There is a common polymorphism in the promoter sequence of the MMP3 gene, with 1 allele containing a run of 6 adenosines (6A) and the other 5 adenosines (5A) (18...
There is a common polymorphism in the promoter sequence of the MMP3 gene, with 1 allele containing a run of 6 adenosines (6A) and the other 5 adenosines (5A) (185250.0001). Ye et al. (1996) followed up on a previously reported 3-year study by Richardson et al. (1989) of patients with coronary atherosclerosis that indicated that those patients who were homozygous for the 6A allele showed a more rapid progression of both global and focal atherosclerotic stenoses. In transient expression experiments, Ye et al. (1996) found that an MMP3 promoter construct with 6A at the polymorphic site expressed less of the reporter gene than a construct containing 5A. Binding of a nuclear protein factor was more readily detectable with an oligonucleotide probe corresponding to the 6A allele than with a probe corresponding to the 5A allele.
Humphries et al. (2002) reported on the relationship between smoking, MMP3 genotype, and risk of clinical CHD in a prospective survey of healthy middle-aged men. They found that current smoking nearly doubled the risk for CHD and examined the hypothesis that this risk was modified by MMP3 genotype. They found that in nonsmoking men, compared with the 5A/5A group, the relative risk was 1.37 in those with the 5A/6A genotype and 3.02 in those with the 6A/6A genotype. Smoking increased risk 1.4-fold in the 5A/6A group to 1.91, 1.3-fold in the 6A/6A group to 4.01, and 3.81-fold in the 5A/5A group. The data indicated a key role for MMP3 in the atherosclerotic process. Men with the 5A/5A genotype represented 29% of the general population, and their high risk, if smokers, provided a strong argument for avoiding smoking.
Medley et al. (2003) determined the MMP3 5A/6A genotype in 203 low cardiovascular risk, unmedicated individuals who were divided prospectively into 2 groups, 30 to 60 years old and greater than 60 years old. In the older group, homozygotes were found to have significantly (p less than 0.01) higher aortic input and characteristic impedance (i.e., greater stiffness) than heterozygotes, after correction for the effects of age, gender, and mean arterial pressure. There was no such difference in the younger group. Gene expression was determined by real-time PCR in dermal biopsies of 40 randomly selected men from the older group and was found to be 4-fold higher in 5A homozygotes (p less than 0.05) and 2-fold lower in 6A homozygotes (p less than 0.05) compared with the heterozygotes, and differences in gene expression were associated with corresponding significant changes in MMP3 protein levels. Medley et al. (2003) concluded that the MMP3 genotype may be an important determinant of vascular remodeling and age-related arterial stiffening, with the heterozygote having the optimal balance between matrix accumulation and deposition.