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Circ Cardiovasc Genet. 2012 Oct 1;5(5):529-37. doi: 10.1161/CIRCGENETICS.112.963082. Epub 2012 Aug 31.

Matrix metalloproteinase-9 genotype as a potential genetic marker for abdominal aortic aneurysm.

Author information

1
Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin School of Medicine and Public Health, 1300 University Ave, Madison, WI 53706, USA.

Abstract

BACKGROUND:

Degradation of extracellular matrix support in the large abdominal arteries contribute to abnormal dilation of aorta, leading to abdominal aortic aneurysms, and matrix metalloproteinase-9 (MMP-9) is the predominant enzyme targeting elastin and collagen present in the walls of the abdominal aorta. Previous studies have suggested a potential association between MMP-9 genotype and abdominal aortic aneurysm, but these studies have been limited only to the p-1562 and (CA) dinucleotide repeat microsatellite polymorphisms in the promoter region of the MMP-9 gene. We determined the functional alterations caused by 15 MMP-9 single-nucleotide polymorphisms (SNPs) reported to be relatively abundant in the human genome through Western blots, gelatinase, and promoter-reporter assays and incorporated this information to perform a logistic-regression analysis of MMP-9 SNPs in 336 human abdominal aortic aneurysm cases and controls.

METHODS AND RESULTS:

Significant functional alterations were observed for 6 exon SNPs and 4 promoter SNPs. Genotype analysis of frequency-matched (age, sex, history of hypertension, hypercholesterolemia, and smoking) cases and controls revealed significant genetic heterogeneity exceeding 20% observed for 6 SNPs in our population of mostly white subjects from Northern Wisconsin. A step-wise logistic-regression analysis with 6 functional SNPs, where weakly contributing confounds were eliminated using Akaike information criteria, gave a final 2 SNP (D165N and p-2502) model with an overall odds ratio of 2.45 (95% confidence interval, 1.06-5.70).

CONCLUSIONS:

The combined approach of direct experimental confirmation of the functional alterations of MMP-9 SNPs and logistic-regression analysis revealed significant association between MMP-9 genotype and abdominal aortic aneurysm.

PMID:
22942228
PMCID:
PMC3670088
DOI:
10.1161/CIRCGENETICS.112.963082
[Indexed for MEDLINE]
Free PMC Article

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