MMP13 promoter polymorphism is associated with atherosclerosis in the abdominal aorta of young black males
Introduction
Previous studies have shown that matrix metalloproteinases (MMPs) are produced by macrophages in human atherosclerotic lesions and are expressed at increased levels in the lesions (Henney et al., 1991, Galis et al., 1994, Belaaouaj et al., 1995, Brown et al., 1995, Nikkari et al., 1995, Halpert et al., 1996, Li et al., 1996, Sukhova et al., 1999). It is not yet clear if increased or decreased expression of one or more of the MMPs is necessary for the progression from early to late stages of atherosclerosis.
Factors that influence the level of expression of MMPs are likely to be related to the rate of progression in atherosclerosis (Preissner et al., 1999). Some sequence variants in the promoters of MMP genes are capable of influencing the levels of transcription in vitro with a particular variant more active than another variant (Ye et al., 1996, Rutter et al., 1998, Zhang et al., 1999, Henney et al., 2000, Jormsjö et al., 2000). Polymorphisms that alter function are useful for dissecting the role of the respective genes in diseases by genetic association studies (Terwilliger and Göring, 2000). Recently, an association between the severity of coronary atherosclerosis and the MMP9 polymorphism (Zhang et al., 1999), and an association between the luminal diameter of coronary arteries in diabetic patients with atherosclerosis and the MMP12 polymorphism (Jormsjö et al., 2000), were reported. Studies using the MMP3 polymorphism found that the 6A allele was associated with more rapid occlusion of coronary arteries in British (Ye et al., 1995) and Finnish (Humphries et al., 1998) men, and conferred greater risk for clinical events such as restenosis in Dutch males (de Maat et al., 1999). In contrast, the 5A allele conferred greater risk for myocardial infarction (MI) in Japanese males (Terashima et al., 1999).
Atherosclerotic lesions progress through three major stages (Ross, 1993). The earliest recognizable stage is the fatty streak lesion, in which there are characteristically lipid-filled macrophages (foam cells), lipid-containing smooth muscle cells, and extracellular lipid present in the subendothelial space. The fatty streak lesion corresponds to types II and III of the American Heart Association (AHA) microscopic classification of lesions (Stary et al., 1995). The fibrous plaque, in which a fibrous cap comprised of smooth muscle cells and collagen usually covers a central core of lipid, corresponds to type V of the AHA classification. The late stage (type VI) is the complex lesion, in which adherent thrombus or hemorrhage has occurred. Progression through the stages involves deposition and degradation of extracellular matrix (ECM).
We postulated that MMPs are involved in the transition from early to intermediate stages of atherosclerosis since it is accompanied by tissue remodeling. We hypothesized that functional promoter polymorphisms in some MMP genes are correlated with the presence of, or extent of, surface area involved in atherosclerotic lesions at early stages of fibrous plaque formation in the abdominal aorta. Specifically, we identified and tested new polymorphisms in MMP13, a recently identified collagenase.
Section snippets
Identification of novel MMP13 promoter variants
In the MMP13 gene two variants were identified, an 11A/12A insertion/deletion at nt −291 (MMP13v1) and an A to G transition at nt −77 (MMP13v2) (Fig. 1). Both variants had allele frequencies that qualified them as polymorphisms (Terwilliger and Göring, 2000) (Table 1). MMP13v2 occurred in a consensus sequence for the transcription factor PEA3 (A̱GGAAR; underlined nucleotide denotes polymorphic site) (Pendas et al., 1997, Wingender et al., 2001).
Genetic association
We studied a subset of 995 samples from the
Discussion
A number of studies have investigated the role of MMPs in atherosclerosis and MI (Ye et al., 1995, Humphries et al., 1998, de Maat et al., 1999, Terashima et al., 1999) (Zhang et al., 1999, Henney et al., 2000, Jormsjö et al., 2000). The studies have yielded apparently contradictory results in that the less active allele of MMP3 (6A) was associated with more rapid occlusion (Ye et al., 1995, Humphries et al., 1998, de Maat et al., 1999, Henney et al., 2000), but the more active allele (5A) was
Study population
The study was approved by the Wayne State University IRB and the PDAY Steering Committee. The 15 participating PDAY centers collected a total of 2876 autopsy cases with causes of death such as homicides, suicides, and car accidents, to minimize bias (McGill et al., 1995, Strong et al., 1999). Coronary arteries and abdominal aortas were scored for the percent total surface involved in fatty streaks, fibrous plaques, and complicated as well as calcified lesions (Strong et al., 1999). The lesions
Acknowledgements
We thank Dr Arthur W. Zieske for assisting with PDAY informatics. Supported in part by grants from the American Heart Association, Midwest Affiliate (9807761; G.T.), the American Foundation for Aging Research (S. Yoon), the National Center for Human Genome Research (HG01577; J.M.O.) and the National Center for Research Resources (RR03655; J.M.O.).
References (53)
- et al.
Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization
J. Biol. Chem.
(1999) - et al.
Human macrophage metalloelastase. Genomic organization, chromosomal location, gene linkage, and tissue-specific expression
J. Biol. Chem.
(1995) - et al.
The AP-1 site and MMP gene regulation: what is all the fuss about?
Matrix Biol.
(1997) - et al.
Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis
Am. J. Cardiol.
(1999) - et al.
The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study. Lopid Coronary Angiography Trial
Atherosclerosis
(1998) - et al.
PEA3 and AP-1 are required for constitutive IL-8 gene expression in hepatoma cells
Biochem. Biophys. Res. Commun.
(2000) - et al.
Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines
Mol. Cells
(2001) - et al.
The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase 1 gene expression
J. Biol. Chem.
(1997) - et al.
Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13)
Genomics
(1997) - et al.
Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD
Chest
(2000)