World Journal of Surgery

, Volume 31, Issue 11, pp 2248–2254 | Cite as

Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Polymorphisms in a Caucasian Population with Abdominal Aortic Aneurysm

  • Irene Hinterseher
  • Dietmar Krex
  • Eberhard Kuhlisch
  • Karl G. Schmidt
  • Christian Pilarsky
  • Wolfgang Schneiders
  • Hans D. Saeger
  • Hendrik Bergert



The formation of a sporadic abdominal aortic aneurysm (AAA) is explained by the remodeling of the extracellular matrix (ECM) and breakdown of structural components of the vascular wall. Matrix metalloproteinases are the principal matrix-degrading proteases and are known to play a major role in the remodeling of the extracellular matrix in arterial vessels. Their activity is controlled by tissue inhibitors of metalloproteinases (TIMPs). Decreased TIMP-1 and TIMP-2 expression in the extracellular matrix of the walls of AAAs has been shown in several studies. This case control study was designed to investigate the possible impact of genetic variants of the TIMP-1 gene in the etiology of AAA.


TIMP-1 single nucleotide polymorphisms (SNPs) were analyzed in a primary study sample of 50 patients with AAA and 44 controls. Differences in genotype and allele frequencies of identified polymorphisms were determined after sequencing the entire coding region and selected parts of the promoter using the automated laser fluorescence technique. A second sample (96 patients vs. 89 controls) was investigated by single-base sequencing to confirm significant results.


Three polymorphisms were identified, one of which, described for the first time in this article, is located in intron 4 (TIMP-1: 328 + 16> T). A statistically significant difference in allele frequencies for SNP TIMP-1 372T>C was detected in the primary study group. The C allele was more frequent in male patients with AAA than in the control group [23 vs. 4, p = 0.029, OR (95% CI) 4.38 (1.13-20.47)]. However, this result could not be confirmed in a second sample of males [52 vs. 45, p = 0.624, OR (95% CI) 1.16 (0.65-2.06)]. There were no statistically significant differences in genotype or allele frequencies of the other detected SNPs between the two groups.


Our analysis of the entire coding region and selected parts of the promoter of the TIMP-1 gene failed to show an association between genetic polymorphisms and AAA, suggesting that variations in the TIMP-1 gene do not contribute to the development of AAA.


