The role of MMP-2 and MMP-9 polymorphisms in sporadic intracranial aneurysms

View More View Less
  • Departments of Internal Medicine and Neurosurgery, The University of Texas Medical School at Houston; and Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

Object

Matrix metalloproteinases (MMPs) are a family of endopeptidases that mediate vascular remodeling by degrading extracellular matrix components, such as collagen and elastin. On the basis of accumulating evidence that implicates increased MMP-2 (gelatinase A) and MMP-9 (gelatinase B) amounts and activity in the pathogenesis of aneurysms, the authors investigated the genetic association between polymorphisms in MMP-2 and MMP-9 and sporadic intracranial aneurysms.

Methods

Eight polymorphisms located in MMP-2 and MMP-9 were genotyped, and the association of these variations with disease was assessed in a Caucasian population consisting of 125 patients with intracranial aneurysms and 234 ethnically matched healthy volunteers.

Polymorphisms in the MMP-2 gene and the haplotypes generated from these polymorphisms were not associated with the occurrence of intracranial aneurysms. However, a polymorphism located in the 3′ untranslated region of MMP-9 showed a significant association with disease in the study population, with individuals carrying the TT genotype at increased risk for developing intracranial aneurysms (odds ratio 1.91, p = 0.005). Haplotypes containing the T allele of this polymorphism also showed a comparable association with disease. Similar results were obtained in an analysis of these polymorphisms in a subgroup of patients who presented with ruptured aneurysms.

Conclusions

The study findings support a role for MMP-9, but not MMP-2, in the pathogenesis of intracranial aneurysms.

Abbreviations used in this paper: CI = confidence interval; eNOS = endothelial nitric oxide synthase; MMP = matrix metal-loproteinase; OR = odds ratio; SAH = subarachnoid hemorrhage; SNP = single nucleotide polymorphism; UTR = untranslated region.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address reprint requests to: Dianna M. Milewicz, M.D., Ph.D., 6431 Fannin, MSB 6.100, Houston, Texas 77030. email: Dianna.M. Milewicz@uth.tmc.edu.
  • 1

    Bengert P, & Dandekar T: A software tool-box for analysis of regulatory RNA elements. Nucleic Acids Res 31:34413445, 2003

  • 2

    Bruno G, , Todor R, , Lewis I, & Chyatte D: Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg 89:431440, 1998

  • 3

    Chase AJ, & Newby AC: Regulation of matrix metalloproteinase (matrixin) genes in blood vessels: a multi-step recruitment model for pathological remodelling. J Vasc Res 40:329343, 2003

    • Search Google Scholar
    • Export Citation
  • 4

    Galis ZS, & Khatri JJ: Matrix metalloproteinases in vascular remodeling and atherogenesis. The good, the bad, and the ugly. Circ Res 90:251262, 2002

    • Search Google Scholar
    • Export Citation
  • 5

    Guo SW, & Thompson EA: Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 48:361372, 1992

  • 6

    Gurjar MV, , Sharma RV, & Bhalla RC: eNOS gene transfer inhibits smooth muscle cell migration and MMP-2 and MMP-9 activity. Arterioscler Thromb Vasc Biol 19:28712877, 1999

    • Search Google Scholar
    • Export Citation
  • 7

    Khurana VG, , Meissner I, , Sohni YR, , Bamlet WR, , McClelland RL, & Cunningham JM, : The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture. J Neurosurg 102:526531, 2005

    • Search Google Scholar
    • Export Citation
  • 8

    Kim DH, , Van Ginhoven G, & Milewicz DM: Familial aggregation of both aortic and cerebral aneurysms: evidence for a common genetic basis in a subset of families. Neurosurgery 56:655661, 2005

    • Search Google Scholar
    • Export Citation
  • 9

    Kim SC, , Singh M, , Huang J, , Prestigiacomo CJ, , Winfree CJ, & Solomon RA, : Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 41:642647, 1997

    • Search Google Scholar
    • Export Citation
  • 10

    Krex D, , Kotteck K, , Konig IR, , Ziegler A, , Schackert HK, & Schackert G: Matrix metalloproteinase-9 coding sequence single-nucleotide polymorphisms in Caucasians with intracranial aneurysms. Neurosurgery 55:207213, 2004

    • Search Google Scholar
    • Export Citation
  • 11

    Krex D, , Schackert HK, & Schackert G: Genesis of cerebral aneurysms-an update. Acta Neurochir (Wien) 143:429449, 2001

