Growth Rate of Small Abdominal Aortic Aneurysms and Genetic Polymorphisms of Matrix MetalloProteases-1, -3, and -9

Abstract

Genetic variants of matrix metalloproteases (MMPs)-1, -3, and 9, together with clinical variables, might predict the growth rate (GR) of abdominal aortic aneurysm (AAA). Genotyping of MMP-1 (−1,607 G+/G−), MMP-3 (− 1,171 6A/5A), and MMP-9 microsatellite (13–26 cytosine–adenosine repeats around -90) from peripheral blood was performed in 137 AAA patients with two AAA diameter measurements (at least 3 months to 1 year apart). When the same technique (either ultrasound or computed tomography) was used for the two measurements, yearly GR was estimated and compared with MMP genotype and clinical features by linear and binary logistic regression. Collectively, 36 patients provided 94 observations, with a median GR of 3 mm/year (interquartile range, 0–5.8); GRs in carriers of MMP-1 polymorphism G−/G−, G−/G+, and G+/G+ genotype were 0.3, 3.5, and 4.7mm/year, respectively (p = 0.008). In linear logistic regression, the main determinant of GR was growth arrest (GA, i.e., GR = 0, occurring in 32 observations, 34%). In turn, GA occurred mainly in G−/G− MMP-1 genotype (odds ratio, 3.9; 95% confidence interval, 1.6–9.7; p = 0.002), while variables accounting for GR > 0 were MMP-1 G + /G+ genotype, intake of any antihypertensive drug, and MMP-3 6A/6A genotype. Carriers of none, one, or two/three of these conditions accounted for a GR of 3, 4, and 9 mm/year, respectively (p = 0.001). MMP-1 (−1,607 G+/−) variant is associated to differential GR in AAA: homozygous G deletion variant shows higher GA prevalence and lower GR, while carriers of G + /G+ MMP-1 genotype, together with intake of antihypertensive drugs, and 6A/6A in MMP-3 present cumulative GR increase.

Keywords

abdominal aortic aneurysm - growth rate - single nucleotide polymorphism - matrix metalloproteases - collagenase - MMP-1

• References

• 1 Kontopodis N, Metaxa E, Papaharilaou Y, Georgakarakos E, Tsetis D, Ioannou CV. Value of volume measurements in evaluating abdominal aortic aneurysms growth rate and need for surgical treatment. Eur J Radiol 2014; 83 (7) 1051-1056
• 2 Thompson SG, Brown LC, Sweeting MJ , et al. Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness. Health Technol Assess 2013; 17 (41) 1-118
• 3 Schlösser FJ, Tangelder MJ, Verhagen HJ , et al; SMART study group. Growth predictors and prognosis of small abdominal aortic aneurysms. J Vasc Surg 2008; 47 (6) 1127-1133
• 4 Powell JT. Genes predisposing to rapid aneurysm growth. Ann N Y Acad Sci 2006; 1085: 236-241
• 5 Hendy K, Gunnarson R, Golledge J. Growth rates of small abdominal aortic aneurysms assessed by computerised tomography—a systematic literature review. Atherosclerosis 2014; 235 (1) 182-188
• 6 Kurvers H, Veith FJ, Lipsitz EC , et al. Discontinuous, staccato growth of abdominal aortic aneurysms. J Am Coll Surg 2004; 199 (5) 709-715
• 7 Trollope A, Moxon JV, Moran CS, Golledge J. Animal models of abdominal aortic aneurysm and their role in furthering management of human disease. Cardiovasc Pathol 2011; 20 (2) 114-123
• 8 Wills A, Thompson MM, Crowther M, Sayers RD, Bell PRF. Pathogenesis of abdominal aortic aneurysms—cellular and biochemical mechanisms. Eur J Vasc Endovasc Surg 1996; 12 (4) 391-400
• 9 Daugherty A, Cassis LA. Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2004; 24 (3) 429-434
• 10 Newman KM, Jean-Claude J, Li H , et al. Cellular localization of matrix metalloproteinases in the abdominal aortic aneurysm wall. J Vasc Surg 1994; 20 (5) 814-820
• 11 Rutter JL, Mitchell TI, Butticè G , et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res 1998; 58 (23) 5321-5325
• 12 Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res 2003; 92 (11) 1254-1261
• 13 Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J 1995; 73 (3) 209-215
• 14 Peters DG, Kassam A, St Jean PL, Yonas H, Ferrell RE. Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke 1999; 30 (12) 2612-2616
• 15 Shimajiri S, Arima N, Tanimoto A , et al. Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett 1999; 455 (1-2) 70-74
• 16 Fiotti N, Moretti ME, Bussani R , et al. Features of vulnerable plaques and clinical outcome of UA/NSTEMI: Relationship with matrix metalloproteinase functional polymorphisms. Atherosclerosis 2011; 215 (1) 153-159
• 17 Miyake T, Aoki M, Masaki H , et al. Regression of abdominal aortic aneurysms by simultaneous inhibition of nuclear factor kappaB and ets in a rabbit model. Circ Res 2007; 101 (11) 1175-1184
• 18 Jamous MA, Nagahiro S, Kitazato KT, Satoh K, Satomi J. Vascular corrosion casts mirroring early morphological changes that lead to the formation of saccular cerebral aneurysm: an experimental study in rats. J Neurosurg 2005; 102 (3) 532-535
• 19 Durmus I, Kazaz Z, Altun G, Cansu A. Augmentation index and aortic pulse wave velocity in patients with abdominal aortic aneurysms. Int J Clin Exp Med 2014; 7 (2) 421-425