Abdominal Aortic Aneurysm Abdominal Aortic Aneurysm Marfan Syndrome Entire Code Region Infrarenal Abdominal Aortic Aneurysm 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Bickerstaff LK, Hollier LH, Van Peenen HJ, et al. (1984) Abdominal aortic aneurysms: The changing natural history. J Vasc Surg 1:6–12PubMedCrossRefGoogle Scholar
  2. 2.
    Mitchell M, Rutherford R, Krupski W (1995) Infrarenal aortic aneurysms. In: Rutherford R (ed), Vascular surgery. Philadelphia, WB Saunders, pp 1032–1060Google Scholar
  3. 3.
    Darling RC III, Brewster DC, Darling RC, et al. (1989) Are familial abdominal aortic aneurysms different? J Vasc Surg 10:39–43PubMedCrossRefGoogle Scholar
  4. 4.
    Webster EL, Ferrell RE, St. Jean PL, et al. (1991) Ultrasound screening of first-degree relatives of patients with an abdominal aortic aneurysm. J Vasc Surg 13:9–14PubMedCrossRefGoogle Scholar
  5. 5.
    Johansen K, Koepsell T (1986) Familial tendency for abdominal aortic aneurysm. JAMA 256:1934–1936PubMedCrossRefGoogle Scholar
  6. 6.
    McKusick VA (1991) The defect in Marfan syndrome. Nature 352:279–281PubMedCrossRefGoogle Scholar
  7. 7.
    Superti-Furga A, Steinmann B, Ramirez F, et al. (1989) Molecular defects of type III procollagen in Ehlers-Danlos syndrome type IV. Hum Genet 82:104–108PubMedCrossRefGoogle Scholar
  8. 8.
    Tromp G, Wu Y, Prockop DJ, et al. (1993) Sequencing of cDNA from 50 unrelated patients reveals that mutations in the triple-helical domain of type III procollagen are an infrequent cause of aortic aneurysms. J Clin Invest 91:2539–2545PubMedGoogle Scholar
  9. 9.
    Crowther M, Brindle N, Sayers R, et al. (1996) Aneurysmal smooth muscle cells exhibit increased matrix metalloproteinase-2 production in vitro. Ann N Y Acad Sci 800:283–285PubMedCrossRefGoogle Scholar
  10. 10.
    Freestone T, Turner RJ, Coady A, et al. (1995) Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 15:1145–1151PubMedGoogle Scholar
  11. 11.
    Dobrin PB, Mrkvicka R (1994) Failure of elastin or collagen as possible critical connective tissue alterations underlying aneurysmal dilatation. Cardiovasc Surg 2:484–488PubMedGoogle Scholar
  12. 12.
    Busuttil RW, Abou-Zamzam A, Machleder HI (1980) Collagenase activity of the human aorta. Arch Surg 115:1373–1378PubMedGoogle Scholar
  13. 13.
    Keeling W, Armstrong P, Stone P, et al. (2005) An overview of matrix metalloproteinases in the pathogenesis and treatment of abdominal aortic aneurysms. Vasc Endovascular Surg 39:457–464PubMedCrossRefGoogle Scholar
  14. 14.
    Sandford RM, Bown MJ, London NJ, et al. (2007) The genetic basis of abdominal aortic aneurysms: A review. Eur J Vasc Endovasc Surg 33:381–390PubMedCrossRefGoogle Scholar
  15. 15.
    Davis VA, Persidskaia R, Baca-Regen L, et al. (1998) Matrix metalloproteinase-2 production and its binding to the matrix are increased in abdominal aortic aneurysms. Thromb Vasc Biol 18:1625–1633Google Scholar
  16. 16.
    McMillan WD, Patterson BK, Keen RR, et al. (1995) In situ localization and quantification of seventy-two-kilodalton type IV collagenase in aneurysmal, occlusive, and normal aorta. J Vasc Surg 22:295–305PubMedCrossRefGoogle Scholar
  17. 17.
    Patel MI, Melrose J, Ghosh P, et al. (1996) Increased synthesis of matrix metalloproteinases by aortic smooth muscle cells is implicated in the etiopathogenesis of abdominal aortic aneurysms. J Vasc Surg 24:82–92PubMedCrossRefGoogle Scholar
  18. 18.
    Sakalihasan N, Delvenne P, Nusgens BV, et al. (1996) Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms. J Vasc Surg 24:127–133PubMedCrossRefGoogle Scholar
  19. 19.
    Nakamura M, Tachieda R, Niinuma H, et al. (2000) Circulating biochemical marker levels of collagen metabolism are abnormal in patients with abdominal aortic aneurysm. Angiology 51:385–392PubMedGoogle Scholar
  20. 20.
    Silence J, Collen D, Lijnen HR (2002) Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) gene. Circ Res 90:897–903PubMedCrossRefGoogle Scholar
  21. 21.
    Allaire E, Forough R, Clowes M, et al. (1998) Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest 102:1413–1420PubMedGoogle Scholar
  22. 22.
    Eskandari MK, Vijungco JD, Flores A, et al. (2004) Enhanced abdominal aortic aneurysm in TIMP-1-deficient mice. J Surg Res 123:289–293CrossRefGoogle Scholar
