Stromelysin-1

Clinical Usage

  • To identify individuals who may have an increased risk for development and progression of coronary artery disease.
  • To identify hypertensive individuals who may have an increased risk of stroke

Background Information

Stromelysin-1, also known as matrix metalloproteinase-3 or MMP-3, is a matrix remodeling enzyme that acts on a collagen, proteoglycans, gelatin and elastin. Matrix composition plays a critical role in lipid accumulation, vascular remodeling, plaque instability and subsequent cardiovascular disease.

Stromelysin-1 is encoded by the human MMP-3 gene. A polymorphism in the promoter of the MMP3 gene is a variation in the number of adenosines (A’s) located at position -1171 relative to the transcription start site. The normal or wild type (wt) promoter contains a tract of 5 consecutive A residues and is called the 5A allele.  A variant form of the MMP-3 promoter contains 6 consecutive A residues in this position and is called the 6A allele. The 6A allele causes decreased stromelysin-1 levels to be made.  Decreased stromelysin-1 levels cause less proteolytic activity,  greater extracellular matrix deposition in atherosclerotic lesions, and increased susceptibility for progression of coronary artherosclerosis.  There is also evidence that the 6A allele is associated with an increased risk of stroke in hypertensive patients.

Gene Information

The human stromelysin-1 gene is MMP-3 and is located on chromosome 11 (11q22.3). The following three genotypes of the MMP-3 promoter are possible:
(5A/5A) – Homozygous wt:  Normal amount of stromelysin-1.
(5A/6A) – Heterozygous: may be associated with reduced amounts of stromelysin-1 
(6A/6A) – Homozygous mutant: decreased amounts of stromelysin-1

Population Information

The MMP-3 6A allele is present in approximately 30-35 % of the population.

Test Method

The test was developed using CLSI guidelines.  Control DNA samples of known genotype are tested together with each patient sample to monitor the performance of the test.  Genomic DNA is extracted from the submitted blood specimen and analyzed by Polymerase chain reaction (PCR) followed by restriction digest.

Specimen

Collection

Whole blood in a purple top (EDTA) tube

Rejection Criteria

  • Blood specimen:

i. It is collected in a heparin-containing tube because heparin can inhibit the PCR reaction.
ii. It leaked in the shipping container.
iii. The name on the tube does not match the name on the paperwork.
iv. It is older than 10 days.
Interpretation

Homozygous normal (5A/5A) – Generally no change in stromelysin-1 levels and is not a cause of increased risk for coronary artery disease progression
Heterozygous (5A/6A) – May be associated with reduced stromelysin-1 levels and increased risk for coronary artery disease progression
Homozygous mutant (6A/6A) – Reduced stromelysin-1 levels and increased risk for coronary plaque rupture and coronary artery disease progression.  This genotype may be associated with an increased risk of stroke in hypertensive patients
This genotype result is but one factor affecting coronary disease progression, and other genetic and clinical factors should also be considered.

CPT code

81479

Test Limitations

Other genetic variants of the MMP-3 gene that are not detected in this assay may influence stromolysin-1 enzyme activity. Other genetic and non-genetic factors may also influence the risk of coronary disease progression.  The detection of genetic variants does not replace the need for appropriate clinical monitoring by the health care provider.  This test wase developed and the performance characteristics were determined by MDL. This test has not been cleared or approved by the US Food and Drug Administration.  The FDA has determined that such approval is not necessary.

References

1. 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. 90(1):132-139.  2003
2. Humphries SE. The stromelysin-1 (MMP-3) gene and risk of coronary artery disease: a candidate gene that has won the election? Thromb Haemost. 90(1):3-6.  2003
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. 20(6):1600-1605.  2000
4. 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. 66(Pt 5-6):343-352.  2002
5. Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J.  73 (3): 209–215.  1995