  • 12

    Longo GM, , Xiong WF, , Greiner TC, , Zhao Y, , Fiotti N, & Baxter BT: Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 110:625632, 2002

    • Search Google Scholar
    • Export Citation
  • 13

    Nahed BV, , Seker A, , Guclu B, , Ozturk AK, , Finberg K, & Hawkins AA, : Mapping a Mendelian form of intracranial aneurysm to 1p34.3-p36 13. Am J Hum Genet 76:172179, 2005

    • Search Google Scholar
    • Export Citation
  • 14

    Onda H, , Kasuya H, , Yoneyama T, , Takakura K, , Hori T, & Takeda J, : Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet 69:804819, 2001

    • Search Google Scholar
    • Export Citation
  • 15

    Pannu H, , Fadulu VT, , Chang J, , Lafont A, , Hasham SN, & Sparks E, : Mutations in transforming growth factor-β receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 112:513520, 2005

    • Search Google Scholar
    • Export Citation
  • 16

    Pannu H, , Kim DH, , Seaman CR, , Van Ginhoven G, , Shete S, & Milewicz DM: Lack of an association between the angiotensin-converting enzyme insertion/deletion polymorphism and intracranial aneurysms in a Caucasian population in the United States. J Neurosurg 103:9296, 2005

    • Search Google Scholar
    • Export Citation
  • 17

    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 30:26122616, 1999

    • Search Google Scholar
    • Export Citation
  • 18

    Price SJ, , Greaves DR, & Watkins H: Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene. Role of Sp1 in allele-specific transcriptional regulation. J Biol Chem 276:75497558, 2001

    • Search Google Scholar
    • Export Citation
  • 19

    Rinkel GJE: Intracranial aneurysm screening: indications and advice for practice. Lancet Neurol 4:122128, 2005

  • 20

    Rinkel GJE, , Djibuti M, , Algra A, & van Gijn J: Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 29:251256, 1998

    • Search Google Scholar
    • Export Citation
  • 21

    Roos YBWEM, , Pals G, , Struycken PM, , Rinkel GJE, , Limburg M, & Pronk JC, : Genome-wide linkage in a large Dutch consanguineous family maps a locus for intracranial aneurysms to chromosome 2p13. Stroke 35:22762281, 2004

    • Search Google Scholar
    • Export Citation
  • 22

    Ruigrok YM, , Rinkel GJE, & Wijmenga C: Genetics of intracranial aneurysms. Lancet Neurol 4:179189, 2005

  • 23

    Schievink WI: Genetics and aneurysm formation. Neurosurg Clin N Am 9:485495, 1998

  • 24

    Stephens M, , Smith NJ, & Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978989, 2001

    • Search Google Scholar
    • Export Citation
  • 25

    Todor DR, , Lewis I, , Bruno G, & Chyatte D: Identification of a serum gelatinase associated with the occurrence of cerebral aneurysms as promatrix metalloproteinase-2. Stroke 29:15801583, 1998

    • Search Google Scholar
    • Export Citation
  • 26

    Tronc F, , Mallat Z, , Lehoux S, , Wassef M, , Esposito B, & Tedgui A: Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO. Arterioscler Thromb Vasc Biol 20:E120E126, 2000

    • Search Google Scholar
    • Export Citation
  • 27

    Van der Voet M, , Olson JM, , Kuivaniemi H, , Dudek DM, , Skunca M, & Ronkainen A, : Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3. Am J Hum Genet 74:564571, 2004

    • Search Google Scholar
    • Export Citation
  • 28

    Yoon S, , Tromp G, , Vongpunsawad S, , Ronkainen A, , Juvonen T, & Kuivaniemi H: Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms. Biochem Biophys Res Commun 265:563568, 1999

    • Search Google Scholar
    • Export Citation
  • 29

    Zhang B, , Dhillon S, , Geary I, , Howell WM, , Iannotti F, & Day INM, : Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke 32:21982202, 2001

    • Search Google Scholar
    • Export Citation
  • 30

    Zhang B, , Ye S, , Herrmann SM, , Eriksson P, , de Maat M, & Evans A, : Functional polymorphism in the regulatory region of gelati-nase B gene in relation to severity of coronary atherosclerosis. Circulation 99:17881794, 1999

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 341 149 6
Full Text Views 200 4 0
PDF Downloads 95 1 0
EPUB Downloads 0 0 0