Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease.
BACKGROUND
Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes may be associated with myocardial infarction (MI) and coronary artery disease (CAD), but studies of multiple MMP genes and their tissue inhibitors (TIMPs) are scarce. Furthermore, differentiation of predictive ability by end point (MI vs CAD) has not been addressed. This study evaluated the association with MI of SNPs in genes encoding MMPs 1, 2, 3, and 9 and TIMPs 1, 2, and 3.


METHODS
Genotypes of patients (N = 5148) with MI (n = 1693) and angiographically defined CAD (> or = 1 lesion of > or = 70% stenosis, n = 1967) were compared with MI-free (n = 3455) and non-CAD patients (n = 1122), respectively. Because of linkage disequilibrium, MMP-1 and MMP-3 SNPs (chromosome 11) were combined, as were the 2 MMP-9 SNPs.


RESULTS
For MI, only MMP-9 group CT/RQ (odds ratio [OR] 1.25, P = .007 vs wild-type CC/RR) had greater MI risk, with TT/QQ having a weak trend (OR 1.43, P = .10). These findings remained (CT/RQ) or were strengthened (TT/QQ) after full adjustment. For CAD, association was found for MMP-1/MMP-3 groups 2G1G/6A6A (OR 1.45, P = .022), 2G1G/6A5A (OR = 1.49, P = .001), 2G1G/5A5A (OR 1.64, P = .003), and 1G1G/5A5A (OR 1.35, P = .035) compared to wild type.


CONCLUSIONS
Composite MMP-9 genotypes but not other SNPs were associated with MI, whereas MMP-1/MMP-3 genotypes were CAD-associated. The largest MMP/TIMP gene study to date, this study suggests care in selection and definition of clinical phenotypes. Furthermore, this suggests that the evaluated SNPs only approximately account for intragenic variation in these genes and that comprehensive evaluation of all variations in these genes should better elucidate associations with MI and CAD phenotypes.
Horne
Benjamin D
BD
Cardiovascular Department, LDS Hospital, Intermountain Medical Center, Salt Lake City, UT 84143, USA. benjamin.horne@intermountainmail.org
Camp
Nicola J
NJ
Carlquist
John F
JF
Muhlestein
Joseph B
JB
Kolek
Matthew J
MJ
Nicholas
Zachary P
ZP
Anderson
Jeffrey L
JL
D000368:Aged; D017023:Coronary Angiography; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*
D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1