The stromelysin-1 5A/6A promoter polymorphism

What Is Stromelysin

The amount of matrix proteins in atheromas is determined by the function of matrix protein synthesis over degradation, the latter is catalyzed by matrix metalloproteinases (MMPs). The MMP family and their endogenous tissue inhibitors regulate the accumulation of extracellular matrix, and thus the growth of the atherosclerotic plaque. Stromelysin-1/MMP3 is a key member of the MMP family with wide substrate specificity. Stromelysin is implicated in the pathogenesis of coronary artery disease (CAD) and acute myocardial infarction (MI)

Pathophysiology / Clinical Significance

Stromelysin expression is regulated primarily at the level of transcription, with the promoter of the stromelysin gene responding to stimuli including growth factors and cytokines. A common variant in the promoter sequence of the stromelysin gene has been detected ~1600 base pairs upstream from the start of transcription, in which one allele has a run of six adenosines (6A) while the other has five (5A). Three independent studies found the most rapid progression of angiographically documented coronary arteriosclerosis in patients with the 6A6A genotype. Because of reduced gene transcription, homozygosity for the 6A allele would be associated with lower stromelysin levels in arterial walls than other genotypes. This lower level of proteolytic activity would favour extra cellular matrix deposition in the atherosclerotic lesions. By contrast, homozygosity for the 5A allele would be associated with higher intra-arterial levels of stromelysin, which would be predicted to predispose to plaque instability and rupture in the presence of a high atherosclerotic burden. This hypothesis was supported in a study of Japanese patients with unstable angina, in whom the 5A5A genotype was associated with acute MI.

A study that analyzed the relation of 5A/6A polymorphism with the risk and severity of coronary artery disease (CAD) and the risk of MI, in which 515 healthy controls and 1848 participants who underwent coronary angiography for diagnostic purposes, was conducted. In the total sample, the mean CAD scores were different between 5A/6A genotypes: 5A5A homozygotes had the lowest, 6A6A genotypes the highest and 5A6A heterozygotes intermediate scores.

Populational Distribution

In a population of 485 French patients with symptomatic CAD, the genotype distribution was 23.9% 5A5A, 51.1% 5A6A, and 24.9% 6A6A. In a group of 494 patients from the Netherlands, with CAD, the genotype distribution was 24.1% 5A5A, 50.2% 5A6A, and 25.7% 6A6A. In a larger populational study in 3333 Caucasian patients with symptomatic CAD, the genotype distribution was 24.8% 5A5A, 49.4% 5A6A, and 25.8% 6A6A.

References

1. Schwarz A, Haberbosch W, Tillmanns H, Gardemann A. The stromelysin-1 5A/6A promoter polymorphism is a disease marker for the extent of coronary heart disease. Dis Markers. 2002;18(3):121-8.
2. Humphries SE, Martin S, Cooper J, Miller G. Interaction between smoking and the stromelysin-1 (MMP3) gene 5A/6A promoter polymorphism and risk of coronary heart disease in healthy men. Ann Hum Genet. 2002 Nov;66(Pt 5-6):343-52.
3. Gnasso A, Motti C, Irace C, Carallo C, Liberatoscioli L, Bernardini S, Massoud R, Mattioli PL, Federici G, Cortese C. Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects. Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1600-5.
4. Humphries S, Bauters C, Meirhaeghe A, Luong L, Bertrand M, Amouyel P. The 5A6A polymorphism in the promoter of the stromelysin-1 (MMP3) gene as a risk factor for restenosis. Eur Heart J. 2002 May;23(9):721-5.
5. Beyzade S, Zhang S, Wong YK, Day IN, Eriksson P, Ye S. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol. 2003 Jun 18;41(12):2130-7.
6. Liu PY, Chen JH, Li YH, Wu HL, Shi GY. Synergistic effect of stromelysin-1 (matrix metallo-proteinase-3) promoter 5A/6A polymorphism with smoking on the onset of young acute myocardial infarction. Thromb Haemost. 2003 Jul;90(1):132-9.
7. Hoppmann P, Koch W, Schomig A, Kastrati A. The 5A/6A polymorphism of the stromelysin-1 gene and restenosis after percutaneous coronary interventions. Eur Heart J. 2004 Feb;25(4):335-41.