulations will be an important area for further research and refinement in terms of cardiovascular risk assessment.

One important observation from the study by Salminen and colleagues is the influence of sample collection conditions in terms of assessing MMP levels and potential biological interactions of other enzyme pathways, such as complement factors.18 MMP levels will not yield equivalent results when measured from decanted plasma or that from serum, and the study by Salminen et al.18 amplifies the importance of the sampling procedure. While this may at first appear to be a minor methodological consideration, it underscores a relative lack of uniformity and standardized process for blood sample preparation in the assessment of labile biological factors, such as MMPs and other proteases. This issue must be resolved through an appropriate consensus panel if biomarker measurements at the genome and post-transcriptional level are to be strategically integrated into predictive models and clinical risk assessment algorithms. Finally, it should be emphasized that the majority of studies that have examined the relation of MMP polymorphisms to that of MMP levels have primarily been performed in mixed venous blood samples. However, the proteolytic activity of MMPs is a highly compartmentalized process, and therefore systemic levels of MMPs may not necessarily reflect ECM degradation and remodeling occurring locally. Furthermore, systemic MMP levels, and for that matter polymorphisms affecting MMP transcription, do not provide an index of actual MMP activity. Future studies that examine the inter-relationship of MMP polymorphisms to true indices of MMP activity, such as through next generation MMP imaging,25 are warranted.

In conclusion, simple sequence substitutions within the MMP gene or promoter region provide only a partial picture into the complex regulation of MMPs within the cardiovascular system. Indeed, the study reported by Salminen et al. demonstrated no association between polymorphisms within the MMP-8 gene itself and relative MMP-8 plasma levels.18 On the other hand, this study provides further evidence that changes in unexpected distal pathways can affect MMP induction and release. It is not surprising that there are multiple checkpoints and intersections of the MMP system given the critical role these proteases play in cardiovascular remodeling and ultimately determining cardiovascular risk.

Acknowledgments

Sources of Funding: Dr. Spinale’s work is supported by the National Institute of Health grants HL111090 and HL113352 and a Merit Award from the Veterans’ Affairs Health Administration.