  23. 23.
    Brophy CM, Marks WH, Reilly JM, et al. (1991) Decreased tissue inhibitor of metalloproteinases (TIMP) in abdominal aortic aneurysm tissue: A preliminary report. J Surg Res 50:653–657PubMedCrossRefGoogle Scholar
  24. 24.
    Defawe OD, Colige A, Lambert CA, et al. (2003) Timp-2 and pai-1 mRNA levels are lower in aneurysmal as compared to athero-occlusive abdominal aortas. Cardiovasc Surg 60:205–213Google Scholar
  25. 25.
    McMillan WD, Pearce WH (1999) Increased plasma levels of metalloproteinase-9 are associated with abdominal aortic aneurysms. J Vasc Surg 29:122–127; discussion 127–129PubMedCrossRefGoogle Scholar
  26. 26.
    Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochim Biophys Acta 1477:267–283PubMedGoogle Scholar
  27. 27.
    den Dunnen J, Antonarakis E (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121–124CrossRefGoogle Scholar
  28. 28.
    Krex D, Röhl H, König I, et al. (2003) Tissue inhibitor of metalloproteinases-1, -2, and -3 polymorphisms in a white population with intracranial aneurysms. Stroke 34:2817–2821PubMedCrossRefGoogle Scholar
  29. 29.
    Jones K, Brull D, Brown L, Sian M, et al. (2001) Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms. Circulation 103:2260–2265PubMedGoogle Scholar
  30. 30.
    Hinterseher I, Bergert H, Kuhlisch E, et al. (2006) Matrix metalloproteinase 2 polymorphisms in a caucasian population with abdominal aortic aneurysm. J Surg Res 133:121–128PubMedCrossRefGoogle Scholar
  31. 31.
    Yoon S, Tromp G, Vongpunsawad S, et al. (1999) Genetic analysis of MMP3, MMP9 and PAI-1 in finnish patients with abdominal aortic or intracranial aneurysms. Biochem Biophys Res Commun 265:563–568PubMedCrossRefGoogle Scholar
  32. 32.
    Ogata T, Shibamura H, Tromp G, et al. (2005) Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms. J Vasc Surg 41:1036–1042PubMedCrossRefGoogle Scholar
  33. 33.
    Armani C, Curcio M, Barsotti MC, et al. (2007) Polymorphic analysis of the matrix metalloproteinase-9 gene and susceptibility to sporadic abdominal aortic aneurysm. Biomed Pharmacother 61:268-271PubMedCrossRefGoogle Scholar
  34. 34.
    Fatini C, Pratesi G, Sofi F, et al. (2005) ACE dd genotype: A predisposing factor for abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 29:227–232PubMedCrossRefGoogle Scholar
  35. 35.
    Tilson MD, Reilly JM, Brophy CM, et al. (1993) Expression and sequence of the gene for tissue inhibitor of metalloproteases in patients with abdominal aortic aneurysms. J Vasc Surg 18:266–270PubMedCrossRefGoogle Scholar
  36. 36.
    Wang X, Tromp G, Cole CW, et al. (1999) Analysis of coding sequences for tissue inhibitor of metalloproteinases 1 (TIMP1) and 2 (TIMP2) in patients with aneurysms. Matrix Biol 18:121–124PubMedCrossRefGoogle Scholar
  37. 37.
    Colhoun HM, McKeigue PM, Davey Smith G (2003) Problems of reporting genetic associations with complex outcomes. Lancet 361:865–872PubMedCrossRefGoogle Scholar
  38. 38.
    Powell JT (2006) Genes predisposing to rapid aneurysm growth. Ann N Y Acad Sci 1085:236–241PubMedCrossRefGoogle Scholar
  39. 39.
    Ernst C (1993) Abdominal aortic aneurysm. N Engl J Med 328:1167–1172PubMedCrossRefGoogle Scholar
  40. 40.
    Rebbeck TR, Martinez ME, Sellers TA, et al. (2004) Genetic variation and cancer: Improving the environment for publication of association studies. Cancer Epidemiol Biomarkers Prev 13:1985–1986PubMedGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2007

Authors and Affiliations

  • Irene Hinterseher
    • 1
  • Dietmar Krex
    • 2
  • Eberhard Kuhlisch
    • 3
  • Karl G. Schmidt
    • 4
  • Christian Pilarsky
    • 1
  • Wolfgang Schneiders
    • 1
  • Hans D. Saeger
    • 1
  • Hendrik Bergert
    • 1
  1. 1.Department of Visceral, Thoracic and Vascular SurgeryMedical School of the Technical University of DresdenFetscherstrGermany
  2. 2.Department of NeurosurgeryTechnical University of DresdenDresdenGermany
  3. 3.Department of Medical Statistics and BiometryTechnical University of DresdenDresdenGermany
  4. 4.Department of OphthalmologyTechnical University of DresdenDresdenGermany

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