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Abdominal Aortic Aneurysm: Matrix Metalloproteinase-9 Genotype as a Potential Genetic Marker

Reporter: Aviva Lev-Ari, PhD, RN

Matrix Metalloproteinase-9 Genotype as a Potential Genetic Marker for Abdominal Aortic Aneurysm

Tyler Duellman, BS, Christopher L. Warren, PhD, Peggy Peissig, PhD, Martha Wynn, MD and Jay Yang, MD, PhD

Author Affiliations

From the Molecular and Cellular Pharmacology Graduate Program (T.D., J.Y.) and Department of Anesthesiology (M.W., J.Y.), University of Wisconsin School of Medicine and Public Health, Madison; Illumavista Biosciences LLC, Madison, WI (C.L.W.); and Biomedical Informatics Research Center, Marshfield Clinics Research Foundation, Marshfield, WI (P.P.).

Correspondence to Jay Yang, MD, PhD, Department of Anesthesiology, University of Wisconsin SMPH, SMI 301, 1300 University Ave, Madison, WI 53706. E-mailJyang75@wisc.edu

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.

SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 529-537

Published online before print August 31, 2012,

doi: 10.1161/ CIRCGENETICS.112.963082