Footnotes

Disclosures: None

References

  • 1.Li T, Lv Z, Jing JJ, Yang J, Yuan Y. Matrix metalloproteinase family polymorphisms and the risk of aortic aneurysmal diseases: A systematic review and meta-analysis. Clin Genet. 2017 May 9; doi: 10.1111/cge.13050. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  • 2.Opstad TB, Arnesen H, Pettersen AÅ, Seljeflot I. The MMP-9 -1562 C/T polymorphism in the presence of metabolic syndrome increases the risk of clinical events in patients with coronary artery disease. PLoS One. 2014;9:e106816. doi: 10.1371/journal.pone.0106816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Pavkova Goldbergova M, Jarkovsky J, Lipkova J, Littnerova S, Poloczek M, Spinar J, et al. Relationship of long-term prognosis to MMP and TIMP polymorphisms in patients after ST elevation myocardial infarction. J Appl Genet. 2017;58:331–341. doi: 10.1007/s13353-016-0388-8. [DOI] [PubMed] [Google Scholar]
  • 4.Tanner RM, Lynch AI, Brophy VH, Eckfeldt JH, Davis BR, Ford CE, et al. Pharmacogenetic associations of MMP9 and MMP12 variants with cardiovascular disease in patients with hypertension. PLoS One. 2011;6:e23609. doi: 10.1371/journal.pone.0023609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Velho FM, Cohen CR, Santos KG, Silvello D, Martinelli N, Biolo A, et al. Polymorphisms of matrix metalloproteinases in systolic heart failure: role on disease susceptibility, phenotypic characteristics, and prognosis. J Card Fail. 2011;17:115–21. doi: 10.1016/j.cardfail.2010.09.017. [DOI] [PubMed] [Google Scholar]
  • 6.Horne BD, Camp NJ, Carlquist JF, Muhlestein JB, Kolek MJ, Nicholas ZP, et al. Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease. Am Heart J. 2007;154:751–8. doi: 10.1016/j.ahj.2007.06.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation. 2003;107:1579–85. doi: 10.1161/01.CIR.0000058700.41738.12. [DOI] [PubMed] [Google Scholar]
  • 8.Zhang B, Ye S, Herrmann SM, Eriksson P, de Maat M, Evans A, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999;99:1788–94. doi: 10.1161/01.cir.99.14.1788. [DOI] [PubMed] [Google Scholar]
  • 9.Terashima M, Akita H, Kanazawa K, Inoue N, Yamada S, Ito K, et al. Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial infarction. Circulation. 1999;99:2717–9. doi: 10.1161/01.cir.99.21.2717. [DOI] [PubMed] [Google Scholar]
  • 10.Beyzade S, Zhang S, Wong YK, Day IN, Eriksson P, Ye S, et al. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol. 2003;41:2130–7. doi: 10.1016/s0735-1097(03)00482-0. [DOI] [PubMed] [Google Scholar]
  • 11.Martin TN, 1, Penney DE, Smith JA, Groenning BA, Dargie HJ, Hillis GS. Matrix metalloproteinase-1 promoter polymorphisms and changes in left ventricular volume following acute myocardial infarction. Am J Cardiol. 2004;94:1044–6. doi: 10.1016/j.amjcard.2004.06.064. [DOI] [PubMed] [Google Scholar]
  • 12.Vasků A, Goldbergová M, Izakovicová Hollá L, Sisková L, Groch L, Beránek M, et al. A haplotype constituted of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) is associated with coronary triple-vessel disease. Matrix Biol. 2004;22:585–91. doi: 10.1016/j.matbio.2003.10.004. [DOI] [PubMed] [Google Scholar]
  • 13.Pearce E, Tregouet DA, Samnegård A, Morgan AR, Cox C, Hamsten A, et al. Haplotype effect of the matrix metalloproteinase-1 gene on risk of myocardial infarction. Circ Res. 2005;97:1070–6. doi: 10.1161/01.RES.0000189302.03303.11. [DOI] [PubMed] [Google Scholar]
  • 14.Beber AR, Polina ER, Biolo A, Santos BL, Gomes DC, La Porta VL, et al. Matrix Metalloproteinase-2 Polymorphisms in Chronic Heart Failure: Relationship with Susceptibility and Long-Term Survival. PLoS One. 2016;11:e0161666. doi: 10.1371/journal.pone.0161666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Pöllänen PJ, Lehtimäki T, Mikkelsson J, Ilveskoski E, Kunnas T, Perola M, et al. Matrix metalloproteinase3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques. Atherosclerosis. 2005;180:73–8. doi: 10.1016/j.atherosclerosis.2004.10.041. [DOI] [PubMed] [Google Scholar]
  • 16.Beilby JP, Chapman CM, Palmer LJ, McQuillan BM, Thompson PL, Hung J. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. J Hypertens. 2005;23:537–42. doi: 10.1097/01.hjh.0000160209.48479.ae. [DOI] [PubMed] [Google Scholar]
  • 17.Djurić T, Stanković A, Končar I, Radak D, Davidović L, Alavantić D, et al. Association of MMP-8 promoter gene polymorphisms with carotid atherosclerosis: preliminary study. Atherosclerosis. 2011;219:673–8. doi: 10.1016/j.atherosclerosis.2011.08.025. [DOI] [PubMed] [Google Scholar]
  • 18.Salminen A, Vlachopoulou E, Havulinna AS, Tervahartiala T, Sattler W, Lokki M-L, et al. Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association with Cardiovascular Diseases: A Genome-Wide Analysis. Circ Cardiovasc Genet. 2017;10:e001731. doi: 10.1161/CIRCGENETICS.117.001731. [DOI] [PubMed] [Google Scholar]
  • 19.Luizon MR, Belo VA, Fernandes KS, Andrade VL, Tanus-Santos JE, Sandrim VC. Plasma matrix metalloproteinase-9 levels, MMP-9 gene haplotypes, and cardiovascular risk in obese subjects. Mol Biol Rep. 2016;43:463–71. doi: 10.1007/s11033-016-3993-z. [DOI] [PubMed] [Google Scholar]
  • 20.Schiopu A, Cotoi OS. S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. Mediators Inflamm. 2013;2013:828354. doi: 10.1155/2013/828354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Metzger IF, Luizon MR, Lacchini R, Tanus-Santos JE. Genetic variants in matrix metalloproteinase-9 gene modify metalloproteinase-9 levels in black subjects. DNA Cell Biol. 2012;31:504–10. doi: 10.1089/dna.2011.1388. [DOI] [PubMed] [Google Scholar]
  • 22.Lacchini R, Metzger IF, Luizon M, Ishizawa M, Tanus-Santos JE. Interethnic differences in the distribution of matrix metalloproteinases genetic polymorphisms are consistent with interethnic differences in disease prevalence. DNA Cell Biol. 2010;29:649–55. doi: 10.1089/dna.2010.1056. [DOI] [PubMed] [Google Scholar]
  • 23.Wang J, Xu D, Wu X, Zhou C, Wang H, Guo Y, et al. Polymorphisms of matrix metalloproteinases in myocardial infarction: a meta-analysis. Heart. 2011;97:1542–6. doi: 10.1136/heartjnl-2011-300342. [DOI] [PubMed] [Google Scholar]
  • 24.Lin RT, Chen CH, Tsai PC, Ho BL, Juo SH, Lin HF. Sex-specific effect of matrix metalloproteinase-9 functional promoter polymorphism on carotid artery stiffness. Atherosclerosis. 2012;223:416–20. doi: 10.1016/j.atherosclerosis.2012.05.031. [DOI] [PubMed] [Google Scholar]
  • 25.Sahul ZH, Mukherjee R, Song J, McAteer J, Stroud RE, Dione DP, et al. Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relationship to myocardial dysfunction. Circ Cardiovasc Imaging. 2011;4:381–91. doi: 10.1161/CIRCIMAGING.110.961854. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES